2010 meeting agenda - cibmtr working committee for regimen ...€¦ · not for publication or...

Not for publication or presentation

AGENDA CIBMTR WORKING COMMITTEE FOR REGIMEN-RELATED TOXICITY / SUPPORTIVE CARE Orlando, Florida Wednesday, February 24, 2010, 12:15 pm – 2:15 pm Co-Chair: Kenneth Cooke, MD, Case Western Reserve University School of Medicine Telephone: 216-368-0481; Fax: 216-368-0741; E-mail: [email protected] Co-Chair: Karen Ballen, MD, Massachusetts General Hospital Telephone: 617-724-1124; Fax: 617-724-1126; E-mail: [email protected] Co-Chair: Vincent T. Ho, MD, Dana-Faber Cancer Institute Telephone: 617-632-5938; Fax: 617-632-5168; E-mail: [email protected] Statisticians: Manza-A. Agovi, MPH, CIBMTR Medical College of Wisconsin Telephone: 414-805-0636; Fax: 414-805-0714; E-mail: [email protected] Brent Logan, PhD, CIBMTR Medical College of Wisconsin Telephone: 414-456-8849; Fax: 414-456-6513; E-mail: [email protected] Scientific Director: Marcelo Pasquini, MD, MS, CIBMTR Medical College of Wisconsin Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected] 1. Introduction a. New incoming chair for RRT, Philip McCarthy, MD. b. Minutes of February, 2009 meeting (Attachment 1) 2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers

a. LE03-01 Marks DI, Ballen K, Logan BR, Wang Z, Sobocinski KA, Bacigalupo A, Burns LJ, Gupta V, Ho V, McCarthy PL, Ringden O, Schouten HC, Seftel M, Rizzo JD. The effect of smoking on allogeneic transplant outcomes. Biol Blood Marrow Transplant 15:1277-1287, 2009.

b. RT05-03 Schriber JR, Agovi M-A., Ballen KK, Bacigalupo A, Hale GA, Gupta V, Lazarus HM, Litzow MR, Marks DI, Giller RH, Maziarz RT, Bornhauser M, Isola LM, Bredeson C, Rizzo JD. Second unrelated donor (URD) transplant as a rescue strategy for 122 patients with primary non engraftment: results from the CIBMTR. Submitted to BBMT

c. D98-70 Uberti, JP, Agovi M-A, Tarima S, Haagenson M, Gandham S, Abella E, Anasetti C, Baker S, Bashey A, Bearman S, Bolwell B, Bornhauser M, Chan KW, Copelan E, Davis S, Dudek A, Elkins S, Finke J, Hale G, Kernan N, Kollman C, McCarthy P, Ratanatharathorn, V, Ringden O, Wade J, Weisdorf D, Rizzo JD. Comparative analysis of busulfan and cyclosphosphamide versus cyclosphosphamide and total body irradiation in full intensity unrelated donor transplantation for acute myelogeous leukemia, chronic myelogenous leukemia and myelodysplasia. Submitted to BMT

1


d. SC03-01/R02-26 Navarro WH, Agovi M-A., Logan BR, Bacigalupo A, Ballen KK, Bolwell BJ, Frangoul H, Gupta V, Hahn T, Juckett M, Lazarus HM, Litzow MR, Liesveld J, Moreb J, Marks DI, McCarthy PL, Rizzo JD. Obesity does not preclude safe and effective myeloablative hematopoietic cell transplantation for acute myeloid leukemia (AML) in adults. Submitted to BBMT

e. RT05-02 Collin C. Barker, Manza-A. Agovi, Brent Logan, Vikas Gupta, Hillard M Lazarus, Karen Ballen, Gregory Hale, Haydar Frangoul, J. Douglas Rizzo, Marcelo C. Pasquini. Obesity Adversely Affects Survival of Pediatric Patients with Severe Aplastic Anemia after Hematopoietic Cell Transplantation. Presented at the American Society of Hematology in New Orleans, Louisiana, December 2009.

f. RT06-02 John Horan, Brent Logan, Manza-A. Agovi, Hillard Lazarus, Andrea Bacigalupo, Karen Ballen, Rodrigo Martino, Mark Juckett , Hannah Khoury, Christopher Bredeson, Vikas Gupta, Frank Smith, Gregory Hale, Mathew Carabasi, Philip McCarthy, Douglas Rizzo, Marcelo C. Pasquini. Reducing the Risk for Transplant Related Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation: How Much Progress Has Been Made? Presented at the American Society of Hematology in New Orleans, Louisiana, December 2009.

4. Studies in progress a. RT05-01 Role of Gemtuzumab Ozogamicin in the

Development of Hepatic Veno-occlusive disease (S Smiley) (Attachment 3)

Protocol Development

b RT06-01 Evaluation of TGF-β1 promoter and signal peptide polymorphisms as risk factors for renal dysfunction in hematopoietic transplant patients treated with cyclosporine A (R Shah) (Attachment 4)

Manuscript Preparation

c. RT07-02 Interaction between comorbidities and aging and their combined impact on the hematopoietic cell transplantation Outcomes (M Sorror) (Attachment 5)

Data Collection

d. RT08-01 End-stage renal disease in bone marrow transplant recipients (H Trivedi, P Hari, E Cohen) (Attachment 6)


e. RT08-02 The effect of prior splenectomy on myeloid engraftment after myeloablative allogeneic stem cell transplantation: An IBMTR analysis (G Akpek) (Attachment 7)

Data File Preparation

f RT09-01 Primary graft failure following allogeneneic HSCT for treatment of hematological malignancies (R Olsson, J Schriber, S Chaudhry, O Ringden) (Attachment 8)


g. RT09-02 Effects of body mass in children with leukemias (R Aplenc, N Bunin) (Attachment 9)


2


5. Proposed studies

a. PROP 1208-30 Comparison of clinical outcomes between myeloablative and RIC for haploidentical stem cell transplantation (S Ciurea) (Attachment 10)

b. PROP 0909-01 Survival after second allografting following a myeloablative conditioning in patients with relapsed hematologic malignancies: A CIBMTR report (G Akpek) (Attachment 11)

c. PROP 1009-01 C-reactive Protein (CRP) To Predict Non-relapse Mortality after Allogeneic Hematopoietic Cell Transplantation (HCT) (A Artz) (Attachment 12)

d. PROP 1009-03 Effect of ATG and TBI on outcomes in patients receiving reduced intensity allogeneic transplants (J Hsu) (Attachment 13)

e. PROP 1209-36 HCT for patients with L-F syndrome (J Schiffman, M Pulshipher) (Attachment 14)

f. PROP 1209-47 Assessment of pulmonary complications posttx in association with A1B8DR3 haplotype in allo tx recipients (H Liu, P McCarthy, T Hahn) (Attachment 15)

Deffered Study g. PROP 1208-49 Genetic Polymorphisms and HCT related mortality Re: Pre HCT conditioning

in MUD HCT (T Hahn) (Attachment 16)

3

Not for publication or presentation Attachment 1

MINUTES CIBMTR WORKING COMMITTEE FOR REGIMEN-RELATED TOXICITY / SUPPORTIVE CARE Tampa, Florida Thursday, February 12, 2009, 12:15 pm – 2:15 pm Co-Chair: Andrea Bacigalupo, MD, San Martino Hospital Telephone: 011-39-010-355-469; Fax: 39-010-355-583 E-mail: [email protected] Co-Chair: Karen Ballen, MD, Massachusetts General Hospital Telephone: 617-724-1124; Fax: 617-724-1126; E-mail: [email protected] Co-Chair: Vincent T. Ho, MD, Dana-Faber Cancer Institute Telephone: 617-632-5938; Fax: 617-632-5168; E-mail: [email protected] Statisticians: Manza-A. Agovi, MPH, CIBMTR Medical College of Wisconsin Telephone: 414-805-0636; Fax: 414-805-0714; E-mail: [email protected] Brent Logan, PhD, CIBMTR Medical College of Wisconsin Telephone: 414-456-8849; Fax: 414-456-6513; E-mail: [email protected] Scientific Director: J. Douglas Rizzo, MD, MS, CIBMTR Medical College of Wisconsin Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected] 1. Introduction

Dr. Karen Ballen began the meeting at 12.15pm. She introduced the RRT chairs, scientific director and statisticians to the group. Dr. Bacigalupo could not attend this year’s meeting due to personal reasons. He is the incumbent chair and will be completing his term at the end of February, 2009. Dr. Ballen acknowledged his contributions as a chair to the RRT committee and introduced Dr. Ken Cooke as the new incoming chair for the committee. Dr. Rizzo introduced Dr. Marcelo Pasquini as the new scientific director for the committee. Both Drs. Cooke and Pasquini will start their new positions March, 1st 2009.

Minutes from the 2008 Tandem meeting in San Diego were accepted and approved by the chairs

and committee members. 2. Accrual summary: Accrual summary was included as reference for committee members in the

meeting materials. 3. Presentations, published or submitted papers

Dr. Ballen informed the group that since the last meeting, the committee had one publication by Dr. Bredeson et al; Biol Blood Marrow Transplant 14:993-1003, 2008 and two oral presentations by Drs. Navarro et al and Schriber et al, at the the 50th American Society of Hematology (ASH) meeting in San Francisco, December 2008. She reminded the committee that the plan is to submit both of these studies for publication by June 2009. Additionally, the study by Marks et al on impact of smoking on transplant outcomes was submitted for publication to Blood and the study by Uberti et al will be submitted for publication this month to the same journal.

4

Not for publication or presentation Attachment 1 4. Studies in progress

RT05-02 The effect of extreme BMI on transplant outcomes in Pediatric Aplastic Anemia patients (C Barker). Analysis. Dr. Barker updated the study to the committee. He informed the group that the initial hypothesis of the study was that underweight children had worse outcomes after transplantation, however the univariate analysis demonstrated worse outcomes in obese children. The final analysis for the study is expected to be completed by April/May 2009. One member asked if we will be looking at the effect of cyclophosphamide dosing in our analysis. Dr. Barker explained that there were not enough patients in the population to look at this question. Dr. Rizzo pointed out that transplant data collected before 2007 has no information on the intended dose or dose adjustment, only the dose received was collected, which will make it difficult to assess this effect. Another committee member asked whether there was any data on race or ethnicity as the current trend shows that obesity in children is worse among certain ethnic groups. Dr Rizzo explained this specific variable was not included in the study population, which could be included as a covariate in the statistical model. Another suggestion was to include some measurements of socioeconomic status in order to adjust in the analysis, since it is known to be a confounder for obesity. Dr Rizzo replied that socioeconomic status is not a well collected variable for non US centers which makes it difficult to be analyzed. Dr. Ho mentioned that there was a shift away from use of TBI conditioning regimen in aplastic anemia over the years, which will probably require a time covariate in the multivariate analysis. Dr Ballen also noted that the findings in the univariate results for this study is different from the findings of the Navarro et al study (SC-03-01) on the effect of weight on transplant outcomes on adults with AML and a similar published study on adults with lymphoma, which will need to be addressed in the discussion section when the manuscript is prepared. RT05-01 Role of Gemtuzumab Ozogamicin in the Development of Hepatic Veno-occlusive disease (S Smiley) Protocol development. Dr. Philip McCarthy presented the study on behalf of Dr. Smiley. Dr. Rizzo added that the data collection will be on the new SCTOD forms using forms net online. One member asked if we had checked that database retrospectively to see if data was collected. Dr. Rizzo reminded the committee the history of this proposal, whichthe RRT committee elected to to proceed with prospective data collection given the limited data collected previously on veno-occlusive disease (VOD) and gemtuzumab ozogamicin (GO) use. Another question was related to the need of collecting data on donor liver function tests. Dr. McCarthy explained that this data will be useful in determining if the donor had a previous undetected hepatitis that might have been missed at time of donation. Dr Rizzo added that we may have to decide whether such data is worth collecting. Dr McCarthy agreed that it should not be collected if it requires a large amount of effort and would delay study completion. Another point raised by a committee member was the use of sirolimus and if we should consider including it in the analysis. Dr. McCarthy noted that GVHD prophylaxis is captured on the form, therefore use of sirolimus would be included in the analysis. The next step for this study will be to finalize the supplemental form and protocol for the study. RT06-01 Evaluation of TGF-β1 promoter and signal peptide polymorphisms as risk factors for renal dysfunction in hematopoietic transplant patients treated with cyclosporine A (R Shah) Data collection. Dr. Carolyn Hurley presented the study on behalf of Dr. Shah. She explained the objectives of the study and provided the group with a brief update on supplemental data collection for the study. She informed that the response for supplemental data was 86% (302/404 responses) and that the study is now ready to move into data file preparation and analysis phase. Dr. Cooke asked how we would control for post transplant medications and post transplant toxicity in the study as this information was not collected on the supplemental form. Dr Hurley pointed out that the initial supplemental form had questions on post transplant medications, however it made the form lengthy and after it was piloted among a few centers, we decided to eliminate those questions so as to make the forms less bulky and easier for the centers to fill out.

5


She noted that we could consider this study as a pilot study and if should find out from our analysis that post transplant medication is important, then we propose a new study that will collect additional information. She added that our inability to collect post transplant medications and toxicity data for the study will be noted as limitations of the study. The next step is the consolidate the data collected from the supplemental form and TGF-β1 polymorphism in order to proceed with the analysis. RT06-02 A longitudinal study of treatment related mortality to determine how innovations in clinical care over the past two decades have affected the safety of myeloablative allogeneic transplantation (J Horan) Analysis. Dr. Rizzo presented the results of the initial analysis to the group on behalf of Dr. Horan. The aim of this study is to look at how TRM and other post transplant outcomes (relapse, overall survival and treatment failure) have changed over time among AML patients who received an allogeneic transplant from an HLA identical sibling or unrelated donor (URD). Dr. Rizzo explained that so far, data from patients in CR1 at transplantation who received HLA-matched sibling donor allografts show that TRM has improved over time. The same result however is less obvious in patients who received URD allografts. This could be explained based on small numbers in the earlier cohorts. Also, when patient and transplant characteristics were adjusted in the analyses, differences in TRM across time periods disappeared. Dr. Akpek asked if the outcomes for the sibling group were different from the outcomes in the URD group. Dr. Logan, the PhD statistician for this study, responded that all outcomes were the same for both groups. He also mentioned that more analysis will have to be done to explain the observed changes, for instance HLA matching is strongly linked with time and the same association is seen between graft source and time, which makes adjusting in the multivariate analysis more complex. He asked the group to wait for the final analysis and not place too much emphasis on the current results being presented. Dr. Akpek observed that there are some centers that increased the number of URD transplants performed at their facility over time and wondered if that may be a center effect that could affect TRM over time. He suggested that we should look at adjusting our analysis for center effect. Dr. Ringden and Dr. Rizzo agreed that it will be important to check for center effect and informed the group that we will check for center effect. Dr. Marks asked if we should look beyond AML CR1 to include MDS patients. He also asked about bone marrow (BM) vs. peripheral blood stem cells (PBSC) changes in practice over time and how that may affect the analysis. Dr. Logan informed that graft type is being addressed in the revised analyzes by evaluating patients receiving BM and PB separately in the time cohorts. The next step in this study is to finalize the multivariate analyzes and distribute to the Writing Committee. RT07-02 Interaction between comorbidities and aging and their combined impact on the hematopoietic cell transplantation Outcomes (M Sorror) Data collection. Dr Mohammed Sorror presented the status of his study to the committee which is currently in data collection. He informed the committee that he received comments from the writing committee to exclude patients with non malignant diseases, especially in the auto cohort group, which will be done. Data collection for this study will continue over the next year. One of the committee members asked of how we would reconcile conflicting publications on the use of the comorbidities index. Dr. Sorror explained that these publications had small sample sizes and heterogeneous patient characteristics, hence this study has a large cohort with many variables which will help us understand the importance of the comorbidities index on transplant outcomes. The next step for this study if to continue data collection RT08-01 End-stage renal disease in bone marrow transplant recipients (H Trivedi, P Hari, E Cohen) Protocol development. Dr. Hari presented the study on behalf of Dr. Trivedi. This study was accepted last year and is currently in protocol development. The main aim is to examine the relative incidence and mortality among patients who developed end stage renal disease after URD transplantation. It will require matching and merging CIBMTR data with data from the United

6


States Renal Data System (USRDS) prior to analysis, Dr Marks asked if patients who died within three months on dialysis are captured in the USRDS database and if they would be included in the study. Dr. Hari replied that these patients would be captured in this study. Dr Cooke also asked if the study could be combined with the Shah study on renal dysfunction. Dr. Rizzo that once the study data file is completed, we would be able to assess whether any patients from Dr. Shah study were also included in this study. If the overlap is significant, it would be possible to describe the number of patients who were hemodyalisis after transplantation. The next step for this study is to complete the protocol and merge the data from both databases. RT08-02 The effect of prior splenectomy on myeloid engraftment after myeloablative allogeneic stem cell transplantation: An IBMTR analysis (G Akpek) Protocol development. Dr Akpek presented the study.. The primary outcomes of the study are to evaluate time to engraftment and 100 day non relapse mortality among patients with or without prior splenectomy. Based on recommendations from the committee, the study population excluded patients who received splenic radiation. Dr Akpek asked for the committee’s input on whether he should include patients who received growth factors after transplant and whether the study population should be restricted to patients with CML, MDS and MPD only. The committee agreed that patients who received post transplant growth factors (G-CSF or GM-CSF) would be important to add to the study population and restriction to patients with CML, MDS and MPD would also be appropriate. Dr. Akpek inquired if the CIBMTR database had any data on cell dose as that will be an important variable to include in the study. Dr. Rizzo responded that total nucleated cell dose is available and will be included in the protocol. Dr Akpek also asked the committee’s input on whether he should merge the related and URD group together and compare donor type as a covariate in the analysis. Dr Rizzo pointed out that we would first have to check the distributions of both groups and check for interactions before deciding on whether to combine the two groups. Dr. Maziarz asked if we should exclude patients with incidental splenectomy or therapeutic splenectomy. Dr Ballen and Dr. Rizzo agreed that was important and would be investigated further. Dr. Ringden suggested that we include GVHD as an endpoint in the study. Another committee member suggested to add non-relapse mortality or transplant related mortality as an endpoint to the study, in order to capture later transplant related events and not restrict to 30 and 100 day mortality. The next step in this study is to finalize the protocol and establish a writing committee that will work on this project.

5. Future/ Proposed studies a. GRAFT FAILURE PROPOSALS (R. Olsson, O.Ringden, S.Chadhury, J. Schriber) Dr.

Rizzo presented the combined proposals on behalf of all the investigators involved to the committee. He explained that following a broadcast announcement from the RRT leadership soliciting new proposals on graft failure, three proposals were submitted for consideration. The RRT committee leadership felt that it will be more beneficial to combine these proposals rather than have each of these proposals compete for approval. All investigators were invited to participate on a conference call with the chairs and scientific directors to discuss on how to proceed with these projects. It was agreed to established an interest group with all PIs in order to combine the studies into one or separate studies. This group would prioritize the questions and elaborate how this should be done using CIBMTR data. It was agreed that it will be important to look at predictors of primary graft failure among patients with hematologic malignancies who received myeloablative conditioning transplants. The group further defined primary graft failure as anyone who failed to achieve an ANC count of ≥ 500 for three consecutive days by day 28 post transplant with no evidence of relapse from the primary malignant disease. Patients who did not engraft and died before day 28 post transplants will be excluded. This is a working definition since it does not capture all patients with primary graft failure. For example, some patients would have received a

7


second transplant or cell infusion prior to day 28 and noted the reason to be primary graft failure. The group would work to refine this criteria. Dr. Rizzo presented the potential numbers (n=276) to the group and explained that there are two potential ways to approach the study and these are:

a) Build a predictive model using all the pre transplant characteristics that are known to affect non engraftment in order to better predict patients who are likely to not engraft

b) Build models with certain time points between day 18- day 28 with a scoring system in order to determine the likelihood of non engraftment.

Dr. Bunin observed that we excluded patients with T-depleted grafts from the population and asked if the forms had data on time to engraftment. Dr. Rizzo pointed out that the forms had date of engraftment however; we did not have any data on daily neutrophil counts which may limit our ability to answer the study question. He added that going back to the teams to request data on daily neutrophils counts would be extremely difficult and delay the study. Dr Cooke added that it might be possible to infer daily neutrophil counts from neutrophil counts 5 days before day 28 post transplant. Dr. Schriber suggested we reconsider the 28 day definition and mentioned that we use the predictive model approach to define the threshold date. Dr. Barker also suggested that we request neutrophil counts from day 0-28 from the centers as many of them have electronic data system and it would seem to be easy to obtain them. Dr. Marks inquired if we had chimerism data for the potential patients in the study. Dr Rizzo replied that although we have chimerism data, it may not be available for patients who received transplantation in the early years, however we will check to see how many of the potential patients have chimerism data. Dr. Ciurea noted that mismatched patients have a much higher incidence of graft failure and asked if we could separate fully matched patients from mismatched patients in the study group. Dr. Olsson suggested that we include patients who received reduced intensive conditioning (RIC) regimens to the study population and agreed that we should include chimerism data to the study. He also noted that it will be more challenging and difficult to use a scoring system approach rather than the predictive model approach for the study. Some of the committee members wanted to know why we choose non engraftment at day 28. Dr. Rizzo explained that day 28 was chosen as an arbitrary point so we would have an operational definition for non engraftment. The committee felt that a day 28 time point might be too late and it would perhaps be better to choose the cut of day for non engraftment scientifically by reviewing study data and published literature on this topic.

b. PROP 1208-30 Comparison of clinical outcomes between myeloablative and RIC for haploidentical stem cell transplantation (S Ciurea) Dr. Ciurea presented his study to the committee. The main hypothesis is that haploidentical stem cell transplantation using RIC is associated with less treatment related mortality and at least similar outcomes as MA conditioning. Additionally, the study will assess the role of T-cell depletion in the setting of haploidentical donor transplants. Overall survival is the primary endpoint of the study. Dr Ho asked if the T-cell depletion included all patients who received ATG or mechanical T-cell depletion. Dr. Cuirea explained that T-cell depletion used in the proposal referred to mechanical T-cell depletion. Dr. Ballen added that different teams use a different mix of t-cell depletion, so if this study gets accepted we will have to examine T-cell depletion carefully. The committee had a concern about the small number of patients in the tables and noted that the numbers maybe too small for a reasonable comparison between the T-cell deplete patients but could be just enough for RIC vs myeloablative comparison.

c. PROP 0708-02 The effect of Palifermin on GVHD, Survival, infection rate and relapse after allogeneic bone marrow transplant (J Lalmuanpui) Dr. Kiran presented the study on behalf of Dr. Lalmuanpui. The study aim is to evaluate and compare the incidence of GVHD

8


among patients who received or not palifermin as part of mucositis prophylaxis treatment. The study will use data prospectively collected in the CIBMTR, which is currently ongoing as part of longitudinal cohort analysis to assess the impact of palifermin on the incidence of second cancers after transplantation. Dr. Rizzo mentioned that because of potential overlap the ongoing Palifermin study, this proposal is limited to assess early survival and GVHD outcomes. The committee members expressed concern that this study would overlap with a recently completed clinical trial on palifermin and transplantation, which included GVHD outcomes as one of the endpoints.

d. PROP 0208-01 Effects of body mass in children with leukemias undergoing allogeneic bone marrow transplant (N Bunnin, R Aplenc). Dr. Bunin presented the study to the committee members. The main aim of the study is to compare leukemia free survival and overall survival in children with leukemias who underwent allogeneic HSCT according to body mass index. Dr. Bunin noted that if the study is accepted we would restrict the patients age to ≥ 5 years as it is difficult to determine obese toddlers. She also mentioned that we could restrict the population to patients with Karnofsky score > 90, transplant patients after 1995 or 1993 because there were changes in supportive care and patients who received cyclophosphamide (CY) based regimens only. She explained that one advantage to restricting to patients who received CY based regimens is to facilitate the assessment on whether the dose was adjusted according to weight. Although, she realizes that this might not be so simple. Dr. Rizzo agreed since dosing details were not collected on the forms before 2007 and one can only infer adjusted doses and actual doses from the information in the database. Dr Bunin added that a recent study in Canada showed that obese patients who received dose adjustment had inferior outcomes after transplantation. One committee member wanted to know what clinicians will be able to do for obese patients if the findings of the study showed that obese children have poorer transplant outcomes. He added that findings from the study will probably not change national policy on obesity. Dr Bunin explained that there will be stronger recommendations against dose adjustments based on patients’ weight. Dr. Akpek acknowledged that it would be interesting to know whether dose adjustments have any effect on transplant outcomes. Dr Rizzo told the group that the new current forms collect data on the intended and delivered doses, thus making it possible addressing these questions in the future. Another committee member asked if we could include socioeconomic status as a variable to the study. Dr. Bunin responded that socioeconomic status is available for the NMDP unrelated donor patients and not all the patients; however, there is ethnicity variables which will be added to the study.

e. PROP 1208-49 Genetic Polymorphisms and HCT related mortality Re: Pre HCT conditioning in MUD HCT (T Hahn) Dr. Hahn presented her study to the committee. The primary purpose of the study is to test whether genetic polymorphisms in genes involved with drug metabolisms are associated with transplant related and overall mortality after matched unrelated donor allogeneic transplantation. The patient population for this study includes AML, ALL and MDS patients with age > 20 years who received a high resolution 10/10 HLA match bone marrow or peripheral blood graft from an unrelated donor and reported to the NMDP between 2000 and 2007. The study would involve performing Genome Wide Association Scan in samples from patients who received URD transplants that are currently stored at the NMDP biorepository. Dr Hahn informed the group that she had submitted this proposal concurrently to the immunobiology working committee for review and approval of sample release. Dr Pasquini added that 1,464 out of the 1,475 eligible patients have samples in the NMDP repository. Dr Akpek suggested that instead of looking at the broad outcome of mortality it would be better to look at the most common complication such as infection that leads to mortality. Dr. Hahn agreed with him, but pointed out that transplant mortality would be a reflection of all of these and other complications.

9


The data from CIBMTR does not capture well morbidity data, and this was the main reason to evaluate mortality outcome. One member asked if the investigators had any numbers of potential estimation points. Dr. Hahn explained that with the current sample size and the trends for multiple testing they estimate that one can detect an odds ratio between 1.6 and 2.1 depending on the allele frequency and that number is consistent with what you would expect in other allele studies.

Dr. Ballen asked the group to complete the evaluation sheets handed out and to rank the studies in progress and proposal on the voting sheets which had been passed out to the committee members. The meeting was adjourned at 2.17pm.

Voting results for RRT working committee Tandem 2009

Proposals Priority score 0 1 2 Total Graft failure proposals- Schriber, Chaudhury, Olsson, Ringden 1 2 18 38 Prop 1208-30 Ciurea 7 12 3 18 Prop 0708-02 Lalmuanpui 13 8 - 8 Prop 0208-01 Bunnin, Aplenc 2 12 7 26 Prop 1208-49 Hahn 5 9 7 23 For proposals

0 = not recommended/doable at this time 1= low priority 2= high priority

10

Not for publication or presentation Attachment 1 • Based on the voting results the goals for the next fiscal year is as follows:

Study # and – PI

Current status at Tandem 02/12/09

Goal by 06 /30/2009

Anticipated Goal by 06/30 /2010

Studies in progress RT05-03- Schriber MS Prep Submit Published SC03-01/R02-26 Navarro MS Prep Submit Published RT05-02- Barker Analysis MS Prep Published RT06-02 Horan Analysis MS Prep Published RT06-01 Shah Data collection Data file prep Submitted RT07-01 Sorror Data collection Data collection Data collection RT05-01 Smiley Protocol development Data collection Data collection RT08-01 (Trivedi) Protocol development Data file prep Analysis RT08-02 (Akpek) Protocol development Data file prep MS Prep Proposals Combined Graft failure proposals New proposal Protocol development Protocol developmentTBD PROP 1208-30 (Cuirea) New proposal Deffered N/A PROP 0708-02 ( Lalmuanpui) New proposal Not accepted N/A PROP 0208-01 (Bunin) New proposal Protocol development Protocol development

PROP 1208-49 (Hahn) New proposal Protocol development pending grant approval

Protocol development pending grant approval

11


Accrual Summary for Regimen-Related Toxicity/ Supportive Care

Characteristics of recipients of allogeneic transplants reported to the CIBMTR between 1996 and 2009.

Characteristics of patients Registered N% Reported N%Number of patients 94590 32315Number of Centers 499 396Age at transplant, median (range), years 35 (<1 – 68) 33 (<1 - 68)

<18 24244 (26) 9704 (30)18-39 31111 (33) 9771 (30)40-59 33001 (35) 10507 (33)≥60 6222 ( 7) 2330 ( 7)

Missing 12 (<1) 3 (<1)Male sex 55367 (59) 18953 (59)Disease

Acute Leukemia/MDS 49341 (52) 16069 (50)Chronic lymphoblactic leukemia 2821 ( 3) 949 ( 3)Chronic Leukemia 15520 (16) 4856 (15)Lymphoma 9758 (10) 2924 ( 9)Solid tumor 900 (<1) 326 ( 1)Multiple Myeloma 2054 ( 2) 651 ( 2)Non-malignant diseases 14196 (15) 6540 (20)

Donor type HLA-identical sibling 50621 (54) 14814 (46)Other related 6537 ( 7) 2267 ( 7)Unrelated donor 35423 (37) 14897 (46)Twin 820 (<1) 280 (<1)Unknown/missing 1150 ( 1) 49 (<1)

Conditioning regimen None 3658 ( 4) 3258 (10)CY + TBI +- oth 26988 (29) 9358 (29)TBI + other 6622 ( 7) 2534 ( 8)Busulf+CY+-oth 22406 (24) 8609 (27)CY +- other 6699 ( 7) 2874 ( 9)CY+irr(noTBI)+-oth 352 (<1) 127 (<1)BU +ATG + Flud 2492 ( 3) 1134 ( 4)BU + FLUD +-other 3137 ( 3) 1093 ( 3)flud +lpam 3885 ( 4) 1475 ( 5)Bu +-other 1692 ( 2) 611 ( 2)Lpam +-other 877 (<1) 249 (<1)ATG +-other 543 (<1) 286 (<1)

12


Continued.

Characteristics of patients Registered N% Reported N% Other/Missing 15239 (16) 707 ( 2)GVHD prophylaxis

None 5535 ( 6) 3858 (12)CsA +- other (not MTX) 10856 (11) 4789 (15)

GVHD prophylaxis continued MTX +- other (not CsA) 1574 ( 2) 318 (<1)MTX + CsA +- other 35854 (38) 12944 (40)T-del. +- other 2531 ( 3) 558 ( 2)Campath +- other 833 (<1) 328 ( 1)FK506 +- Other (Not MTX) 2306 ( 2) 823 ( 3)MTX + FK506 +- Other 10759 (11) 4133 (13)ATG +- Other 337 (<1) 82 (<1)FK506 + MMF +- Other 2759 ( 3) 1122 ( 3)CsA + MMF +- Other 4278 ( 5) 1994 ( 6)Other 1511 ( 2) 468 ( 1) Missing 15457 (16) 898 ( 3)

Year of transplant 1996-1997 12992 (14) 3715 (11)1998-1999 14192 (15) 4761 (15)2000-2001 14799 (16) 4929 (15)2002-2003 14541 (15) 4771 (15)2004-2005 14392 (15) 5156 (16)2006-2007 13558 (14) 3514 (11)2008-2009 10116 (11) 5469 (17)

Graft type Bone marrow 41627 (44) 14286 (44)Peripheral blood 44352 (47) 14553 (45)Cord blood 6079 ( 6) 2952 ( 9)BM+PB 748 (<1) 325 ( 1)other/missing 1784 ( 2) 199 (<1)

Causes of Death Still alive 50826 (54) 14632 (45)Primary disease 12965 (14) 5029 (16)New malignancy 280 (<1) 153 (<1)GVHD 4723 ( 5) 1852 ( 6)IPN 1457 ( 2) 849 ( 3)Infection 6380 ( 7) 2718 ( 8)Organ failure 3782 ( 4) 1722 ( 5)

13


Continued.

Characteristics of patients Registered N% Reported N% Other cause 6227 ( 7) 1961 ( 6)graft failure 652 (<1) 305 (<1)hemorrhage 428 (<1) 253 (<1)intracranial hemorrhage 325 (<1) 186 (<1)Gastrointestinal 95 (<1) 63 (<1)

Unknown/Missing 6450 ( 7) 2592 ( 8)Median follow-up survivors, mo (range) 37 (<1-163) 44 (<1-163)Abbreviations: MDS = myelodysplastic syndromes/myeloproliferative disorders, TBI = total body irradiation, CY = cyclophosphamide, BU = busulfan, GVHD = graft-versus-host-disease, mo = months FK506=Tacrolimus

14


Accrual Summary for Regimen-Related Toxicity/ Supportive Care

Characteristics of recipients of autologous transplants reported to the CIBMTR between 1996 and 2009.

Characteristics of patients Registered N% Reported N%Number of patients 105627 20429Number of Centers 521 359Age at transplant, median (range), years 50 (<1 - 73) 52 (<1 - 73)

<18 7539 ( 7) 1599 ( 8)18-39 20981 (20) 3325 (16)40-59 52738 (50) 9871 (48)≥60 24362 (23) 5632 (28)

Missing 7 (<1) 2 (<1)Male sex 54032 (51) 10465 (51)Disease

Acute Leukemia/MDS 5783 ( 5) 910 ( 4)Chronic lymphoblactic leukemia 525 (<1) 70 (<1)Chronic Leukemia 451 (<1) 87 (<1)Non Hodgkin Lymphoma 29564 (28) 4799 (23)Hodgkin Lymphoma 11888 (11) 1372 ( 7)Multiple Myeloma 33104 (31) 7530 (37)Non-malignant diseases 593 (<1) 181 (<1)Solid tumor 23719 (22) 5480 (27)

Breast cancer 14063 (59) 3045 (56)Central nervous system 3484 (15) 820 (15)Testicular/Germ cell 989 ( 4) 406 ( 7)Lung cancer 106 (<1) 48 (<1)Ovarian cancer 1111 ( 5) 274 ( 5)Sarcoma 1283 ( 5) 363 ( 7)PNET/ Medullobalstoma/Wilms 1144 ( 5) 262 ( 5)Other 1539 ( 6) 262 ( 5)

Conditioning regimen None 1130 ( 1) 362 ( 2)CY + TBI +- oth 4345 ( 4) 882 ( 4)TBI + other 2073 ( 2) 468 ( 2)Busulf+CY+-oth 7024 ( 7) 1511 ( 7)CY +- other 24773 (23) 5302 (26)CY+irr(noTBI)+-oth 97 (<1) 14 (<1)BU +ATG + Flud 3 (<1) 0

15


Continued.

Characteristics of patients Registered N% Reported N%BU + FLUD +-other 63 (<1) 16 (<1)flud +lpam 40 (<1) 9 (<1)Bu +-other 2918 ( 3) 647 ( 3)Lpam +-other 39673 (38) 9394 (46)ATG +-other 15 (<1) 1 (<1)

Other/Missing 23473 (22) 1823 ( 9)Year of transplant

1996-1997 16855 (16) 3691 (18)1998-1999 18403 (17) 4145 (20)2000-2001 14650 (14) 2370 (12)2002-2003 14344 (14) 1703 ( 8)2004-2005 15397 (15) 2554 (13)2006-2007 14663 (14) 2662 (13)2008-2009 11315 (11) 3304 (16)

Graft type Bone marrow 3793 ( 4) 645 ( 3)Peripheral blood 94618 (90) 18957 (93)Cord blood 16 (<1) 5 (<1)BM+PB 2545 ( 2) 550 ( 3)other/missing 4655 ( 4) 272 ( 1)

Causes of Death Still alive 64717 (61) 10227 (50)Primary disease 23039 (22) 6545 (32)New malignancy 360 (<1) 134 (<1)GVHD 228 (<1) 63 (<1)IPN 208 (<1) 121 (<1)Infection 1508 ( 1) 412 ( 2)Organ failure 1564 ( 1) 503 ( 2)Other cause 3299 ( 3) 633 ( 3)graft failure 80 (<1) 29 (<1)hemorrhage 82 (<1) 41 (<1)intracranial hemorrhage 57 (<1) 30 (<1)Gastrointestinal 24 (<1) 8 (<1)

Unknown/Missing 10461 (10) 1683 ( 8)Median follow-up survivors, mo (range) 38 (<1-161) 44 (<1-150)Abbreviations: MDS = myelodysplastic syndromes/myeloproliferative disorders, TBI = total body irradiation, CY = cyclophosphamide, BEAM = BCNU + etoposide + Ara-C + melphalan, mo = months. PNET=primitive Neuroectodermal tumors

16


CIBMTR RT05-01

ROLE OF GEMTUZUMAB OZOGAMICIN IN THE DEVELOPMENT OF HEPATIC VENO-OCCLUSIVE DISEASE (SINUSOIDAL OBSTRUCTION SYNDROME)

DRAFT PROTOCOL

Study Chair: Shannon L. Smiley, MD

Department of Medicine Division of Blood and Marrow Transplantation Roswell Park Cancer Institute Elm & Carlton Streets Buffalo, NY 14263 Telephone: 716- 845-2990 Fax: 716- 845-8446 E-mail: [email protected]

Study Statistician: Manza-A. Agovi, MPH

CIBMTR Medical College of Wisconsin 9200 W. Wisconsin Ave., CLCC Milwaukee, WI 53226 USA Telephone: 414-805-0636 Fax: 414-805-0714 E-mail: [email protected]

Scientific Director: Marcelo C. Pasquini, MD, MS


17


Working Committee Chairs: Karen Ballen, MD Hematology/Oncology

Massachusetts General Hospital Box 640 100 Blossom Street Boston, MA 02114 Phone: 617-724-1124 Fax: 617-724-1126 E-mail: [email protected]

Kenneth Cooke, MD Director, Pediatric Blood and Marrow Transplantation Program University Hospitals Rainbow Babies & Children’s Hospital Cleveland, OH 44106 Phone: 216-368-1481

Fax: 216- E-mail: [email protected] Vincent T. Ho, MD Dana Farber Cancer Institute 44 Binney Street Boston, MA 02115 Phone: 617-632-5938 Fax: 617-632-5168

E-mail: [email protected]

18


1.0 HYPOTHESIS:

Gemtuzumab Ozogamicin used as therapy for AML increases the incidence of hepatic toxicity in transplant recipients.

2.0 OBJECTIVES:

2.1 To determine the incidence of hepatic toxicity (including VOD/SOS) in transplant recipients who received gemtuzumab as therapy for AML compared to those who did not. 2.1.1 Does timing of gemtuzumab in relation to transplant impact risk of hepatic

toxicity 2.1.2 Determine type of hepatic toxicity in transplant recipients who received

gemtuzumab compared to those who did not. 2.2 To determine the incidence of treatment related mortality and aGvHD in transplant

recipients who received gemtuzumab as therapy for AML compared to those who did not. 2.3 Determine if gemtuzumab is associated with leukemia free survival or overall survival.

3.0 SCIENTIFIC JUSTIFICATION:

Allogeneic hematopoietic stem cell transplantation (HCT) and its conditioning with chemoradiotherapy often results in liver toxicity. Liver injury is caused by many different processes including toxic injury to hepatic sinusoids (i.e., sinusoidal obstruction syndrome [SOS], also known as venooclusive disease [VOD]); cholestasis related to septicemia (cholangitis lenta), graft versus host disease (GvHD) or drug injury; and hepatocellular necrosis caused by infection, ischemia, or drug injury.[1] The incidence of liver toxicity following HCT varies widely by report. As an example, VOD/SOS varies from less than 5% to as high as 70% in different reports, depending on the diagnostic criteria used, the population studied (e.g. pediatric vs. adult), and the differences in conditioning therapy used.[2-5] Because liver injury is a common and sometimes fatal complication of HCT, gaining an understanding of its pathogenesis remains an important task. The most severe form of liver toxicity after HCT is hepatic VOD/SOS. Various patient characteristics pertaining to the pre-transplantation and transplantation phases have been identified as risk factors for the development of VOD and include older age, poor performance status, female gender, advanced malignancy, prior abdominal radiation, alternative donor transplants, intensive preparative regimens, elevated transaminases at the time of conditioning therapy, and fever during conditioning therapy [6, 7] . Now with widespread use of the immunotoxin, gemtuzumab ozogamicin (GO) for the treatment of AML, several groups have reported an increased risk of VOD when GO was given prior to transplant.[8] There is also data to suggest that GO given for post-transplant relapse can result in VOD.[9, 10] Thus the safety of gemtuzumab in patients undergoing transplantation is unclear. We propose to employ the CIBMTR database to address these objectives.

4.0 STUDY POPULATION:

The study will include all adult patients with AML who underwent an autologous or non T-cell depleted allogeneic stem cell transplant after December 3, 2007 (date when new CIBMTR forms were introduced) regardless of conditioning regimen or disease status at transplant and for whom comprehensive report forms were collected.

19


5.0 OUTCOMES: The primary outcome to be compared is the incidence of hepatic toxicity (including VOD/SOS) among transplant recipients who received vs. those who did not receive GO as therapy for AML prior to HCT. Liver toxicity is defined as any non-infectious liver toxicity directly caused by the preparative regimen or immunologic complications represented by GvHD. This event will be summarized by the cumulative incidence curve, with death prior to development of hepatic toxicity as the competing risk. 5.1 Regimen-related liver toxicity as defined as: 5.1.1 Bearman regimen-related hepatic toxicity[11]

– Mild hepatic dysfunction – Bilirubin > 2.0 mg/dL but < 6.0 mg/dL; or – Weight gain >2.5% and <5% from baseline of non-cardiac origin; or – Increase in serum AST more than two-fold but less than 5-fold from

lowest preconditioning – Moderate hepatic dysfunction

– Bilirubin > 6.0 mg/dL but < 20 mg/dL; or – Clinical ascites or image-documented ascites > 100mL; or – Weight gain >5% from baseline of non-cardiac origin; or – Increase in serum AST more than five-fold from preconditioning

– Severe hepatic dysfunction – Bilirubin > 20 mg/dL; or – Ascites compromising respiratory function; or – Hepatic encephalopathy

5.1.2 Veno-occlusive disease

– Jaundice – Hepatomegaly – Right upper quadrant pain – Ascites – Weight gain >5%

5.1.3 Cirrhosis

5.2 Hepatic GvHD defined as:

– Stage 0: bilirubin <2.0 mg/dL or <34 μmol/L – Stage 1: bilirubin 2.0-3.0 mg/dL or 34-52 μmol/L – Stage 2: bilirubin 3.1-6.0 mg/dL or 53-103 μmol/L – Stage 3: bilirubin 6.1-15.0 mg/dL or 104-256 μmol/L – Stage 4: bilirubin >15.0 mg/dl or >256 μmol/L

Secondary outcomes to be studied include: 5.3 Treatment-related mortality: Time to death without evidence of leukemia recurrence.

This event is summarized by the cumulative incidence estimate with relapse as the competing risk. Patients not experiencing relapse or death are censored at time of last follow-up.

5.4 Leukemia-free survival: Time to treatment failure (death or relapse). Patients are censored at time of last follow-up.

20


5.5 Overall survival: Time to death. Death from any cause will be considered an event. Surviving patients will be censored at time of last follow-up.

5.6 Acute GvHD: Development of grades II-IV acute GvHD using Glucksberg system which

grades GvHD based on the pattern and severity of abnormalities in the skin, gastrointestinal tract, and liver. The event will be summarized by the cumulative incidence estimate. Patients not experiencing acute GvHD or death will be censored at time of last follow-up. Death and second transplant are competing risks.

6.0 VARIABLES TO BE ANALYZED:

Patient related (at time of transplant): – Age at transplant – Karnofsky score at transplant – Gender – Total serum bilirubin pre-transplant – AST (SGOT) – ALT (SGPT) – Donor and Recipient hepatitis serology

– Hep B surface antibody – Hep B core antibody – Hep B surface antigen – Hep C antibody – Hep A antibody

– Ferritin – Prior transplant (auto or allo for any disease) – Prior abdominal radiation – History of liver cirrhosis

Disease related:

– De Novo or secondary AML (treatment related leukemia, MDS) – Cytogenetic risk groups (standard good, int, poor risk) – Induction chemotherapy

– Regimen(s) given – ADE: Cytarabine Daunorubicin, Etoposide (Induction as per CALGB 9720) – HiDAC + Idarubicin: High-dose cytarabine, idaubicin – Gemtuzumab + Cytarabine – Other

– Number of regimens needed to achieve 1st CR – Consolidation therapy

– Regimen(s) given – ADE: Cytarabine, Daunorubicin, Etoposide – HiDAC: High-dose cytarabine – other

– Therapy after first relapse – Re-Induction HiDAC + Mitoxantrone: High-dose cytarabine +

Mitoxantrone – Other

– Disease status at transplant – Use of gemtuzumab,

– Number of cycles of gemtuzumab

21


– Time of first and last dose – Total number doses received – Cumulative dose

Transplant related:

– Gemtuzumab for pre-transplant conditioning – Dates given – Cumulative dose

– Donor type (auto, related, unrelated) – Graft source (PB, BM, CB) – Degree of HLA matching – Recipient/donor CMV status – Recipient/donor sex – Conditioning regimen intensity (myeloablative vs. RIC)

– Myeloablative regimens (TBI, BU/CY, others) – RIC regimens (BU based, TBI, others)

– GvHD prophylaxis regimen, – T-cell depletion – CsA + MTX ± other – CsA±other – FK506 + MTX ± other – MTX ± other – FK506 ± other – None – Other

– Development of GvHD (particularly liver) – Use of sirolimus as GvHD prophylaxis or treatment of GvHD prior to development

of liver toxicity – Use of Total Parenteral Nutrition (TPN)

Post-transplant complications:

– Liver toxicity – as described in section 5.0 – VOD method of diagnosis – VOD markers of severity:

– peak bilirubin, – time of diagnosis from transplant, – % weight gain, – presence of renal/respiratory failure, encephalopathy

Prophylaxis or Therapy given for VOD/DVT: – Defibrotide – Unfractionated heparin – Low molecular weight heparin – Factor Xa inhibitors (e.g. fondaparinux) – Warfarin – Ursodiol – tPA – Other

22


7.0 DATA COLLECTION: Longitudinal prospective study utilizing new CIBMTR comprehensive data collection forms. Requested data will also include all demographic and pre-transplant data collected on the CIBMTR data collection forms. After 18-24 months (roughly December 2010), post-HCT follow-up will be collected.

8.0 STUDY DESIGN:

To summarize the characteristics of the dataset, descriptive tables of patient-, disease-, donor-, and transplant-related factors will be reported. For continuous factors, the median and ranges will be calculated.

Cumulative incidence of hepatic toxicity will be computed with 95% confidence intervals separately for patients exposed and not exposed to Gemtuzumab, treating death as a competing risk. Probabilities for overall survival and disease-free survival will be calculated using the Kaplan-Meier estimator with variance estimated by Greenwood's formula. Treatment-related mortality will be described using the cumulative incidence estimate, treating relapse as the competing risk. Acute GVHD will be estimated using cumulative incidence treating death as the competing risk. Comparison of cumulative incidences and survival probabilities between the Gemtuzumab and no Gemtuzumab exposure groups will be conducted using pointwise comparisons at selected time points. Multivariate analyses will be performed using the proportional hazards model to compare outcomes between patients who used gemtuzumab prior to transplant vs. those who did not. A stepwise model building approach will then be used to develop models for all primary and secondary outcomes. Proportional hazards will be tested, and if non proportional hazards are detected, time dependent covariates will be used. All interactions with the main effect will be tested. Center effects will be tested for using the score test of Commenges and Andersen.

9.0 REFERENCES:

1. Strasser, S.I., Hepatobiliary complications of hematopoietic cell transplantation, in Schiff's Diseases of the Liver, E.R. Schiff, Editor. 2003, J.B. Lippincott Company: Philadelphia. p. 1636-1663.

2. Carreras, E., et al., Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood, 1998. 92(10): p. 3599-604.

3. Jones, R.J., et al., Venoocclusive disease of the liver following bone marrow transplantation. Transplantation, 1987. 44(6): p. 778-83.

4. McDonald, G.B., et al., Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology, 1984. 4(1): p. 116-22.

5. Shulman, H.M. and W. Hinterberger, Hepatic veno-occlusive disease--liver toxicity syndrome after bone marrow transplantation. Bone Marrow Transplant, 1992. 10(3): p. 197-214.

6. Kumar, S., et al., Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc, 2003. 78(5): p. 589-98.

7. Wadleigh, M., et al., Hepatic veno-occlusive disease: pathogenesis, diagnosis and treatment. Curr Opin Hematol, 2003. 10(6): p. 451-62.

23


8. Wadleigh, M., et al., Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood, 2003. 102(5): p. 1578-82.

9. Giles, F.J., et al., Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer, 2001. 92(2): p. 406-13.

10. Rajvanshi, P., et al., Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy. Blood, 2002. 99(7): p. 2310-4.

11. Bearman, S.I., et al., Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol, 1988. 6(10): p. 1562-8.

24


Data currently being collected Combine 2000 Baseline form

Preparative Regimen

AML Form

25


Combine 2200 Follow up form

26


Supplemental Data for RT01-05:

1. Use of Gemtuzumab: – Dates given – Regimen (e.g. GO single agent; GO + Ara-c – GO dose; GO cumulative dose

2. Use of anticoagulation from start of conditioning through day 30 post-transplant – Dates of anticoagulation. – Reason for anticoagulation (e.g. DVT prophylaxis, therapeutic for VTE). – Agent used

– Unfractionated heparin – Low molecular weight heparin – Factor Xa inhibitor (e.g. fondaparinux) – Warfarin – Other

3. Use of ursodiol from start of conditioning through day 30 post-transplant

– Dates given – Reason for use of ursodiol (e.g prophylaxis; therapy etc)

4. Use of defibrotide from start of conditioning through day 30 post-transplant – Dates given – Reason for use of defibrotide

5. Treatment for VOD – Defibrotide – tPA – Other

6. Use of total parenteral nutrition (TPN) from time of conditioning through day 100 post-transplant

– Dates TPN given – Reason TPN given

7. Pre-transplant ferritin level

27


ABSTRACT

EVALUATION OF TGF-B1 PROMOTER AND SIGNAL PEPTIDE POLYMORPHISMS AS RISK FACTORS FOR RENAL DYSFUNCTION IN HEMATOPOIETIC TRANSPLANT

PATIENTS TREATED WITH CYCLOSPORINE A Study Chair Name(s): Riddhishkumar Shah, MD, PhD, Georgetown University Medical Center, Washington, DC, USA MS Statistician Name: Manza Agovi ([email protected]) PhD Statistician Name: Brent Logan ([email protected]) Study Status: Manuscript Preparation Purpose: To evaluate the impact of single nucleotide polymorphisms (SNPs) associated with increased TGF-β1 production on the risk of cyclosporine A (CsA) induced renal dysfunction. Patients and Methods: The study included CMV-negative recipients who received their CMV-negative allogenic hematopoietic stem cell transplant between 2000 and 2004 and who were treated with CsA. Patients with aplastic anemia and CsA exposure of more then 30 days before transplant were excluded. Patients were genotyped for -1550, -509 and +869 SNPs. Renal dysfunction was measured by serum creatinine collected at five time points: at preconditioning, days 30, 100, 180 and 365 following transplant. Results: There was no clear association of the three TGF-β1 SNPs and the development of renal insufficiency post transplant regardless of the definition of this event. Conclusion: The frequency of TGF-β1 high expression SNPs was low compared to the other polymorphisms which could have reduced our ability to detect a small impact on renal function post transplant.

28

mailto:[email protected]



CIBMTR RT07-02

PROSPECTIVE VALIDATION OF THE IMPACTS OF THE HEMATOPIETIC CELL

TRANSPLANTATION COMORBIDITY INDEX, ALONE AND COMBINED WITH AGING ON HEMATOPOIETIC CELL TRANSPLANTATION OUTCOMES

Study Chair: Mohamed L. Sorror, MD, MSc

Fred Hutchinson Cancer Research Center University of Washington, Department of Oncology

1100 Fairview Ave. North, D1-107 P. O, Box 19024 Seattle, WA 98109 USA Phone: 206-667-2765 Fax: 206-667-6124 E-mail: [email protected]

Study Statistician: Manza-A. Agovi, MPH

CIBMTR Medical College of Wisconsin 9200 West Wisconsin Avenue Suite C5500 Milwaukee, WI 53226 USA Telephone: 414-805-0636 Fax: 414-456-6530 E-mail: [email protected]

Scientific Director: Marcelo Pasquini, MD, MS


29

Not for presentation or publication Attachment 5

Working Committee Co-Chairs: Karen Ballen, MD Division of Hematology & Oncology Bone Marrow Transplant Program Massachussetts General Hospital 100 Blossom Street, Box 640 Boston, MA 02114 USA Telephone: 617-724-1124

Fax: 617-724-1126 E-mail: [email protected] Kenneth R. Cooke, M.D Director, Pediatric BMT Program Case Western Reserve University School of Medicine Department of Pediatrics Wolstein Research Building 6th Floor, Room 6524 2103 Cornell Road Cleveland, OH 44106-7288 Phone: 216- 368-0481 Fax: 216- 368-0741 Email: [email protected] Vincent T. Ho, MD Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115 Phone: 617-632-5938 Fax: 617-632-5168 E-mail: [email protected]

30


1.0 OBJECTIVES:

1.1 To prospectively:

1.1.1 Validate the prognostic impacts of the HCT-CI on the HCT outcomes among patients diagnosed with various hematological diseases.

1.1.2 Validate the prognostic impacts of the HCT-CI + aging scores on HCT outcomes and compare its predictive capacity to that of the HCT-CI alone.

1.1.3 Stratify outcomes of recipients of nonmyeloablative and myeloablative allogeneic HCT using the HCT-CI ± aging scoring systems.


Comorbidities have been reported to affect chemotherapy dosing, treatment toxicity, survival, and quality of life of patients with cancer. [1,2] The use of comorbidity indices has facilitated the incorporation of comorbidities into decision-making for treatment and clinical trial design.(Reviewed in[3]) The Charlson comorbidity index (CCI) [4] has been the most widely used comorbidity index to predict mortality risks in various diseases and solid malignancies. [5] Allogeneic conventional HCT is considered potentially curative for many patients with hematological malignancies but has been limited to patients without significant comorbidities and who were less than 50 to 65 years of age. [6-13] With the advent of minimally toxic conditioning regimens, the HCT choices have been expanded to include older patients and those with comorbidities. We developed an nonablative regimen, which consists of 2 Gy total body irradiation (TBI) either alone or in combination with fludarabine. [14,15] The regimen largely relies on graft-versus-leukemia effects for tumor cell kill. This nonablative regimen has expanded allogeneic HCT to include elderly and comorbid patients with various hematological malignancies. [16-18] There are continued efforts to evaluate novel approaches in the laboratory to further reduce the intensity of conditioning regimen thereby further minimizing its side effects. As these novel approaches will be introduced in the clinic in the future, it has become important to comprehensively study the comorbidity differences between patient groups, investigate the interactions between comorbidities and aging and their impacts on HCT outcomes and quality of life to help standardize comorbidity assessment for future clinical trials. Several investigators have studied single organ comorbidities as predictors for HCT outcomes. [19-26] None of these has taken into account the impact of different comorbidities or their interaction with age. We began systematic analyses of the roles of comorbidities on HCT outcomes using the CCI as a non-transplantation specific comorbidity index. We applied the CCI to the settings of myeloablative and nonmyeloablative allogeneic HCT in patients with hematological malignancies. We found that an adapted form of the CCI successfully predicted the risks of 1-year NRM in patients given HCT from unrelated [27] or related donors [28]. In a further analysis, we found that the CCI detected comorbidities among only 35% of all HCT patients (12% among myeloablative patients [27]). Therefore, we developed a new index that more specifically addressed comorbidities in HCT patients.

We refined comorbidity definitions, added newly identified comorbidities, and, evaluated each comorbidity category by Cox regression hazard models in a training set of patients. The HCT-CI was then tested in a randomly-selected validation set of Seattle patients, where 62% of patients had HCT-CI scores of >0 compared with 12% by the original CCI. [29] Overall, the HCT-CI was

31


better able to capture comorbidities and to predict NRM than the CCI among HCT recipients. Results were further retrospectively validated among a different patient population diagnosed with a single disease entity, AML in first remission, and transplanted in MD Anderson Cancer Center.[30] The HCT-CI could also be used to efficiently compare the risk-benefit ratios among nonmyeloablative versus myeloablative patients diagnosed with either myeloid[31] or lymphoid malignancies.[32] Our ongoing studies are aimed at understanding the correlation between comorbidities and another important pretransplant factor, age and investigating their joint importance for outcomes. To this purpose, retrospective data are being collected from six academic institutions within the Seattle Consortium, and comorbidities are assessed by a single investigator. The data is being used to develop a new HCT-CI + ageing scoring system, which should further refine risk assessment among transplanted patients with different HCT strategies. It is of extreme importance to validate these findings in a large cohort of patients, who are prospectively treated and assessed by multiple local investigators. This would ensure the accuracy and the universal application of the HCT-CI ± aging scoring systems in comparing clinical trial outcomes with given treatment modalities obtained at given academic centers to those achieved at others and in assessing the risk-benefit ratios for planned treatments.

3.0 STUDY POPULATION: The study population will include all patients who received an autologous or allogeneic HCT for a hematological malignant or non malignant disease of any stage, reported to the CIBMTR within a duration of 12 montsh starting roughly from January 2008. No restrictions for age, degree of host-donor HLA-matching, or type of conditioning regimen, however, patients receiving a cord blood transplant will be excluded. Potential numbers of subjects are given in Table 1.

4.0 OUTCOMES: Primary Outcomes: 4.1 Impacts of HCT-CI scores on post-HCT outcomes: We will analyze predictive capacity

of the HCT-CI for non-relapse mortality (NRM) and overall survival among recipients of allogeneic and autologous HCT seprately. Stratification by the individual HCT-CI scores as well as the collapsed risk groups will be investigated. Events will be summarized by a cumulative incidence and Kaplan Meier survival curves, respectively. The competing risk for non-relapse mortality is relapse. Patients alive (or alive and without relapse) at last observation are considered censored for this event. The independent impacts of the HCT-CI on NRM and overall survival will be tested in multivariate models, after adjustment for other pre-transplant variables, among all patient population. Separate analyses for patients with myeloid and lymphoid malignancies and nonmalignant diseases will be performed. The prognostic ability of these models will be examined at four time points: Day 100, Day 180, Day 365, and Day 730.

4.2 Effect of the comorbidity-age composite scores on HCT outcomes: We will compare the

discriminative capacity of the HCT-CI + age composite scores and HCT-CI scores for predicting the previously mentioned HCT outcomes. Assess whether specific outcomes might be better predicted by the composite scoring system.

32


Secondary outcomes: 4.3 Comparison of the HCT outcomes between recipients of nonmyeloablative and

myeloablative allogeneic HCT: The most successful measure from the analysis of the primary outcomes will be used to risk-stratify and compare the outcomes of patients given nonmyeloablative versus myeloablative regimens and separately for the myeloid and lymphoid malignancies.

5.0 DATA COLLECTION:

Comorbidity data and HCT-CI scores will be collected prospectively from patients transplanted within one year duration (roughly between January and December 2008) using the new CIBMTR SCTOD forms. Requested data will also include all demographic and pre-transplant data collected on the CIBMTR data collection forms. Follow up data will be collected starting from day 100 (roughly in April 2009) and to be continued at days 180, 365, and 730.


Patient-related variables

– Age at transplant – Gender: Male vs. female – Karnofsky score at transplant – Pre-transplant comorbidities and HCT-CI score

Disease-related variables

– Disease – Disease status prior to transplant(where applicable) – Interval between diagnosis and HCT – Donor/Recipient CMV sero-status – Cytogenetics (if applicable)

Transplant-related variables

– Year of transplant – Type of transplant – Conditioning regimen – Type of preparative regimen: ablative vs. non-ablative – Planned sequential transplant or not. – Source of stem cells – Graft manipulation – Number of CD34+ and CD3+ cells – Type of Donor (where applicable) – Donor sex – HLA match status – GVHD prophylaxis

7.0 STUDY DESIGN:

Data from the CIBMTR will be used for validation of the impacts of comorbidities ± aging scores on HCT outcomes. Descriptive tables of patient-, disease-, and transplant-related factors will be prepared. These tables will list median and range for continuous variables and percent of total for

33


categorical variables. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. Cumulative incidence or Kaplan-Meier curves will be calculated for incidences of NRM and overall survival. Analyses of survival and NRM incidences will be done using the Cox regression model. Relapse will be treated as a competing risk for NRM, and vice versa. The relationship between comorbidity scores and HCT outcomes will be examined using Cox regression. The prognostic discriminatory capacity of the HCT-CI as compared to a composite score incorporating age will be assessed by comparing the Brier scores [29] of the two models at each of the four time points of interest.

8.0 REFERENCES:

1. Feinstein AR. The pre-therapeutic classification of co-morbidity in chronic disease. J Chron Dis 23: 455-468, 1970.

2. Van Spronsen DJ, Janssen-Heijnen ML, Breed WP, Coebergh JW. Prevalence of co-morbidity and its relationship to treatment among unselected patients with Hodgkin's disease and non-Hodgkin's lymphoma, 1993-1996. Ann Hematol 78: 315-319, 1999.

3. Extermann M. Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol 35: 181-200, 2000.

4. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40: 373-383, 1987.

5. Di Iorio B, Cillo N, Cirillo M, De Santo NG. Charlson Comorbidity Index is a predictor of outcomes in incident hemodialysis patients and correlates with phase angle and hospitalization. Int J Artif Organs 27: 330-336, 2004.

6. Goldstein LB, Samsa GP, Matchar DB, Horner RD. Charlson Index comorbidity adjustment for ischemic stroke outcome studies. Stroke 35: 1941-1945, 2004.

7. Hemmelgarn BR, Manns BJ, Quan H, Ghali WA. Adapting the Charlson Comorbidity Index for use in patients with ESRD. American Journal of Kidney Diseases 42: 125-132, 2003.

8. Sachdev M, Sun JL, Tsiatis AA, Nelson CL, Mark DB, Jollis JG. The prognostic importance of comorbidity for mortality in patients with stable coronary artery disease. J Am Coll Cardiol 43: 576-582, 2004.

9. Lubke T, Monig SP, Schneider PM, Holscher AH, Bollschweiler E. Does Charlson-comorbidity index correlate with short-term outcome in patients with gastric cancer? [German]. Zentralblatt fur Chirurgie 128: 970-976, 2003.

10. Firat S, Byhardt RW, Gore E. Comorbidity and Karnofksy performance score are independent prognostic factors in stage III non-small-cell lung cancer: an institutional analysis of patients treated on four RTOG studies. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 54: 357-364, 2002.

11. Sabin SL, Rosenfeld RM, Sundaram K, Har-el G, Lucente FE. The impact of comorbidity and age on survival with laryngeal cancer. Ear, Nose, & Throat Journal 78: 578-4, 1999.

12. Singh B, Bhaya M, Stern J, Roland JT, Zimbler M, Rosenfeld RM, Har-el G, Lucente FE. Validation of the Charlson comorbidity index in patients with head and neck cancer: a multi-institutional study. Laryngoscope 107: 1469-1475, 1997. Extermann M. Measuring comorbidity in older cancer patients (Review). Eur J Cancer 36: 453-471, 2000.

34


13. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, Chauncey TR, Gooley TA, Hegenbart U, Nash RA, Radich J, Wagner JL, Minor S, Appelbaum FR, Bensinger WI, Bryant E, Flowers MED, Georges GE, Grumet FC, Kiem H-P, Torok-Storb B, Yu C, Blume KG, Storb RF. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97: 3390-3400, 2001.

14. Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D, Petersdorf E, McSweeney P, Pulsipher M, Woolfrey A, Chauncey T, Agura E, Heimfeld S, Slattery J, Hegenbart U, Anasetti C, Blume K, Storb R. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 102: 2021-2030, 2003.

15. Maris MB, Sandmaier BM, Storer BE, Chauncey T, Stuart MJ, Maziarz RT, Agura E, Langston AA, Pulsipher M, Storb R, Maloney DG. Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood 104: 3535-3542, 2004.

16. Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol 23: 3819-3829, 2005.

17. Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W, Storer B, Hegenbart U, Somlo G, Chauncey T, Bruno B, Appelbaum FR, Blume KG, Forman SJ, McSweeney P, Storb R. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102: 3447-3454, 2003.

18. Bearman SI, Petersen FB, Schor RA, Denney JD, Fisher LD, Appelbaum FR, Buckner CD. Radionuclide ejection fractions in the evaluation of patients being considered for bone marrow transplantation: Risk for cardiac toxicity. Bone Marrow Transplant 5: 173-177, 1990.

19. Hertenstein B, Stefanic M, Schmeiser T, Scholz M, Göller V, Clausen M, Bunjes D, Wiesneth M, Novotny J, Kochs M, Adam W-E, Heimpel H, Arnold R. Cardiac toxicity of bone marrow transplantation: Predictive value of cardiologic evaluation before transplant. J Clin Oncol 12: 998-1004, 1994.

20. Fujimaki K, Maruta A, Yoshida M, Sakai R, Tanabe J, Koharazawa H, Kodama F, Asahina S, Minamizawa M, Matsuzaki M, Fujisawa S, Kanamori H, Ishigatsubo Y. Severe cardiac toxicity in hematological stem cell transplantation: predictive value of reduced left ventricular ejection fraction. Bone Marrow Transplant 27: 307-310, 2001.

21. Goldberg SL, Klumpp TR, Magdalinski AJ, Mangan KF. Value of the pretransplant evaluation in predicting toxic day-100 mortality among blood stem-cell and bone marrow transplant recipients. J Clin Oncol 16: 3796-3802, 1998.

22. Crawford SW, Fisher L. Predictive value of pulmonary function tests before marrow transplantation. Chest 101: 1257-1264, 1992.

23. Chien JW, Maris MB, Sandmaier BM, Maloney DG, Storb RF, Clark JG. Comparison of lung function after myeloablative and 2 Gy of total body irradiation-based regimens for hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11: 288-296, 2005.

24. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RA. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 118: 255-267, 1993.

35


25. Rozman C, Carreras E, Qian C, Gale RP, Bortin MM, Rowlings PA, Ash RC, Champlin RE, Henslee-Downey PJ, Herzig RH, Hinterberger W, Klein JP, Prentice HG, Reiffers J, Zwaan FE, Horowitz MM. Risk factors for hepatic veno-occlusive disease following HLA-identical sibling bone marrow transplants for leukemia. Bone Marrow Transplant 17: 75-80, 1996.

26. Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu R, Flowers C, Maloney DG, Storb R. Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplant comorbidities. Blood 104: 961-968, 2004.

27. Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, Sandmaier BM, Storb R. Morbidity and mortality with nonmyeloablative compared to myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors. Blood 104: 1550-1558, 2004.

28. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106: 2912-2919, 2005.

29. Graf E, Schmoor C, Sauerbrei W, and Schumacher M. Assessment and comparison of prognostic classification schemes for survival analysis. Statistics in Medicine 18: 2529-2545, 1999.

30. Sorror ML, Giralt S, Sandmaier BM, de Lima M, Shahjahan M, Maloney DG, Deeg HJ, Appelbaum FR, Storer B, Storb R. Hematopoietic cell transplantation-specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: Combined FHCRC and MDACC experiences. Blood 110: 4608-4613, 2007. Reference ID: 33146

31. Sorror ML, Sandmaier BM, Storer BE, Maris MB, Baron F, Maloney DG, Scott BL, Deeg HJ, Appelbaum FR, Storb R. Comorbidity and disease status-based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 25: 4246-4254, 2007. Reference ID: 32391

32. Sorror ML, Storer BE, Maloney DG, Sandmaier BM, Martin PJ, Storb R. Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative regimens for treatment of lymphoma and chronic lymphocytic leukemia. Blood 111: 446-452, 2008. Reference ID: 33209

36


Table 1. Characteristics of US patients who recieved an allogeneic bone marrow or peripheral HSCT for a malignant or non-malignant disease after 2006 and registered with the CIBMTR

Characteristics of patientsa NST/RIC

N% Myeloablative

N% Number of patients 2255 5479Age, median (range), years 58 (<1 - 73) 43 (<1 - 68)

0-9 139 ( 6) 579 (11)10-19 88 ( 4) 589 (11)20-29 65 ( 3) 622 (11)30-39 99 ( 4) 665 (12)40-49 231 (10) 1122 (20)50-59 685 (30) 1345 (25)60-69 861 (38) 531 (10)

≥ 70 87 ( 4) 26 (<1)Male sex 1408 (62) 3100 (57)Karnofsky score

<90 757 (34) 1472 (27)≥90 1385 (61) 3661 (67)

Missing 113 ( 5) 346 ( 6)Disease

Acute myelogenous leukemia or ANLL 743 (33) 2083 (38)Acute lymphoblastic leukemia 88 ( 4) 1109 (20)Chronic lymphocytic leukemia/prolymphocytic leukemia 275 (12) 158 ( 3)Chronic myelogenous leukemia 44 ( 2) 266 ( 5)Myelodysplastic/myeloprolifterative disorders 363 (16) 670 (12)Other acute leukemiab 28 (<1) 91 ( 1)Non-Hodgkin lymphoma 419 (19) 506 ( 9)Hodgkin lymphoma 22 (<1) 36 (<1)Plasma cell disorder/Multiple Myeloma 12 (<1) 63 ( 1)Non malignant diseasesc 253 (14) 496 ( 11)

Year of transplant 2007 132 ( 6) 362 ( 7)2008 1193 (53) 3090 (56)2009 930 (41) 2027 (37)

Donor type HLA-identical sibling 932 (41) 2497 (46)Other related 205 ( 9) 311 ( 6)Unrelated donor 1110 (49) 2594 (47)Identical twin 8 (<1) 69 ( 1)

Missing 0 8 (<1)

37


Table 1. Continued.

Characteristics of patients NST/RIC

N% Myeloablative

N% Graft type

Bone marrow 364 (16) 1587 (29)Peripheral blood 1882 (83) 3855 (70)Bone marrow +peripheral blood 9 (<1) 37 (<1)

Conditioning regimen None 4 (<1) 17 (<1)Cy + TBI ± other 218 (10) 1716 (31)TBI ± other 413 (18) 493 ( 9)Bu +CY± other 29 ( 1) 1415 (26)Cy ± other 229 (10) 242 ( 4)Cy+ irradiation (noTBI) ± other 20 (<1) 16 (<1)Bu +Atg + Flud 318 (14) 273 ( 5)Bu + Flud ± other 369 (16) 670 (12)Flud +Lpam 487 (22) 298 ( 5)Bu ± other 44 ( 2) 134 ( 2)Lpam ± other 14 (<1) 144 ( 3)ATG +TLI ± other 81 ( 4) 1 (<1)

Other 29 ( 1) 60 ( 1)GVHD prophylaxis

None 40 ( 2) 218 ( 4)CSA ± other (not MTX) 81 ( 4) 176 ( 3)MTX ± other (not CsA) 11 (<1) 57 ( 1)MTX + CSA ± other 129 ( 6) 911 (17)Campath ± other 70 ( 3) 30 (<1)FK506 ± other (not MTX) 202 ( 9) 514 ( 9)MTX + FK506 ± other 772 (34) 2590 (47)ATG ± other 11 (<1) 12 (<1)FK506 + MMF ± other 397 (18) 541 (10)CSA + MMF ± other 401 (18) 171 ( 3)Other/Missing 141 ( 6) 259 ( 4)

Co-existing morbid conditions pre-transplant? No 713 (32) 2403 (44)Yes 1523 (68) 3001 (55)Missing 19 (<1) 75 ( 1)

Co-morbid conditions at time of transplantd Arrhythmia 110 ( 7) 118 ( 4)Cardiac 241 (16) 312 (10)Inflammatory Bowel disease 31 ( 2) 52 ( 2)Diabetes 211 (14) 341 (11)Cerebrovascular disease 53 ( 3) 62 ( 2)

38


Table 1. Continued.

Characteristics of patients NST/RIC

N% Myeloablative

N% Co-morbid conditions continued

Psychiatric disturbance 270 (18) 630 (21)Mild chronic hepatitis 126 ( 8) 180 ( 6)Obesity BMI > 35kg/m2 138 ( 9) 335 (11)Infection 137 ( 9) 273 ( 9)Peptic ulcer 29 ( 2) 29 (<1)Renal moderate/severe 30 ( 2) 50 ( 2)Pulmonary moderate 318 (21) 714 (24)Heart valve disease 28 ( 2) 31 ( 1)Pulmonary severe 225 (15) 381 (13)Hepatic moderate/severe 42 ( 3) 61 ( 2)Other co-morbidity 745 (49) 1369 (46)Solid tumor prior to transplant 178 ( 8) 284 ( 5)

HCT-CI scoree 0 995 (44) 3065 (56)1 500 (22) 998 (18)2 142 ( 6) 347 ( 6)3 347 (15) 691 (13)4 207 ( 9) 284 ( 5)5 27 ( 1) 41 ( 1)6 37 ( 2) 53 ( 1)

Research or Ted track patient? Ted (registration) patient 847 (38) 2877 (53)cRF (research) patient 1408 (62) 2602 (47)

Median follow-up of survivors, range, months 7 (1-28) 7 (<1-25) Abbreviations: Cy= cyclosphosphamide; Bu=Busulfan; TBI=total body irradiation;GVHD=graft vs host disease; TLI= total lymphoid irradiation; flud=fludarabine; Lpam=melphalan; CSA= cyclosporine; MMF= mycophenolate; MTX=methotrexate; FK506= Tacrolimis; CI=co-morbidity index; BMI=body mass index. a Includes patients from the Seattle consortium (n=336), City of Hope National Medical Center (n=273), University of Utah (n=40), Rocky Mountain Cancer Center (n=97), Oregon Health & Sciences University (n=131), and University of Iowa centers (n=56). b Other Leukemia = TED Other leukemia specified (n=13); Acute mast cell leukemia (n=2); Biphenotypic, bilineage/hybrid leukemia (n=54); acute undifferentiated leukemia (n=6). c Non Malignant diseases = Other malignancies (n=13); Severe aplastic anemia (n=459); Inherited abnorm. erythrocyte (n=53); SCID (n=108); Inherited abnorm. of platelets (n=5); Inherited abnorm. of metabolism (n=48); Histiocytic disorders (n=51); Autoimmune diseases (n=5); Other specify (=14). d Co-morbid conditions for patients with morbidity pre transplant. Patients are counted more than once for >1 co-morbodity. eScoring for co-morbidity is based on HCT-CI scoring published by Sorror et al 106 (8): 2005 in Blood. Patients with other existing co-morbid conditions were given a score of 0.

39


Table 2. Characteristics of US patients who received an autologous bone marrow or peripheral HSCT for a malignant or non-malignant diseases after 2006 and registered with the CIBMTR

Characteristics of patientsa N% Number of patients 10516Age, median (range), years 56 (<1 - 75)

0-9 520 ( 5)10-19 273 ( 3)20-29 618 ( 6)30-39 718 ( 7)40-49 1531 (15)50-59 3064 (29)60-69 3176 (30)

≥ 70 613 ( 6)Male sex 6335 (60)Karnofsky score

<90 3183 (30)≥90 6204 (59)

Missing 1129 (11)Disease

Acute myelogenous leukemia or ANLL 242 ( 2)Acute lymphoblastic leukemia 16 (<1)Chronic lymphocytic leukemia/prolymphocytic leukemia 7 (<1)Myelodysplastic/myeloprolifterative disorders 3 (<1)Other acute leukemiab 5 (<1)Non-Hodgkin lymphoma 3010 (29)Hodgkin lymphoma 1161 (11)Plasma cell disorder/Multiple Myeloma 4997 (48)Non malignant diseasesc 832 ( 8)

Missing 243 ( 2)Year of transplant

2007 885 ( 8)2008 5528 (53)2009 4103 (39)

Graft type Bone marrow 77 (<1)Peripheral blood 10379 (99)Bone marrow +peripheral blood 60 (<1)

Conditioning regimen None 335 ( 3)Cy + TBI ± other 224 ( 2)TBI ± other 57 (<1)Bu +CY± other 471 ( 4)Cy ± other 969 ( 9)

40


Table 2. Continued. Characteristics of patients N% Conditioning regimen continued

Cy+ irradiation (noTBI) ± other 21 (<1)Bu + Flud ± other 7 (<1)Flud +Lpam 1 (<1)Bu ± other 251 ( 2)Lpam ± other 7826 (74)

Other 354 ( 3)Co-existing morbid conditions pre-transplant?

No 3991 (38)Yes 5909 (56)Missing 616 ( 6)

Co-morbid conditions at time of transplantd

Arrhythmia 351 ( 3)Cardiac 820 ( 8)Inflammatory Bowel disease 68 (<1)Diabetes 904 ( 9)Cerebrovascular disease 113 ( 1)Psychiatric disturbance 1100 (10)Mild chronic hepatitis 176 ( 2)Obesity BMI > 35kg/m2 726 ( 7)Infection 165 ( 2)Peptic ulcer 129 ( 1)Renal moderate/severe 366 ( 3)Pulmonary moderate 1270 (12)Heart valve disease 51 (<1)Pulmonary severe 812 ( 8)Hepatic moderate/severe 26 (<1)Other co-morbidity 2752 (26)Solid tumor prior to transplant 580 ( 6)

HCT-CI scoree

0 5716 (54)1 1898 (18)2 792 ( 8)3 1348 (13)4 518 ( 5)5 101 (<1)6 143 ( 1)

Research or Ted track patient? Ted (registration) patient 7310 (70)cRF (research) patient 3206 (30)

Median follow-up of survivors, range, months 7 (<1-32)

41


Table 2. Continued. Abbreviations: Cy= cyclosphosphamide; Bu=Busulfan; TBI=total body irradiation; flud=fludarabine; Lpam=melphalan; CI=co-morbidity index; BMI=body mass index; a Includes patients from the Seattle consortium (n=273), City of Hope National Medical Center (n=117), University of Utah (n=128), Rocky Mountain Cancer Center (n=229), Oregon Health & Sciences University (n=88), and University of Iowa centers (n=69). b Other Leukemia = TED Other leukemia specified (n=5);). c Non Malignant diseases = Other malignancies (n=787); Breast cancer (n=5); SCID (n=1); Histiocytic disorders (n=1); Autoimmune diseases (n=27); Other specify (=11). d Co-morbid conditions for patients with morbidity pre transplant. Patients are counted more than once for >1 co-morbodity. eScoring for co-morbidity is based on HCT-CI scoring published by Sorror et al 106 (8): 2005 in Blood. Patients with other existing co-morbid conditions were given a score of 0.

42


Table 3. Patient and disease characteristics from the original HCT-CI manuscript. [29]

Characteristics

Patients (n=1055)

Conditioning regimens % 2 Gy TBI 6 Fludarabine + 2 Gy TBI 22 CY + ≥12 Gy TBI 29 BU + CY 43 Postgrafting immunosuppression % CSP + MMF 18 CSP + MTX 82 Donor type % Related donor 58 Unrelated donor 42 Diagnoses % AML 27 CML 20 MDS 19 ALL 10 NHL 9 MM 6 CLL 4 HD 2 Non-malignant hematological* 3 Disease risk group %† High 41 Low 59 Age at transplantation Median (range), years 44.8 (0.8-72.7) Preceding myeloablative HCT % 13 Allogeneic % 2 Failed autologous % 6 Planned autologous % 5 Hematopoietic cell source % G-PBMC 71 Marrow 29 Gender of patients % Male/female 56/44 Gender of donors % Male/female 51/49 TBI indicates total body irradiation; BU, busulfan; CY, cyclophosphamide; CSP, cyclosporine; MMF, mycophenolate mofetil; MTX, methotrexate; MDS, myelodysplastic syndromes; CML, chronic myeloid leukemia; NHL, non-Hodgkin’s lymphoma; HD, Hodgkin’s disease; MM, multiple myeloma; CLL, chronic lymphocytic leukemia; HCT, hematopoietic cell transplantation; and G-PBMC, granulocyte colony stimulating factor-mobilized peripheral blood mononuclear cells. * Immunodeficiency syndrome, chronic granulomatous disease, congenital dyserythropoietic anemia, paroxysmal nocturnal hemoglobinuria, polycythemia vera, thalassemic syndrome, and sickle cell anemia. †Low indicates acute leukemia in first remission, CML in first chronic phase, MDS-refractory anemia, or non-malignant hematological disease; while high indicates all other diagnoses.

43


CIBMTR RT08-01

END-STAGE RENAL DISEASE IN BONE MARROW TRANSPLANT RECIPIENTS Study Co-Chairs: Hariprasad Trivedi, MD Medical College of Wisconsin 9200 W. Wisconsin Avenue Milwaukee, WI 53005 Telephone: 414-805-9069 Fax: 414-805- Email: [email protected] Parameswaran Hari, MD

Medical College of Wisconsin 9200 W. Wisconsin Avenue, CLCC Milwaukee, WI 53226 USA Telephone: 414-805-0700 Fax: 414-805-0714 Email:[email protected]

Eric Cohen, MD Medical College of Wisconsin 9200 W. Wisconsin Avenue

Milwaukee, WI 53226 USA Telephone: 414-384-2000 x 42875 Fax: 414-805-9059 Email: [email protected]

John P. Klein, PhD Department of Biostatistics Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226 Telephone: 414-456-8280 Fax: 414-456-6513 Email: [email protected]

44


Study Statistician: Manza-A. Agovi, MPH CIBMTR Medical College of Wisconsin 9200 W. Wisconsin Ave., CLCC Milwaukee, WI 53226 USA Telephone: 414-805-0636 Fax: 414-805-0714 E-mail: [email protected]



Working Committee Co-Chairs: Karen Ballen, MD Division of Hematology & Oncology Bone Marrow Transplant Program Massachusetts General Hospital 100 Blossom Street, Box 640 Boston, MA 02114 USA Telephone: 617-724-1124

Fax: 617-724-1126 E-mail: [email protected] Vincent T. Ho, MD Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115 Phone: 617-632-5938 Fax: 617-632-5168 E-mail: [email protected] Kenneth R. Cooke, M.D Director, Pediatric BMT Program Case Western Reserve University School of Medicine Department of Pediatrics 2103 Cornell Road Cleveland, OH 44106-7288 Phone: 216- 368-0481 Fax: 216- 368-0741 Email: [email protected]

45


1.0 SPECIFIC OBJECTIVES:

The primary objectives of this study are: 1.1 To describe the incidence of ESRD and the time to development in URD HCT recipients. 1.2 To describe the relative incidence of end-stage renal disease in bone marrow transplant

recipients from unrelated donors (URD) as compared to the general population. 1.3 To describe changes in incidence rates of ESRD after BMT in URD over time (e.g.

incidence rates in 1990’s compared to early 2000’s) 1.4 To determine the mortality after ESRD in URD compared to transplant recipients of

URD transplants who do not develop ESRD (including subgroup analysis according to modality of renal replacement therapy, dialysis vs. kidney transplantation), and to ESRD patients who have not undergone BMT.


Bone marrow transplantation has shown a steady growth over the last several years along with improvement in patient survival.1 At present in the United States more than 12,000 bone marrow transplants are performed annually. With improvement in long-term results we are beginning to see an increase in long-term morbidity in bone marrow transplant (BMT) survivors. In particular, chronic kidney disease is being increasingly recognized in long-term survivors of BMT.1,2 Causes of chronic kidney disease in BMT recipients include calcineurin inhibitor nephrotoxicity, glomerular disease related to graft-versus-host disease, hemolytic-uremic syndrome, and BMT nephropathy. We and others have detected a 23 to 25% occurrence rate of chronic kidney disease in long-term survivors of BMT. 1,2 However, there are few data regarding the occurrence of end-stage renal disease (ESRD) requiring renal replacement therapy in BMT recipients. In a single center analysis (n= 1341) we recently reported a significant increase in end-stage renal disease in BMT recipients.3 We estimated the rate of ESRD was nineteen times the age-adjusted rate in the general population and greatly exceeds the rate of occurrence of solid tumors post-BMT. There are significant implications of chronic kidney disease in BMT recipients. In non-renal solid organ transplants, chronic kidney disease is associated with a significantly increased risk of death.4 However, there are scant data regarding similar outcomes in BMT recipients. In a small case-control study we found that ESRD after BMT was associated with shortened survival as compared to ESRD from other causes.5 There was a trend towards increased mortality in BMT recipients who developed ESRD as compared to BMT recipients who did not develop ESRD though statistical significance was not achieved probably due to the small sample size. Changes in transplantation techniques over the last two decades (e.g. less use of high dose radiation) may affect the incidence of ESRD after BMT. In summary, there is a need to study on a larger scale and in a more systematic manner the problem of end-stage renal disease in recipients of bone marrow transplants, which is the purpose of the present proposal.


Selection criteria: Our study population will include all patients with available SSN’s who received a bone marrow or peripheral blood transplant from an unrelated donor facilitated by the National Marrow Donor Program between 1996 and 2007. We will link data about these patients from the CIBMTR registry to the United States Renal Data System (USRDS).

46


Data sources: CIBMTR: The Center for International Blood and Marrow Transplant Research (CIBMTR) will provide USRDS a data file containing linked identifiers for all recipients of unrelated donor HCT facilitated by the NMDP in the period in question. USRDS, in its capacity as a government contractor and public health authority will undertake the linkage of the two databases as the “honest broker”. United States Renal Data System (USRDS): USRDS is a National Institutes of Health sponsored registry of ESRD maintained at the University of Minnesota. The USRDS data are available upon approval and signing a data use agreement with the National Institutes of Diabetes, Digestive, and Kidney Diseases (NIDDK). The investigators have considerable experience with this process, obtaining USRDS data, and the USRDS registry itself through participation in ongoing and completed research projects using USRDS data.6-8 The USRDS Project Officer at the NIDDK (Paul Eggers, PhD, Email contact [email protected], Tel: (301-594-8305) has been contacted to confirm the feasibility of this project. Initiation of renal replacement therapy in the US necessitates filing of a Medical Evidence Form with Centers for Medicare and Medicaid (CMS; formerly Health Care Financing Administration) that contains information regarding demographics, co-morbidities, and baseline laboratory variables for every subject requiring dialysis. Every ESRD patient who dies necessitates notification of death to CMS and filing of the Death Notification Form. These data are transmitted annually to the USRDS. Therefore, every ESRD recipient in the US should have data available in the USRDS database. Details regarding USRDS data can be found at www.usrds.org. The USRDS has created datasets for studies involving ESRD similar to this protocol on approximately 40 to 50 occasions in the past. Database linking: Data provided by CIBMTR to the USRDS will contain a listing of subject identifiers for all patients meeting inclusion criteria, including direct identifiers when possible. Other HCT-related variables required for this study will not be included in the dataset used for matching with USRDS. USRDS will use these identifiers to link HCT recipients with USRDS registrants who have received replacement therapy. A matching protocol will be discussed by CIBMTR and USRDS prior to matching to assure the greatest number of possible matches with the least ambiguity. A linked study file will be created by USRDS using a unique ID that is linked to the CIBMTR data as provided by CIBMTR, as well as a USRDS linked identifier. The study file created will contain the variables of interest from ESRDS database (see below), as well as all variables provided by CIBMTR excluding direct identifiers. The direct identifiers (social security number) will be eliminated by USRDS following case matching. Upon receipt of the matched dataset, CIBMTR will use its identifier to add remaining HCT variables of interest to create a final study file. This will facilitate development of a unique dataset that can be used to address the objectives for this study, and maintain linked identifiers to address questions that may arise during analysis, without risking compromise of subject identities. Procedures for handling possible matches will be discussed with the USRDS. Patients determined to have a “record” with the USRDS database will be considered as having ESRD, those without a record will be considered to not have renal failure requiring dialysis for

47


http://www.usrds.org/


the purposes of this study. However, information from the CIBMTR database regarding renal failure will be used, when possible, to confirm this status. Date of onset of renal failure and dialysis will be compared against relevant dates, including HCT date. Variables to be used for matching include: Social security number, date of birth, date of first HCT, gender and zip code for reported address at HCT.

4.0 OUTCOMES:

The primary outcomes to be studied are: 4.1 Overall survival: Time to death. Patients become at risk for this event when they develop

ESRD. Death from any cause will be considered an event. Surviving patients are censored at time of last follow-up.

4.2 Incidence of ESRD: The time to event for occurrence of ESRD after HCT will be derived

by analysis of actual time to occurrence of ESRD by identifying BMT subjects who reached ESRD as outlined above. Estimates of incidence will be based on a cumulative incidence function with death as a competing risk.

5.0 VARIABLES TO BE CONSIDERED: Variables from the CIBMTR

Patient related: - Age - Race - Ethnicity - Gender: female vs male - Karnofsky performance score: <90% vs ≥90% - Geographic area of residence by zip code - Primary disease type - BMI - Presence of diabetes mellitus - Presence of hypertension - Genitourinary disease, specified type

Disease related: - Pre HCT chemotherapy exposure - Pre HCT radiation therapy (site and dose) - Disease - Disease status at HCT - Time from dx to transplant

Transplant related: - Year of transplant: TBD - HLA matched status: well matched vs partially matched vs mismatch vs missing - Source of stem cell: bone marrow vs peripheral blood - Donor-recipient CMV status: +/+ vs +/- vs -/+ vs -/-

48


- Donor-recipient sex match: male/male vs female/female vs male/female vs female/male

- Conditioning regimen: Bu/CY vs TBI/CY, others - Radiation dose - GVHD prophylaxis: T depletion vs CsA ±other vs MTX±other vs CsA+MTX±other

vs other/none - Causes of death

Post transplant variables

- Acute GVHD, maximum grade, date of onset, organ involvement - Chronic GHVD, maximum grade, date of onset, organ involvement - Post-transplant microangiopathythrombotic thrombocytopenic purpura (TTP)

hemolytic uremic syndrome (HUS) or other similar syndrome - Cyclosprine use - FK 506 use (e.g. tacrolimus, Prograf)

Variables from the USRDS

- Date of starting dialysis - Type of dialysis - Age - Gender - Race - Ethnicity - Cause of ESRD - Tobacco use - Alcohol dependence - Drug dependence - BMI - Serum albumin - Hematocrit - Serum Creatinine - Co-morbidities - Prior EPO use - Date of renal transplant - Type of renal transplant- related vs living unrelated vs deceased donor - Date of death - Cause of death - Zip code

6.0 STUDY METHODS: The incidence of ESRD in BMT patients will be estimated by a cumulative incidence function with death as a competing risk. To compare this to rates in the general population a relative incidence model in the spirit of Andersen and Vaeth (1989) will be developed and applied to adjust comparisons for age, gender and region. Survival of patients with and without ESRD will be compared using a time dependent covariate approach adjusting for patient, disease, transplant characteristics and available laboratory variables. Cox models will also be used to examine risk factors for the development of ESRD.

49


Depending on numbers we will look at separate models by primary disease. The statistical models will be adjusted as necessitated by the data.

6.1 Data Security

Both the CIBMTR and the USRDS are experienced at securely and confidentially handling direct identifiers. Multiple layers of security are in place at both organizations. CIBMTR and NMDP are designated Public Health Authorities. For the purposes of executing the matching of datasets, the USRDS will act as the honest broker. CIBMTR will securely provide a dataset with the necessary identifying information about all URD BMT recipients for consideration for study inclusion. No variables that are not required for the matching will be provided, to limit the risk of the dataset. USRDS will match, using a pre-determined algorithm those patients with the records of the USRDS dataset to identify those BMT patients who have developed ESRD and were reported to the USRDS. They will then create a secure dataset with indirect linking identifiers, and stripping the direct identifiers used for matching. This dataset will also contain all the requested USRDS variables needed for the study. No additional identifiers will be added. Once the matched dataset is provided back to CIBMTR, CIBMTR will use its remaining linked identifier to create the full study dataset that includes the BMT related variables. This dataset will be shared with the CIBMTR master’s level statistician, who will prepare the final dataset for analysis after cleaning missing and inconsistent data. Once data preparation is complete, a final dataset for analysis will be prepared for the PhD statistician. This dataset will be de-identified, and will only contain relevant intervals. No identifiers will be included; however the MS statistician will retain the linked dataset for queries that may become necessary during the final analysis. All study-related staff will sign confidentiality agreements if required by NIDDK. All CIBMTR staff are trained and compliant with humans subjects protection regulations, as well as privacy regulations in place for CIBMTR (including HIPAA and FISMA). Any linked datasets will be kept on secure computing systems that have Authority to Operate from HSRA Office of Information Technology in compliance with FISMA, and only de-identified datasets will be shared with non-CIBMTR employees. Similarly, all data will be kept in a secure location within the CIBMTR or NMDP offices.

7.0 REFERENCES:

1. Cohen EP, Lawton CA, Moulder JE, Ash RC. Clinical course of late-onset bone marrow transplant nephropathy. Nephron 1993; 64: 626-635.

2. Hinograni S, Guthrie KA, Schoch G, Weiss NS, McDonald GB. Chronic kidney disease in long-term survivors of hemopoietic cell transplant. Bone Marrow Transplant 2007; 39: 223-229.

3. Cohen EP, Drobyski WR, Moulder JE. Significant increase in end-stage renal disease after hematopoietic stem cell transplantation. Bone Marrow Transplant 2007; 39: 571-572.

4. Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM. Chronic Renal Failure after Transplantation of a Nonrenal Organ. N Engl J Med 2003; 349:931-940.

5. Cohen EP, Piering W, Kabler-Babbitt C, Moulder J. End-stage renal disease (ESRD) after bone marrow transplantation: Poor survival compared to other causes of ESRD. Nephron 1998; 79: 408-412.

50

http://search.nejm.org/search?p=R&srid=S9%2d4&lbc=nejm&w=ojo&url=http%3a%2f%2fcontent%2enejm%2eorg%2fcgi%2fcontent%2fshort%2f349%2f10%2f931&rk=1&uid=371199359&sid=2&ts=subs&rsc=tBp:hvYfBxfw04ca&method=and&isort=score


6. Trivedi HS, Pang MMH. Discrepancy in the epidemiology of non-diabetic chronic renal insufficiency end-stage renal disease in black and white Americans: the Third National Health and Nutrition Examination Survey and United States Renal Data System Am J Nephrol 2003; 23: 448 – 457.

7. Trivedi H, Xiang Q, Klein J. Risk factors of non-fatal myocardial infarction and cardiac death in incident dialysis patients. Nephrol Dial Transplant 2008 (In Press).

8. Trivedi HS, Kaufman J. Event rates of non-fatal myocardial infarction and cardiac death in incident dialysis patients without history of coronary artery disease. J Am Soc Nephrol 2004; 15: 401A.

9. Cohen EP, et al. End-stage renal disease after marrow transplantation: higher mortality compared to other causes of ESRD. J Am Soc Nephrol 1997; 8:135A.

10. Andersen, P. K. and Væth, M. (1989). Simple Parametric And Nonparametric Models For Excess And Relative Mortality. Biometrics, 45, 523-535.

51


Table 1. Characteristics of patients who received a hematopoietic stem cell transplant from an unrelated donor and reported to the NMDP between 1996 and 2007.

Patient Characteristics N (eval) N (%)Number of NMDP patients 9280Age, median (range), years 9280 35 (<1 - 65)

0-20 1801 (19)21-40 2963 (32)41-60 3801 (41)>60 714 ( 8)

Male sex 9280 5357 (58)Karnofsky score at transplant 9280

<90 2751 (30)≥90 5978 (64)Missing 551 ( 6)

Disease 9280Acute myelogenous leukemia 2946 (32)Acute lymphoblastic leukemia 1612 (17)Other leukemia 474 ( 5)Chronic myelogenous leukemia 1692 (18)Myelodysplastic-myeloprolific disorder 1133 (12)Non hodgkin lymphoma 739 ( 8)Hodgkin lymphoma 38 (<1)Multiple myeloma / plasma cell disorder 87 (<1)Other malignancies 27 (<1)Breast cancer 3 (<1)Severe Aplastic anemia 328 ( 4)Inherited abnormalities erythrocyte diff-function 11 (<1)SCID & other immune system disorders 92 (<1)Inherited abnormalities of platelets 8 (<1)Inherited disorder. of metabolism 42 (<1)Histiocystic disorders 41 (<1)Other diseasea 7 (<1)

Patient’s ethnicity 9280White 8094 (87)African-American/Black 515 ( 6)Hispanic 308 ( 3)Asian 125 ( 1)Native Hawaiian 4 (<1)Pacific Islanders 52 (<1)Unknown 31 (<1)

52


Table 1. Continued Patient Characteristics N (eval) N (%)

Middle Eastern/North coast of Africa 29 (<1) Missing 122 ( 1)Renal failure severe enough to warrant dialysis? 9280

No 6429 (69)Yes 882 (10)Missing 1969 (21)

Received dialysis? 9280No 233 ( 3)Yes 503 ( 5)Missing 8544 (92)

Graft type Bone marrow 5861 (63)Peripheral blood 3419 (37)

Year of transplant 92801996 656 ( 7)1997 710 ( 8)1998 770 ( 8)1999 789 ( 9)2000 785 ( 8)2001 753 ( 8)2002 742 ( 8)2003 809 ( 9)2004 915 (10)2005 832 ( 9)2006 818 ( 9)2007 701 ( 8)

Conditioning regimen 9280CY + TBI 4597 (50)Bu + CY 1813 (20)TBI +- other 844 ( 9)Cy +- other 379 ( 4)Bu +-other 871 ( 9)Fludara + Lpam +-other 611 ( 7)Fludara + Atg +-other 17 (<1)Fludara +- other 66 (<1)Lpam +-other 40 (<1)Otherb 42 (<1)

53


Table 1. Continued. Patient Characteristics N (eval) N (%)Was irradiation given as part of pre-transplant conditioning regimen? 9280

No 3682 (40)Yes 5585 (60)Missing 13 (<1)

Radiation dosec , median (range), cGy 5585 1200 (8-2000)HLA match status 9280

Well matched 5000 (54)Partially matched 2994 (32)Mismatched 1277 (14)Unknown/missing HLA data 9 (<1)

Donor/recipient sex match 9280Male/male 3631 (39)Male/female 1726 (19)Female/male 2277 (25)Female/female 1646 (18)

Donor/recipient CMV match 9280Negative 2940 (32)Positive 1955 (21)Positive/Negative 1233 (13)Negative/Positive 2972 (32)Unknown 180 ( 2)

GVHD prophylaxis 9280None (Will be checked with teams) 37 (<1)T-cell depletion 980 (11)CSA + MMF +-other 651 ( 7)CSA + MTX +- other 3346 (36)CSA +-other (not mtx) 309 ( 3)FK506 + MMF +- other 749 ( 8)FK506 + MTX +- other 2513 (27)FK506 +- other (not mtx) 336 ( 4)MTX alone 13 (<1)MTX + Cort +- other 13 (<1)Other 52 (<1)Missing 281 ( 3)

54


Table 1. Continued. Patient Characteristics N (eval) N (%)Causes of Death 9280

Still alive 3525 (38)Primary disease 1539 (17)New malignancy 47 (<1)Graft vs Host disease 877 ( 9)IPN 554 ( 6)Infection 1150 (12)Organ failure 897 (10)Graft failure 356 ( 4)Hemorrhage 110 ( 1)Intracranial 154 ( 2)Other cause 59 (<1)Missing 12 (<1)

Median follow-up of survivors, (median) range, months 2372 50(<1-141)Abbreviations: CSA= cyclosporine; MMF= mycophenolate; MTX=methotrexate; TBI= total body irradiation; Bu=busulfan; Cy=cyclophosphamide; GVHD= graft vs host disease; Fludara= fludarabine; Lpam=melphalan; FK506= Tacrolimis; Cort=corticosteroids; IPN= interstitial pneumoniatis; CMV=cytomegalovirus; HLA=human leukocyte antigen; NMDP= National marrow donor program.

Selection/Exclusion Criteria # excluded Total N remaining

First transplant a llogeneic patients transplanted between 1996 and 2007 39674 NMDP URD patients only 24,125 15549 Cap modeled data set 925 14624 Excluded patients with CB graft type 949 13679 Excluded patients without SSN 4399 9280 aOther disease include; AITP (n=1); Hypersinophilic syndrome (n=1); NK Lymphocybrosis (n=1); Osteogenesis imperfecta (n=3); Osteopetrosis (n=1).

b Other conditioning regimen: Thiotepa only (n=3)

ATG + Cytarabine + mitoxantrone (n=4) ATG + Cytarabine (n=8) ATG + monoclonal antibody (n=3) ATG + monoclonal antibody + TLI (n=6 ) ATG + TLI (n=8) ATG + Other (not specified) (n=1 ) ATG + Cytarabine +Cisplatin (n=1)

Cytarabine +Cisplatin (n=3) Monoclonal antibody only (n=1) Cytarabine + mitoxantrone (n=2)

cRadiation dose pre-transplant includes: Total body radiation dose, Total lymphoid or nodal regions dose and Thoraco-abdominal region dose.

55


CIBMTR RT08-02

THE EFFECT OF PRIOR SPLENECTOMY ON MYELOID ENGRAFTMENT AFTER

MYELOABLATIVE ALLOGENEIC STEM CELL TRANSPLANTATION: A CIBMTR ANALYSIS

Study Chair: Gorgun Akpek, MD, MHS University of Maryland Greenebaum Cancer Center 22 South Greene Street Baltimore, MD 21201

Telephone: 410-328-2594 Fax: 410-328-0248

E-mail: [email protected]




56


Working Committee Chairs: Karen Ballen, MD Division of Hematology & Oncology Bone Marrow Transplant Program Massachussetts General Hospital 100 Blossom Street, Box 640 Boston, MA 02114 USA Telephone: 617-724-1124

Fax: 617-724-1126 E-mail: [email protected] Kenneth R. Cooke, MD

Director, Pediatric BMT Program Case Western Reserve University School of Medicine Department of Pediatrics Wolstein Research Building 6th Floor, Room 6524 2103 Cornell Road Cleveland, OH 44106-7288 Phone: 216- 368-0481 Fax: 216- 368-0741 E-mail: [email protected]

Vincent T. Ho, MD Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115 Phone: 617-632-5938 Fax: 617-632-5168 E-mail: [email protected]

57


1.0 SPECIFIC OBJECTIVES:

1.1 The primary purpose of the study is to compare engraftment and 100-day survival between transplant recipients with or without splenectomy prior to stem cell transplantation.

1.2 Secondary objectives include comparing the cumulative incidence of acute and chronic GVHD and overall survival at 1 year post transplant,


Hematopoietic stem cell transplantation (HCT) from related or unrelated donors is a potentially curative treatment modality for patients with malignant and non-malignant hematologic diseases. However, transplant-related mortality (TRM) remains high after myeloablative conditioning. Two potential causes of TRM after allogeneic engraftment are infections and bleeding due to prolonged cytopenia.

The use of peripheral blood as a source of hematopoietic stem cells has reduced the duration of severe neutropenia and thrombocytopenia after myeloablative HCT. There remains however, about 10-15% mortality due to cytopenia seen early post-transplant. The mortality secondary to severe cytopenia is a limiting factor to offer myeloablative allogeneic transplant for patients older than 55 and those with co-morbid conditions. Prolonged cytopenia and engraftment failure still remain major cause of failure after cord blood transplantation. The potential utility of cord blood stem cells in adult recipients has also been limited to small number patients with lower body weight due to insufficient nucleated cell dose in a cord blood unit. Clearly, additional studies are needed to decrease the duration of cytopenia and to improve engraftment rates following allogeneic stem cell transplantation.

Splenectomy prior to transplant is a potential way of reducing time to engraftment after allogeneic stem cell transplant. Pre-transplant splenectomy has been conducted occasionally in patients with myeloproliferative disorders such as agnogenic myeloid metaplasia for symptom palliation due to significant splenomegaly resulting in faster hematopoietic recovery1-3

Splenectomy is an effective palliative procedure with an acceptable morbidity in selected patients with hematologic malignancies such as myelofibrosis.4 Progressive transfusion-dependent anemia is also considered an indication for splenectomy in patients with myelofibrosis in the absence of leukemic evolution.5 Also splenectomy is an effective treatment approach with low morbidity and mortality in patients with refractory idiopathic autoimmune hemolytic anemia.6 The operating mortality of conventional open splenectomy is approximately 10% in patients with myelofibrosis5 Laparoscopic splenectomy appears to be associated with much lower operating mortality (less than 1%).

The effect of the splenomegaly on engraftment kinetics and on immune reconstitution following transplantation is not well studied. Animal studies suggest that circulating hematopoietic stem cells (HSCs) can migrate into the spleen after infusion. Therefore, splenectomy before transplantation may increase homing efficiency of the stem cells into the bone marrow (BM).

This study will compare engraftment and mortality rates between patients who had splenectomy prior to HCT with those with intact spleens using a retrospective cohort design. The findings to be extracted may be critical for uncovering whether pre-transplant splenectomy is associated with earlier engraftment and lower mortality which may translate into a potential clinical benefit to these patients. For example, patients at high-risk for delayed engraftment or non-engraftment

58


after myeloablative HCT and/or those with massive splenomagaly can be offered laparascopic splenectomy prior to transplant to improve outcomes.


Inclusion criteria: – HLA identical sibling or unrelated donor transplant for hematologic malignancy between

1990-2006 – Bone marrow or peripheral blood stem cells – Patients with age ≥ 18 – Diagnosis of CML, MDS/MPD – Myeloablative conditioning

Exclusion criteria:

– Cord blood transplant – Patients who received splenic radiation – Patients with PNH diagnosis

Myeloablative conditioning regimen will be classified according to the CIBMTR working definition:

– CY+TBI (TBI dose > 500 cGy single dose or TBI dose >800 cGy fractionated) – CY+VP16+TBI (TBI dose > 500 cGy) – BU+CY

4.0 OUTCOMES:

The primary outcomes to be studied are: 4.1 Neutrophil engraftment - Achievement of a sustained absolute neutrophil count (ANC)

>500 x 106/L for 3 consecutive days. Death and second transplants for primary graft failure will be considered competing risks for this endpoint. Patients who survive < 21 days without recovery will be considered non evaluable.

4.2 Platelet engraftment - Achievement of a continued platelet count of greater than 20,000

and 50,000 x 109/L. Death and second transplants for primary graft failure will be considered competing risks for this endpoint.

4.3 30 day mortality -This is defined as death on or before 30 days post transplant. Patients

alive at last observation with fewer than 30 days of follow-up are considered censored for this event.

4.4 100 day mortality - This is defined as death on or before 100 days post transplant.

Patients alive at last observation with fewer than 100 days of follow-up are considered censored for this event.

59


Secondary endpoints are: 4.5 Acute GVHD - The occurrence of skin, gastrointestinal or liver abnormalities fulfilling

the Consensus criteria of Grades II, III and/or IV acute GVHD are considered events. Death is a competing risk, and patients alive without acute GVHD will be censored at the time of last follow-up. Patients receiving a second transplant will be censored at the time of second transplant.

4.6 Chronic GVHD - Occurrence of symptoms in any organ system fulfilling the criteria of

limited or extensive chronic GVHD. Death is a competing risk, and patients alive without chronic GVHD will be censored at time of last follow-up

4.7 Overall survival – Time to death from any cause. Event will be summarized by Kaplan-

Meier estimate. Cases will be analyzed at the time of last follow-up.

5.0 VARIABLES TO BE ANALYZED: Patient related:

– Age – Gender: female vs male – Karnofsky score at transplant: <90 vs ≥ 90

Disease related:

– Disease at transplant: CML vs MDS/MPD, – Disease status at transplant: Early (chronic phase CML) vs. others (intermediate +

advanced) Transplant related:

– Year of transplant – Graft type: BM vs PBSC – Donor type: Related vs matched unrelated – Conditioning regimen – GvHD prophylaxis – Donor/recipient sex match: M-M vs. M-F vs. F-M vs. F-F – Donor/recipient CMV status: -/- vs. -/+ vs. +/- vs. +/+ vs. Unknown – HLA match status: well matched vs partial vs mismatched – Total nucleated cell dose

6.0 STUDY DESIGN:

The study proposed here will analyze CIBMTR data to address the working hypothesis that splenectomy done prior to HCT with myeloablative conditioning is associated with shorter time to engraftment and lower mortality during first 100 days post-transplant as compared to patients who did not receive splenectomy.

Medians and ranges will be tabulated for continuous demographic variables and percentages for categorical demographic variables.

Time to neutrophil and platelet engraftment will be described using cumulative incidence estimates. Patients who died within 21 days after transplant due to other causes before the engraftment (event) will not be evaluable for engraftment endpoint. Overall survival will be

60


calculated using Kaplan Meier estimates. Acute and chronic GVHD will be described using cumulative incidence estimates. We will calculate 95% confidence intervals for each outcome at specified time points separately for the two groups. We will test the null hypothesis that the probability of each transplant outcome is the same in the two groups by using pointwise chi-square tests.

We will adjust for covariates that may influence the study endpoints using Cox proportional hazards regression models. The proportional hazards assumption will be assessed for each variable using time-dependent or graphical approaches. Time-dependent covariates will be used when non proportional hazards are detected, where the best-fitting model with time-varying risk coefficients will be found by maximizing the partial likelihood. Forward stepwise regression with alpha=0.05 will be used to build models, with the prior splenectomy variable forced into the model. Two way interactions will be checked between the main effect and all other variables in the model. The effect of prior splenectomy on the incidence of neutrophil engraftment by day 30 and the incidence of platelet engraftment by day 60 will be modeled using logistic regression or pseudo-value techniques depending on the presence of censoring prior to each time point.

7.0 REFERENCES

1. Li Z, Gooley T, Appelbaum FR, Deeg HJ. Splenectomy and hemopoietic stem cell transplantation for myelofibrosis (letter). Blood 2001;97:2180-2181.

2. Martino R, Altes A, Muniz-Diaz E, Brunet S, Sureda A, Domingo=Albos A, Madz P. Reduced transfusion requirements in a splenectomized patient undergoing bone marrow transplantation. Acta Haematol 1994;92:167-168.

3. von Bueltzingsloewen A, Bordigoni P, Dorvaux Y, Witz F, Schmitt C, Chastagner P, Sommelet D. Splenectomy may reverse pancytopenia occurring after allogeniec bone marrow transplantation (letter). Bone Marrow Transplant 1994;14:339-340.

4. Li Z, Deeg HJ. Pros and cons of splenectomy in patients with myelofibrosis undergoing stem cell transplantation. Leukemia 2001;15:465-467.

5. Akpek G, McAneny D, Weintraub L. Risks and benefits of splenectomy in myelofibrosis with myeloid metaplasia: a retrospective analysis of 26 cases. J Surg Oncol. 2001 May;77(1):42-8)

6. Akpek G, McAneny D, Weintraub L. Comparative response to splenectomy in Coombs-positive autoimmune hemolytic anemia with or without associated disease. Am J Hematol. 1999 Jun;61(2):98-102

61


Table 1. Characteristics of patients(≥ 18), who received traditional myeloablative conditioning for an allogeneic bone marrow or peripheral blood stem cell transplant for CML and MDS/MPD, from an HLA-identical sibling or an unrelated donor between 1990 and 2006 and reported to the CIBMTR.

Characteristics of patients No Splenectomy Splenectomy P-valued

Patient related

Number of patients 8329 1236Age at transplant, median (range), years 38 (18 - 58) 43 (18 - 61) <0.001**

18-21 271 ( 3) 37 ( 3) <0.00121-40 4550 (55) 513 (42)41-60 3474 (42) 667 (54)>60 34 (<1) 19 ( 2)

Male Sex 4917 (59) 722 (58) 0.853Karnofsky score at transplant <0.001

<90 1425 (17) 422 (34)≥90 6737 (81) 762 (62)Missing 167 ( 2) 52 ( 4)

Disease related

Disease related <0.001Chronic myelogenous leukemia 7101 (85) 318 (26)MDS/MPD disease 1228 (15) 918 (74)

Disease status at transplant MDS/MPD

RA 285 (23) 149 (16)RAEB 354 (29) 206 (22)RAEB-T 223 (18) 176 (19)CMML 58 ( 5) 80 ( 9)RARS 32 ( 3) 21 ( 2)MDS unknown 66 ( 5) 30 ( 3)

Myelofibrosis 77 ( 6) 105 (12) Otherc 132 (11) 153 (16) CML

First & second chronic phasea 6047 (81) 225 (64)Accelerated Phase 972 (13) 87 (25)Otherb 39 (<1) 5 ( 1)Missing 44 ( 1) 1 (<1)

Transplant related

Donor type <0.001HLA identical sibling 4359 (52) 497 (40)Unrelated Donor 3970 (48) 739 (60)

62


Table 1. Continued. Characteristics of patients No Splenectomy Splenectomy P-value

Year of transplant <0.0011990-1994 3097 (37) 247 (20) 1995-1999 3310 (40) 490 (40) 2000-2004 1501 (18) 347 (28) 2005-2006 421 ( 5) 152 (12)

Graft type <0.001Bone marrow 6890 (83) 868 (70) Peripheral blood 1439 (17) 368 (30)

Donor/recipient sex match 0.608Male-Male 3013 (36) 431 (35) Male-Female 1886 (23) 289 (23) Female-Male 1809 (22) 264 (21) Female-Female 1591 (19) 249 (20)

Unknown 30 (<1) 3 (<1) Donor/recipient CMV match 0.001

Negative/Positive 1709 (21) 308 (25) Positive/Negative 1066 (13) 147 (12) Negative/Negative 2271 (27) 353 (29) Positive/Positive 2951 (35) 373 (30)

Unknown 332 ( 4) 55 ( 4) HLA match status <0.001

Well matched 1193 (14) 306 (25) Partially matched 1577 (19) 270 (22) Mismatched 1200 (14) 163 (13)

HLA-Identical siblings 4359 (52) 497 (40) Growth factor given post tx to promote engraftment? <0.001

No 5892 (71) 766 (62) Yes 2298 (28) 429 (35)

Missing 139 ( 2) 41 ( 3) Conditioning regimen 0.435

CY + TBI 4477 (54) 668 (54) Bu + CY 3804 (46) 566 (46) Otherf 48 ( 1) 2 (<1)

ATG use? 0.0003Yes 7595 (91) 1086 (88) No 734 ( 9) 150 (12)

63


Table 1. Continued. Characteristics of patients No Splenectomy Splenectomy P-value

GVHD prophylaxis <0.001T-cell depletion 991 (12) 222 (18) CSA + MTX +- other 5791 (70) 719 (58) CSA + MMF +-other 23 (<1) 9 (<1) CSA +CORT +-other (not mtx) 343 ( 4) 43 ( 3) CSA +- Other 29 (<1) 0 CSA alone 228 ( 3) 13 ( 1) MTX + FK506 701 ( 8) 178 (14) MTX + CORT +-other 18 (<1) 4 (<1) FK506 + other (not mtx) 119 ( 1) 36 ( 3) MTX +-other 21 (<1) 3 (<1) Other 20 (<1) 2 (<1) None (will be checked with the teams) 40 (<1) 4 (<1) Missing 5 (<1) 3 (<1)

GVHD prophylaxis grouped <0.001CSA based 6414 (77) 784 (63) FK based 820 (10) 214 (17) Other 1050 (13) 231 (19) None 40 (<1) 4 (<1) Missing 5 (<1) 3 (<1)

BM TNC 108 cells/kg, median (range) 3 (<1-96) 3 (<1-92) 0.188**PB TNC 108 cells/kg, median (range) 8 (<1-69) 8 (<1-68) 0.838 **Median follow-up of survivors, range, months 89 (1-211) 72(1-207) Abbreviations: CSA= cyclosporine; MMF= mycophenolate; MTX=methotrexate; TBI= total body irradiation; Bu=busulfan; Cy=cyclophosphamide; GVHD= graft vs host disease; Fludara= fludarabine; Lpam=melphalan; FK506= Tacrolimis; Cort=corticosteroids; PIF=primary induction failure; CR1= first complete response; R2=second complete response; CR3=third complete response; Relapse1= first relapse; CP=chronic phase; CML= chronic myelogenous leukemia; TNC=total nucleated cell dose; IPN=interstitial pnemoniatis. a Includes (N=532) 2CP and (N=5739) 1CP patients.

bOther CML disease stage includes; prior tx CP (n=2); prior tx AP/BP (n=4) and “089-more adv. Disease (n=38).

cMDS/MPD other disease subtype includes subtype: polycythemia vera (n=11); Essential/primary thrombocythemia, myelofiborosis with myeloid metaplasia (n=18), and other MDS/MPD (n=254) d Chi-Square p-value for categorical variables ** Krukall Wallis p-value for continuous variables f Other conditioning regimen includes Cy± Other (n=50) Fludarabine ± other (n=1) Other (n=1)

64


Table 2. Primary causes of death among patients(≥ 18), who received traditional myeloablative conditioning for an allogeneic bone marrow or peripheral blood stem cell transplant for CML and MDS/MPD, from an HLA-identical sibling or an unrelated donor between 1990 and 2006 and reported to the CIBMTR Causes of Death No Splenic therapy Splenectomy

Still alive 3864 (46) 451 (36) <0.001Primary disease 618 ( 7) 165 (13) New malignancy 38 (<1) 17 ( 1) GVHD 887 (11) 119 (10) IPN 654 ( 8) 83 ( 7) Infection 948 (11) 149 (12) Organ failure 572 ( 7) 115 ( 9) Other cause 292 ( 4) 49 ( 4) Graft failure 129 ( 2) 19 ( 2) Hemorrhage not specified 222 ( 3) 45 ( 4) Intracranial 22 (<1) 7 (<1) Gastrointestinal 5 (<1) 1 (<1) Missing (Will be checked with team) 78 (<1) 16 ( 1)

65


CIBMTR RT09-01

PRIMARY GRAFT FAILURE FOLLOWING ALLOGENEIC HSCT FOR THE TREATMENT OF HEMATOLOGICAL MALIGNANCIES

DRAFT PROTOCOL

Study Chairs: Richard Olsson, MD, PhD

Karolinska University Hospital, B87 SE-141 86 Stockholm, Sweden Telephone: +46 8 585 851 21 Fax: +46 8 746 6699 E-mail: [email protected] Jeffery Schriber, MD Banner BMT Program 1111 E McDowell Rd Phoenix Az 85006 Telephone: 602-239 4242 Fax: 602-239-4668 E-mail: [email protected] Sonali Chaudhury, MD Northwestern University School of Medicine, 2300 Children's Plaza, Box #30 Chicago, IL 60614. Telephone: 773-880-6941 Fax: 773-880-3019 E-mail: [email protected]

Olle Ringdén, MD, PhD Karolinska University Hospital, F79 SE-141 86 Stockholm, Sweden Telephone: +46 8 585 82672 Fax: +46 8 746 6699 E-mail: [email protected]

66






Fax: 617-724-1126 E-mail: [email protected] Kenneth R. Cooke, M.D Case Western Reserve University School of Medicine Department of Pediatrics Wolstein Research Building 6th Floor, Room 6524 2103 Cornell Road Cleveland, OH 44106-7288 Phone: 216- 368-0481 Fax: 216- 368-0741 E-mail: [email protected] Vincent T. Ho, MD Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115 Phone: 617-632-5938 Fax: 617-632-5168 E-mail: [email protected]

67


1.0 OBJECTIVES AND AIMS:

The aim of this study is to identify risk factors for primary graft failure following myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of hematological malignancies, and develop a scoring/stratification system to discern patients at risk of developing primary graft failure.

1.1 Evaluate risk factors for primary graft failure in adults and children (≤ 17 years old) undergoing allogeneic HSCT for the treatment of hematological malignancies.

1.2 Evaluate risk factors for graft failure among patients who have not yet engrafted by day 14 or by day 21 to assess whether there are certain patient populations for whom early intervention may be needed.


After myeloablative allogeneic HSCT, primary graft failure is a significant complication with high morbidity and mortality (1, 2). Primary graft failure is defined as failure to engraft, i.e. failure to recover from neutropenia and achieve absolute neutrophil count (ANC) ≥0.5x109/l for three consecutive post-transplant days. Immunologic rejection of the donor hematopoietic cells, mediated by recipient T cells, natural killer (NK) cells, or antibodies may cause graft failure. Moreover, graft failure may be induced by viral infections such as cytomegalovirus (CMV), human herpes virus type 6 (HHV-6), or parvovirus. Factors associated with an augmented risk of graft failure are HLA-mismatched grafts, unrelated grafts, T cell depleted grafts, cord blood grafts, sensitized recipients and reduced intensity conditioning (RIC) (3-7). Recent data also suggest that preformed antibodies against CD34+/VEGFR-2+ endothelial cell precursors may result in graft failure (8). Importantly, graft failure may be mitigated by intensifying the conditioning regimen, augmenting the graft cell dose, or with increased immunosuppression (9-11). Identification of patients who will develop primary graft failure early in their transplant course is paramount clinical importance since these patients could potentially be rescued with second stem cell infusions. Unfortunately, recent unpublished data from the CIBMTR show that only 12% of all primary graft failures move to a second transplantation, and as many as one third of all patients who did proceed to a second transplantation died from graft failure (12). Thus, further studies are warranted to identify predictors of primary graft failure aiming to improve the clinical outcome of allogeneic HSCT


Our study population will include patients with hematologic malignancies who received an allogeniec marrow or peripheral blood transplant from an URD or HLA-identical sibling between 1995 and 2008 and reported to the CIBMTR. Only patients who received myeloablative conditioning (defined below) regimen will be included in the study. Myeloablative conditioning (MAC)

– Total body irradiation (TBI dose >5 Gy single dose, or fractionated TBI >8 Gy). – Busulfan (BU dose >9 mg/kg). – Melphalan (dose >150mg/m2).

Exclusion criteria – Non-malignant disorders – Solid tumors

68


– Prior allogeneic transplant – Cord blood transplants – Reduced intensity conditioning (RIC)

– TBI dose <5 Gy single or TBI dose <8 Gy fractionated – Melphalan dose ≤150 mg/m2 – BU dose ≤9 mg/kg – BEAM (upper limit of RIC)

– Non-myeloablative conditioning: – TBI dose = 2 Gy – Fludarabine + TBI dose = 2 Gy – Fludarabine + Ara-C + Ida – CDA + Ara-C

4.0 OUTCOMES:

4.1 Primary Graft failure: Failure to engraft, i.e. patients who never recover from neutropenia and achieve ANC ≥0.5x109 by day 28 post-transplant. The day of engraftment is defined as the first day of three consecutive days with ANC ≥0.5x109/l. Patients who undergo a second transplant for graft failure prior to day 28 will be considered as having primary graft failure.


A large number of variables may affect the outcomes of patients with graft failure after an allogeniec transplant for a hematologic malignancy. These are described below:

Patient-related:

– Age at transplant as continuous variable – Age grouped: Children (≤17 yrs) vs. adults (>17 yrs) – Gender: female vs. male – Karnofsky performance score: <90% vs. ≥90% – Significant fungal infection prior to conditioning – Interval between diagnosis and transplantation: <12 months vs. ≥12months. (This

variable will be considered for each disease)

Disease-related: – Disease: ALL vs AML vs CML vs other leukemia vs MDS vs NHL vs MM. – Disease status pre-transplant: early vs. intermediate vs. advanced (applicable to

certain diseases, see table 1)

Transplant-related: – Donor type: HLA-identical sibling vs. unrelated donor – Donor-recipient ABO incompatibilities: matched ABO vs. minor vs. major vs other – HLA match: well matched vs. partially matched vs. mismatched – Source of stem cells: BM vs. PBSC – Ex vivo T-cell depleted vs. repleted – Cell dose: Total nucleated cells and CD34+ cells/kg continuous variable (separately

by graft type) – Year of transplant: continuous variable – Donor age as a continuous variable – Donor-recipient gender match: F-M vs. M-F vs. M-M vs. F-F

69


– Donor-recipient CMV status: -/- vs. -/+ vs. +/- vs. +/+ – GVHD prophylaxis: cyclosporine ± MTX ± other, tacrolimus ± MTX ± other vs.

other. – ATG vs. Campath vs. none – TBI vs. no TBI conditioning – ANC <0.5x109/l at 14 or 21 days post-transplant – Use of preplanned growth factors post transplant

6.0 STUDY DESIGN:

To summarize the characteristics of the dataset, descriptive tables of patient, disease and transplant related variables will be reported for all patients in the cohort as well as for patients surviving without engraftment at day 14 and at day 21 post transplant. For discrete factors, the number of cases and their respective percentages will be calculated. For continuous factors, the median and ranges will be calculated. The main objective of this study is to discern risk factors for primary graft failure after allogeneic HSCT in both adults and children (≤17 years old). Stepwise logistic regression will be used to model the odds of graft failure as a function of pre-transplant prognostic factors. All two-way interactions will be checked. Secondary objectives include evaluation and modeling of the risk of primary graft failure in the subgroup of patients alive but with ANC <0.5x109/l at 14 as well as at 21 days post-transplant. Similar techniques will be used for this analysis as for the analysis in the larger cohort.

7.0 REFERENCES:

1. Guardiola P, Kuentz M, Garban F et al. Second early allogeneic stem cell transplantations for graft failure in acute leukaemia, chronic myeloid leukaemia and aplastic anaemia. French Society of Bone Marrow Transplantation. Br J Haematol 2000;111(1): 292-302.

2. Davies SM, Weisdorf DJ, Haake RJ et al. Second infusion of bone marrow for treatment of graft failure after allogeneic bone marrow transplantation. Bone Marrow Transplant 1994;14(1): 73-7.

3. Petersdorf EW, Hansen JA, Martin PJ et al. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. N Engl J Med 2001;345(25): 1794-800.

4. Marmont AM, Horowitz MM, Gale RP et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991;78(8): 2120-30.

5. Rocha V, Cornish J, Sievers EL et al. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood 2001;97(10): 2962-71.

6. Champlin RE, Horowitz MM, van Bekkum DW et al. Graft failure following bone marrow transplantation for severe aplastic anemia: risk factors and treatment results. Blood 1989;73(2): 606-13.

7. Mattsson J RO, Storb R. Graft failure after allogeneic hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation 2008;14: 165-170.

8. Nordlander A, Mattsson J, Sundberg B, Sumitran-Holgersson S. Novel antibodies to the donor stem cell population CD34+/VEGFR-2+ are associated with rejection after hematopoietic stem cell transplantation. Transplantation 2008;86(5): 686-96.

9. Baron F, Baker JE, Storb R et al. Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 2004;104(8): 2254-62.

10. Storb R, Blume KG, O'Donnell MR et al. Cyclophosphamide and antithymocyte globulin to condition patients with aplastic anemia for allogeneic marrow transplantations: the experience in four centers. Biol Blood Marrow Transplant 2001;7(1): 39-44.

70


11. Kahl C, Leisenring W, Deeg HJ et al. Cyclophosphamide and antithymocyte globulin as a conditioning regimen for allogeneic marrow transplantation in patients with aplastic anaemia: a long-term follow-up. Br J Haematol 2005;130(5): 747-51.

12. Schriber JR, Agovi, Manza- A, Ballen, Karen K, Bacigalupo, Andrea, Hale, Gregory A., Gupta, Vikas, Lazarus, Hillard M., Litzow, Mark R., Marks, David I., Giller, Roger H., Maziarz, Richard T., Bornhauser, Martin, Isola, Luis M., Bredeson, Christopher, Rizzo, J. Douglas. Second Unrelated Donor (URD) Transplant as a Rescue Strategy for 122 Patients with Primary Non Engraftment: Results from the CIBMTR. In: ASH Annual Meeting Abstracts 2008; 2008; 2008. p. 794.

71


Table 1. Characteristics of patients with graft failure vs non graft failure patients who received myeloablative conditioning for an allogeneic transplant from an HLA-identical sibling or unrelated donor as treatment for a malignant disease between 1995 and 2008 and reported to the CIBMTR

Characteristics of patients No Graft failure Graft failureNumber of patients 25192 464Age at transplant, median (range), years 33 (<1 - 61) 27 (1 - 60)

0-10 3388 (13) 83 (18)11-20 3810 (15) 100 (22)21-30 4072 (16) 78 (17)31-40 5015 (20) 80 (17)41-50 5473 (22) 84 (18)51-60 3078 (12) 36 ( 8)>60 326 ( 1) 3 (<1)

Missing 30 (<1) 0Male Sex 14605 (58) 275 (59)Karnofsky score

<90 15667 (62) 304 (66)≥90 8491 (34) 146 (31)Missing 1034 ( 4) 14 ( 3)

Disease AML 8079 (32) 118 (25)ALL 6101 (24) 118 (25)CML 769 ( 3) 14 ( 3)MDS 5771 (23) 137 (30)Other Acute Leukemia 2461 (10) 56 (12)NHL 1574 ( 6) 17 ( 4)HD 90 (<1) 0MYE 347 ( 1) 4 (<1)

Disease status pre transplanta

AML,ALL/CML Early 9937 (39) 164 (35)AML,ALL/CML Intermediate 6854 (27) 137 (30)AML,ALL/CML advanced 3047 (12) 75 (16)MDS early 533 ( 2) 9 ( 2)MDS Advanced 1204 ( 5) 26 ( 6)Lymphoma chemo-sensitive 766 ( 3) 7 ( 2)Lymphoma chemo-resistant 376 ( 1) 6 ( 1)

Other diseases N/A 2475 (10) 40 ( 9)Graft type

Bone marrow 15131 (60) 265 (56)Peripheral blood 8640 (34) 77 (16)Bone marrow + peripheral blood 1447 ( 6) 129 (27)

72


Table 1. Continued. Characteristics of patients No Graft failure Graft failureDonor type

HLA-identical sibling 10505 (42) 72 (15)Unrelated donor 14713 (58) 399 (85)

Conditioning Regimen CY + TBI 13598 (54) 252 (54)BU+CY 8160 (32) 132 (28)TBI+ flud +-other 1757 ( 7) 42 ( 9)CY +-other 40 (<1) 0Bu +-other 1432 ( 6) 36 ( 8)Flud +-other 178 (<1) 2 (<1)ATG +-other 5 (<1) 0

None 22 (<1) 0Year of transplant

1995-1996 5043 (20) 100 (22)1997-1998 4505 (18) 81 (17)1999-2000 3893 (15) 82 (18)2001-2002 3486 (14) 71 (15)2003-2004 3556 (14) 50 (11)2005-2006 3869 (15) 62 (13)2007-2008 840 ( 3) 18 ( 4)

Donor/recipient sex match Male/male 8963 (36) 135 (29)Male/female 5575 (22) 136 (29)Female/male 5682 (23) 95 (20)Female/female 4827 (19) 92 (20)Unknown 145 (<1) 6 ( 1)

Donor/recipient CMV match Negative 7104 (28) 100 (22)Positive 7688 (31) 113 (24)+ve/-ve 3104 (12) 46 (10)-ve/+ve 5549 (22) 115 (25)Unknown 1747 ( 7) 90 (19)

HLA match statusb

Well matched 4876 (19) 47 (10)Partially matched 7679 (30) 242 (52)Mismatched 2142 ( 9) 110 (24)Unknown/missing HLA data 1 (<1) 0HLA-identical sibs 10494 (42) 65 (14)

73


Table 1. Continued. Characteristics of patients No Graft failure Graft failureEngraftment

Engrafted, dead ≤ 28days 493 ( 2) 0Engrafted, survived >28 days 23603 (94) 0Engrafted, with persistent disease in bone marrow 4 (<1) 0No engraft, with persistent dz in BM survived ≤28 days 90 (<1) 0No engraft with persistent dz in BM, survived > 28 days 114 (<1) 0No engraft died ≤ 28days 888 ( 4) 0No engraft, received 2nd tx ≤ 28days 0 30 ( 6)No engraft, received 2nd tx after 28days 0 434 (94)

Significant fungal infection prior to conditioning? No 22251 (88) 410 (88)Yes 2201 ( 9) 46 (10)Missing 740 ( 3) 8 ( 2)

GVHD prophylaxis None (Will be checked with teams) 464 ( 2) 10 ( 2)T-cell depletion 1 (<1) 0CSA + MMF +-other 343 ( 1) 12 ( 3)CSA + MTX +- other 14642 (58) 207 (45)CSA +-other (not mtx) 1984 ( 8) 83 (18)CSA alone 1538 ( 6) 40 ( 9)FK506 + MMF +- other 637 ( 3) 19 ( 4)FK506 +- other (not mtx) 168 (<1) 9 ( 2)FK506 alone 692 ( 3) 10 ( 2)MTX alone 3722 (15) 54 (12)MTX +- other 394 ( 2) 8 ( 2)Other 377 ( 1) 7 ( 2)Missing 230 (<1) 5 ( 1)

Total number of transplants 1 22849 (91) 202 (44)2 1895 ( 8) 229 (49)3 304 ( 1) 28 ( 6)4 95 (<1) 5 ( 1)5 28 (<1) 06 10 (<1) 07 8 (<1) 08 2 (<1) 09 1 (<1) 0

Time from diagnosis to transplant, months <12 months 14185 (56) 221 (48)≥ 12 months 10911 (43) 241 (52)

Missing 96 (<1) 2 (<1)

74


Table 1. Continued. Characteristics of patients No Graft failure Graft failureATG use?

No 20580 (82) 306 (66)Yes 4612 (18) 158 (34)

Campath use? No 24725 (98) 455 (98)Yes 467 ( 2) 9 ( 2)

Prior chemotherapy for MDS patients No 1739 ( 7) 35 ( 8)Yes 702 ( 3) 21 ( 5)N/A 22751 (90) 408 (88)

ABO incompatibilities Major & bi ABO 6374 (25) 161 (35)Minor ABO 4982 (20) 115 (25)Matched ABO 11932 (47) 157 (34)Other 1904 ( 8) 31 ( 7)

Median follow-up of survivors, (range), months 63 (<1-173) 62 (1-168)Abbreviations; AML= Acute myelogenous leukemia; ALL= Acute lymphoblastic leukemia; CML=chronic myelogenous leukemia; HL=Hodgkin’s lymphoma; NHL = Non-Hodgkin’s lymphoma; CLL = Chronic lymphocytic leukemia; MFS/MPS = Myelodysplastic/myeloproliferative disorders ; MM= multiple myeloma; CMV = cytomegalovirus; Cy = cyclophosphamide; TBI = total body irradiation;Bu = Busulfan; Flud = fludarabine; CSA = cyclosporine; MTX = methotrexate, FK506 = tacrolimus MMF=Mycophenolate; HLA= human leukocyte antigen; GVHD=graft versus host disease; ANC= Absolute neutrophile count; N/A= not applicable .

Selection/Exclusion criteria: 1. First allogenic transplant for a malignant disease transplanted between 1995 and 2008 N=36288 2. Donor type: unrelated, HLA identical sibling only. N= 33816 3. MAC intensity only. N= 26460 4. Graft type:BM, PB, and BM+ PB patients N=26455 5. Delete patients with previous transplants- N=26414 6. Exclude (n=440) patients with missing information on ANC recovery post tx. N=25974 7. Patients whose neutrophil count never dropped below ANC 500/no neutropenia reported N=25951 8. Select for patients with complete forms (core+ graft insert +disease insert). N=25656

a Disease status pre-transplant defined: -Other disease N/A includes PNH Proxysmal nocturnal hemoglobinuria, not applicable,Polycythemia vera, not applicable, Essential or primary thrombocythemia, not applicable ,Myelofibrosis with myeloid metaplasia, not applicable, MPS, NOS, not applicable, Acute Myelofib/Myelosclerosis, not applicable ,Other MDS, spec, not applicable,Other MFS/MPS, specify, not applicable.-Lymphoma includes unknown sensitivity or untreated lymphoma.

bHLA match status: Well matched was defined as no known disparity at HLA A,B,C,DRB1, partially matched as one locus known or likely disparity with their donors and mismatched as ≥2 locus disparity.

75


Table 2. Causes of death of patients with graft failure vs non graft failure patients who received myeloablative conditioning for an allogeneic transplant from an HLA-identical sibling or unrelated donor as treatment for a malignant disease between 1995 and 2008 and reported to the CIBMTR.

Causes of Deatha No Graft failure Graft failure

Still alive 10754 (43) 60 (13)Primary disease 4629 (18) 31 ( 7)New malignancy 135 (<1) 2 (<1)Graft vs host disease 1951 ( 8) 37 ( 8)Intestitial pneumoniatis 1392 ( 6) 42 ( 9)Infection 2522 (10) 88 (19)Organ failure 1990 ( 8) 71 (15)Other cause 867 ( 3) 15 ( 3)graft failure 163 (<1) 96 (21)Hemorrhage 416 ( 2) 13 ( 3)Intracranial hemorrhage 140 (<1) 5 ( 1)Gastrointestinal 22 (<1) 1 (<1)Missing 211 (<1) 3 (<1)

aSelf reported and assessed by teams.

76


Table 3. Characteristics of patients with engraftment or without engraftment at day 14 post transplant who received myeloablative conditioning for an allogeneic transplant from an HLA-identical sibling or unrelated donor as treatment for a malignant disease between 1995 and 2008 and reported to the CIBMTR

Characteristics of patients No Engraftment @

day 14 Engraftment @ day

14 Number of patients 17399 8257Age at transplant, median (range), years 32 (<1 - 60) 36 (<1 - 63)

0-10 2693 (15) 778 ( 9)11-20 2889 (17) 1021 (12)21-30 2776 (16) 1374 (17)

31-40 3429 (20) 1666 (20)41-50 3600 (21) 1957 (24)51-60 1824 (10) 1290 (16)>60 170 (<1) 159 ( 2)

Missing 18 (<1) 12 (<1)Male Sex 10206 (59) 4674 (57)Karnofsky score ≥90 5994 (34) 2643 (32)Disease

AML 5228 (30) 2969 (36)ALL 4416 (25) 1803 (22)CML 507 ( 3) 276 ( 3)MDS 4430 (25) 1478 (18)Other Acute Leukemia 1730 (10) 787 (10)NHL 875 ( 5) 716 ( 9)HD 47 (<1) 43 (<1)MYE 166 (<1) 185 ( 2)

Donor type HLA-identical sibling 6448 (37) 4111 (50)Unrelated donor 10951 (63) 4146 (50)

Graft type Bone marrow 12097 (70) 3290 (40)Peripheral blood 3903 (22) 4794 (58)Bone marrow + peripheral blood 1399 ( 8) 173 ( 2)

Year of transplant 1995-1996 3838 (22) 1305 (16)1997-1998 3354 (19) 1232 (15)1999-2000 2755 (16) 1220 (15)2001-2002 2371 (14) 1186 (14)2003-2004 2231 (13) 1375 (17)2005-2006 2320 (13) 1611 (20)2007-2008 530 ( 3) 328 ( 4)

77


Table 3. Continued.

Characteristics of patients No Engraftment @

day 14 Engraftment @ day

14 Graft failure?

No 16935 (97) 8257Yes 464 ( 3) 0

78


Table 4. Characteristics of patients with engraftment or without engraftment at day 21 post transplant who received myeloablative conditioning for an allogeneic transplant from an HLA-identical sibling or unrelated donor as treatment for a malignant disease between 1995 and 2008 and reported to the CIBMTR

Characteristics of patients No Engraftment

@ day 21 Engraftment @

day 21 Number of patients 17399 8257Age at transplant, median (range), years 29 (<1 - 60) 34 (<1 - 62)

0-10 1284 (18) 2187 (12)11-20 1244 (18) 2666 (14)21-30 1096 (16) 3054 (16)31-40 1283 (18) 3812 (20)41-50 1382 (20) 4175 (22)51-60 670 (10) 2444 (13)>60 52 (<1) 277 ( 1)

Missing 8 (<1) 22 (<1)Male Sex 4182 (60) 10698 (57)Karnofsky score ≥90 2352 (34) 6285 (34)Disease

AML 1949 (28) 6248 (34)ALL 1833 (26) 4386 (24)CML 200 ( 3) 583 ( 3)MDS 1888 (27) 4020 (22)Other Acute Leukemia 769 (11) 1748 ( 9)NHL 304 ( 4) 1287 ( 7)HD 17 (<1) 73 (<1)MYE 59 (<1) 292 ( 2)

Donor type HLA-identical sibling 2231 (32) 8328 (45)Unrelated donor 4788 (68) 10309 (55)

Graft type Bone marrow 5024 (72) 10363 (56)Peripheral blood 971 (14) 7726 (41)Bone marrow + peripheral blood 1024 (15) 548 ( 3)

Year of transplant 1995-1996 1659 (24) 3484 (19)1997-1998 1325 (19) 3261 (17)1999-2000 1118 (16) 2857 (15)2001-2002 986 (14) 2571 (14)2003-2004 825 (12) 2781 (15)2005-2006 876 (12) 3055 (16)2007-2008 230 ( 3) 628 ( 3)

79


Table 4. Continued. Characteristics of patients No Engraftment @

day 21Engraftment @ day

21Graft failure?

No 5400 (77) 15486 (83)Yes 1619 (23) 3151 (17)

80


CIBMTR RT09-02

EFFECTS OF BODY MASS IN CHILDREN WITH LEUKEMIAS UNDERGOING ALLOGENEIC BONE MARROW TRANSPLANT

DRAFT PROTOCOL

Study Chairs: Richard Aplenc, MD, MSCE,

The Children’s Hospital of Philadelphia Center for Clinical Epidemiology and Biostatistics 3615 Civic Center Blvd, 916G ARG Philadelphia, PA 19104 Telephone: 267- 426-7252 Fax: 215-590-4744 E-mail: [email protected] Nancy Bunin, MD Director, Blood and Marrow Transplantation Division of Oncology The Children’s Hospital of Philadelphia 34th St & Civic Center Blvd, Philadelphia, PA 19104 Telephone: 215-590-2255 Fax: 215-590-4744 E-mail: [email protected]

Lillian Sung, MD, PhD Division of Haematology/Oncology The Hospital for Sick Children Toronto, Ontario, M5G1X8

Telephone: 416-813-5827 Fax: 416-813-5979 E-mail: [email protected]

81






Fax: 617-724-1126 E-mail: [email protected] Kenneth R. Cooke, M.D Case Western Reserve University School of Medicine Department of Pediatrics Wolstein Research Building 6th Floor, Room 6524 2103 Cornell Road Cleveland, OH 44106-7288 Phone: 216- 368-0481 Fax: 216- 368-0741 E-mail: [email protected] Vincent T. Ho, MD Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115 Phone: 617-632-5938 Fax: 617-632-5168 E-mail: [email protected]

82


1.0 SPECIFIC AIMS: 1.1 To compare leukemia free survival and overall survival in children with leukemias who

underwent allogeneic HSCT by body mass index (BMI) in under, over, and normal weight patients.

1.2 To compare transplant related morbidity and mortality in under, over and normal weight

patients. 1.3 To evaluate the impact of chemotherapy dose intensity on survival by BMI


There is a growing prevalence of overweight and obesity not only in developed countries, but in the developing world as well (1-4). According to the International Obesity Task Force at least 155 million children worldwide are overweight or obese. Little is known about the pharmacokinetics of chemotherapy in overweight and obese patients. Obese patients may have altered chemotherapy distribution, which may lead to differences in kidney and liver blood flow with diminished clearance. Drug features may lead to high adipose distribution, altering the volume of distribution and clearance. Increased toxicity may result without dose adjustment, and this may be exacerbated with the very high doses used in conditioning (5). On the other hand, inadequate dosing may increase risk of relapse or graft rejection. Busulfan pharmacokinetic study has served as a paradigm of these problems (6). These dosing concerns may be magnified due to the limitations of pharamokinetic data in children, and there is no standard approach to chemotherapy dosing in conditioning regimens. Some centers dose adjust for all agents, others for some agents, and other centers for none. Several studies have looked at the impact of obesity in outcomes of adults following autologous or allogeneic HSCT. Tarella et al found that overweight conferred a RR of death of 2.9 in multivariate analysis for patients undergoing autologous HSCT for NHL (7). Meloni et al. noted statistically significant inferior outcomes in obese patients undergoing autologous HSCT for AML (8). Fleming et al. reported a single institution case-control study, and noted significantly inferior OS for obese patients. The obese patient group included a slightly higher proportion of relapsed AML patients, but no differences in relapse were noted. There was no difference in OS between obese and non-obese children in this study, but only 80 patients <16 years were included (9). There is minimal data for children, but Drs. Sung and Aplenc recently published a single institution pediatric retrospective cohort study that included patients receiving allogeneic HSCT for both malignant and non-malignant disorders. In this patient cohort, 17% were overweight, and of these, 41% had chemotherapy dose adjustments. However, the dose adjustment did not mitigate the adverse outcomes in the overweight group, and OS, ES, and TRM were higher in this group (10). Thus, a large multi-institutional study will provide additional valuable information upon the effects of overweight in outcome for children undergoing allogeneic BMT.

83



The study population will include patients aged >5 and ≤18 years who underwent myeloablative primary allogeneic bone marrow transplant for one of the following diagnoses between 1990 and 2007.

– Acute lymphoblastic leukemia CR1, CR2 – Acute myeloid leukemia CR1, CR2 – Chronic myeloid leukemia – Myelodysplastic syndromes

Exclusion criteria :

– Second HSCT – DNA fragility syndromes (Fanconi’s, Bloom’s, AT) – Cord blood and peripheral blood graft types

4.0 OUTCOMES:

Primary outcomes to be studied include: 4.1 100 day mortality: This is defined as death on or before 100 days post transplant. Patients

alive at last observation with fewer than 100 days of follow-up are not considered at risk for this event.

4.2 Overall survival: Time to death from any cause. Event will be summarized by a survival

curve. Cases will be analyzed at the time of last follow-up or date last form was due. There are no competing risks

4.3 Treatment-related mortality: Time to death without evidence of leukemia recurrence.

Patients are censored at time of relapse or at last follow-up. This event is summarized by the cumulative incidence estimate with relapse as the competing risk

4.4 Relapse: Time to onset of leukemia recurrence. Patients will be censored at death in

continuous CR, second transplant or, for patients surviving in continuous complete remission, at last contact. This event is summarized by the cumulative incidence estimate with treatment related mortality as the competing risk.

4.5 Leukemia-free survival: Time to treatment failure (death or relapse). Patients are

censored at time of last follow-up. Secondary outcomes include: 4.6 Day 100 treatment related morbidity, particularly GVHD, hepatic, pulmonary and

infectious complications.

4.7 Overall transplant related morbidity, particularly GVHD, hepatic, pulmonary and infectious complications.

84



Patient-related: – Age – Gender: female vs male – Karnofsky performance score: <90% vs ≥90% – Ethnicity: Caucasian vs Hispanic vs AA vs others

Disease related: – Risk classification by disease and treatment status

– low risk: ALL CR 1,2; AML CR1; CML CP1 – high risk: all others

Transplant related: – Year of transplant: – HLA matched status: well matched vs partially matched vs mismatch vs missing. – BMI group: Overweight >95percentile, Underweight <10 percentile, Middleweight >10

and <95percentile – Donor type: related vs unrelated donor – Source of stem cell: bone marrow vs peripheral blood – Total nucleated cell dose per Kg – Lung shielding: yes vs no vs missing – Chemotherapy dosing: chemotherapy dose delivered for chemotherapy agents

administered in transplant conditioning – Donor-recipient CMV status: +/+ vs +/- vs -/+ vs -/- – Donor-recipient sex match: male/male vs female/female vs male/female vs female/male – Conditioning regimen: Bu/CY vs TBI/CY vs other – GVHD prophylaxis: T depletion vs CsA+MTX +/- other vs. CsA +/- other vs. FK+MTX

+/- other vs. FK+/- other vs/ MTX+/-other vs. Other +/- none – Transplant related morbidity/mortality

– VOD (yes/no) – Pulmonary and other organ toxicity – Infection complication data – Acute GVHD site and overall grades

6.0 STUDY DESIGN: (TO BE REVIEWED BY PHD STATISTICIAN)

Dr. Aplenc, Dr. Sung, and statisticians at the both Center for Clinical Effectiveness Research at Children's Hospital and the Hospital for Sick Children are available to perform the statistical analysis. This study will use a retrospective cohort design. BMI will be categorized into one of three groups: underweight will include BMI <10percentile overweight BMI >95 percentile and others will be classified as middleweight. Although dose adjustment for individual patients in not available, the actual chemotherapy dose administered is available for each patient. Thus, all analyses will include actual chemotherapy dose delivered as a covariate. Dose adjustment will be explored by inferring expected dose from the conditioning regimen used, patient height, and patient weight. Estimated dose adjustment will be described with descriptive statistics. Univariate analysis will be used to describe the study population. Bivariate analysis will evaluate differences in the distribution of covariates including administered chemotherapy dose between

85


BMI groups. Day 100 and overall treatment related mortality will be summarized overall and by BMT category. Cumulative incidence analysis will be used to describe graphically outcome by BMI category. Cox proportional hazards models will be used to analyze the effect of BMI on the outcomes of interest after controlling for clinically relevant covariates. In order to determine whether the effect of obesity on survival differs depending on chemotherapy dose intensity, the interaction between chemotherapy dose delivered and overweight status will be examined with Cox proportional hazards models.

7.0 REFERENCES:

1. Joliffe D. Extent of overweight among US children and adolescents from 1971 to 2000.

International Journal of Obesity and Related Metabolic Disorders 28:4-9, 2004. 2. Childhood Obesity. Parliamentary Office of Science and Technology. Sept 2003, 205. 3. Nafziger AN, Stenlund H, Wall S, et al. High obesity incidence in northern Sweden: How

will Sweden look by 2009? Eur J Epidemiol 21: 377-382, 2006. 4. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world- A growing

challenge. N Eng J Med 356: 213-215, 2007. 5. Bulley S, Gassas A, Dupuis IL, et al. Inferior outcomes for overweight children undergoing

allogeneic stem cell transplantation. Br J Haematol 140:214-217, 2007. 6. Navarro WH. Impact of obesity in the setting of high dose chemotherapy. Bone Marrow

Transplant 31: 961-966, 2003. 7. Gibbs JP, Gooley T, Corneau B et al. The impact of obesity and disease on busulfan oral

clearance in adults. Blood 93: 4436-4440, 1999. 8. Tarella C, Caracciolo D, Gavarotti P, et al. Overweight as an adverse prognostic factor for

non-Hodgkin’s lymphoma patients receiving high dose chemotherapy and autograft. Bone Marrow Transplant 26: 1185-1191, 2000.

9. Meloni G, Proia A, Capria S, et al. Obesity and autologous stem cell transplantation in acute myeloid leukemia. Bone Marrow Transplant 28: 365-367, 2001.

10. Fleming DR, Rayens MK, Garrison J. Impact of obesity on allogeneic stem cell transplant patients: A matched case-controlled study. J Am Med 102:265-268, 1997.

86


Table 1. Characteristics of patients (5-18) who recieved an allogeneic bone marrow transplant from an HLA-identical sibling or an unrelated donor for AML, CML or MDS between 1990 and 2007 and reported to the CIBMTR.

Characteristics of patients UnderweightAt risk for

underweight Normal At risk for overweight

Morbidly overweight

Number of patients 289 561 1533 1049 513Age at transplant, median (range), years 13 (5 - 18) 13 (5 - 18) 12 (5 - 18) 12 (5 - 18) 11 (5 - 18)

5-10 93 (32) 196 (35) 580 (38) 458 (44) 246 (48)11-15 113 (39) 223 (40) 562 (37) 381 (36) 175 (34)15-18 83 (29) 142 (25) 391 (26) 210 (20) 92 (18)

Male sex 193 (67) 348 (62) 872 (57) 615 (59) 338 (66)Karnofsky score

<90 56 (19) 90 (16) 182 (12) 136 (13) 59 (12)≥90 227 (79) 461 (82) 1297 (85) 879 (84) 442 (86)

Missing 6 ( 2) 10 ( 2) 54 ( 4) 34 ( 3) 12 ( 2)Disease

Acute myelogenous leukemia or anll 90 (31) 157 (28) 450 (29) 269 (26) 108 (21)Acute lymphoblastic leukemia 120 (42) 249 (44) 683 (45) 583 (56) 303 (59)Chronic myelogenous leukemia 55 (19) 106 (19) 295 (19) 135 (13) 68 (13)Myelodysplastic-myeloprolif.disorder 24 ( 8) 49 ( 9) 105 ( 7) 62 ( 6) 34 ( 7)

Disease status at transplant AML/ALL/CML Early 169 (58) 284 (51) 776 (51) 455 (43) 194 (38)AML/ALL/CML Intermediate 84 (29) 215 (38) 619 (40) 518 (49) 279 (54)AML/ALL/CML advanced 11 ( 4) 12 ( 2) 30 ( 2) 13 ( 1) 5 (<1)MDS early 7 ( 2) 9 ( 2) 27 ( 2) 24 ( 2) 9 ( 2)MDS Advanced 16 ( 6) 36 ( 6) 72 ( 5) 28 ( 3) 18 ( 4)Missing 2 (<1) 5 (<1) 9 (<1) 11 ( 1) 8 ( 2)

Ethnicity/Race White 165 (57) 367 (65) 1085 (71) 742 (71) 363 (71)African american-black 9 ( 3) 26 ( 5) 73 ( 5) 49 ( 5) 35 ( 7)Hispanic 5 ( 2) 20 ( 4) 80 ( 5) 64 ( 6) 27 ( 5)Asian 35 (12) 54 (10) 113 ( 7) 75 ( 7) 25 ( 5)Pacific islanders 2 (<1) 3 (<1) 9 (<1) 3 (<1) 6 ( 1)Middle Eastern/North coast of Africa 52 (18) 56 (10) 100 ( 7) 47 ( 4) 21 ( 4)Unknown 21 ( 7) 29 ( 5) 65 ( 4) 50 ( 5) 28 ( 5)Missing 0 6 ( 1) 8 (<1) 19 ( 2) 8 ( 2)

Time from dx to tx, median (range), mths 7 (<1 - 93) 9 (<1 - 78) 10 (1 - 98) 13 (1 - 103) 16 (<1 - 85)BMI prior to transplant, median (range), Kg/m2

15 (11 - 18) 16 (14 - 19) 18 (15 - 23) 21 (16 - 29) 27 (18 - 39)

Donor type HLA-identical sibling 168 (58) 290 (52) 711 (46) 448 (43) 179 (35)Other related 23 ( 8) 53 ( 9) 135 ( 9) 85 ( 8) 42 ( 8)Unrelated donor 98 (34) 218 (39) 687 (45) 516 (49) 292 (57)

87


Table 1. Continued.

Characteristics of patients Underweight At risk for underweight

Normal At risk for overweight

Morbidly overweight

Region US 77 (27) 217 (39) 693 (45) 580 (55) 338 (66)Canada 9 ( 3) 26 ( 5) 85 ( 6) 59 ( 6) 24 ( 5)Europe 78 (27) 143 (25) 422 (28) 221 (21) 82 (16)Asia 33 (11) 41 ( 7) 76 ( 5) 60 ( 6) 15 ( 3)Australia/New Zealand 22 ( 8) 39 ( 7) 103 ( 7) 60 ( 6) 24 ( 5)Mideast/Africa 59 (20) 63 (11) 92 ( 6) 45 ( 4) 18 ( 4)Central/South America 11 ( 4) 32 ( 6) 62 ( 4) 24 ( 2) 12 ( 2)

Year of transplant 1990-1992 68 (24) 114 (20) 313 (20) 169 (16) 78 (15)1993-1995 61 (21) 136 (24) 358 (23) 242 (23) 116 (23)1996-1998 67 (23) 127 (23) 360 (23) 236 (22) 109 (21)1999-2001 40 (14) 71 (13) 218 (14) 145 (14) 73 (14)2002-2004 33 (11) 60 (11) 167 (11) 132 (13) 72 (14)2005-2007 20 ( 7) 53 ( 9) 117 ( 8) 125 (12) 65 (13)

HLA match status Well matched 21 ( 7) 44 ( 8) 155 (10) 127 (12) 85 (17)Partially matched 82 (28) 180 (32) 528 (34) 363 (35) 179 (35)Mismatched 18 ( 6) 47 ( 8) 139 ( 9) 111 (11) 70 (14)HLA Id sibs 168 (58) 290 (52) 711 (46) 448 (43) 179 (35)

Donor/recipient CMV match Negative/ negative 83 (29) 195 (35) 551 (36) 380 (36) 211 (41)Positive/ positive 105 (36) 184 (33) 418 (27) 287 (27) 118 (23)Positive/ negative 39 (13) 60 (11) 235 (15) 160 (15) 87 (17)Negative/ positive 47 (16) 102 (18) 270 (18) 188 (18) 86 (17)Missing 15 ( 5) 20 ( 4) 59 ( 4) 34 ( 3) 11 ( 2)

Donor/recipient sex match Male/Male 98 (34) 176 (31) 475 (31) 366 (35) 195 (38)Male/Female 94 (33) 172 (31) 396 (26) 248 (24) 141 (27)Female/Male 42 (15) 109 (19) 331 (22) 238 (23) 92 (18)Female/Female 54 (19) 104 (19) 328 (21) 196 (19) 83 (16)

Missing 1 (<1) 0 3 (<1) 1 (<1) 2 (<1)

88


Table 1. Continued.

Characteristics of patients Underweight At risk for underweight

Normal At risk for overweight

Morbidly overweight

Conditioning regimen CY + TBI 156 (54) 319 (57) 906 (59) 677 (65) 352 (69)Bu + CY 103 (36) 171 (30) 446 (29) 248 (24) 103 (20)TBI +- other 26 ( 9) 57 (10) 156 (10) 110 (10) 49 (10)Cy +- other 1 (<1) 2 (<1) 7 (<1) 2 (<1) 1 (<1)Bu +-other 2 (<1) 6 ( 1) 14 (<1) 8 (<1) 8 ( 2)Flud + Atg +-other 0 1 (<1) 0 0 0Lpam +-other 0 1 (<1) 1 (<1) 0 0Other 1 (<1) 4 (<1) 3 (<1) 4 (<1) 0

ATG used? No 243 (84) 475 (85) 1287 (84) 870 (83) 412 (80)Yes 46 (16) 86 (15) 246 (16) 179 (17) 101 (20)

GVHD prophylaxis T-cell depletion 46 (16) 80 (14) 263 (17) 191 (18) 108 (21)CSA + MTX +- other 187 (65) 359 (64) 999 (65) 636 (61) 288 (56)CSA + MMF +-other 0 0 1 (<1) 3 (<1) 0CSA +CORT +-other (not mtx) 12 ( 4) 19 ( 3) 47 ( 3) 42 ( 4) 20 ( 4)CSA +- Other 0 2 (<1) 6 (<1) 3 (<1) 1 (<1)CSA alone 21 ( 7) 48 ( 9) 110 ( 7) 85 ( 8) 33 ( 6)MTX + FK506 13 ( 4) 23 ( 4) 45 ( 3) 46 ( 4) 38 ( 7)MTX + CORT +-other 0 3 (<1) 6 (<1) 4 (<1) 6 ( 1)Fk506 + other (not mtx) 0 6 ( 1) 7 (<1) 9 (<1) 3 (<1)MTX +-other 5 ( 2) 11 ( 2) 36 ( 2) 17 ( 2) 11 ( 2)Other 2 (<1) 4 (<1) 2 (<1) 3 (<1) 0None 2 (<1) 3 (<1) 5 (<1) 3 (<1) 1 (<1)Missing 1 (<1) 3 (<1) 6 (<1) 7 (<1) 4 (<1)

Median follow-up of survivors, range, mths 86 (3-189) 86 (3-221) 84 (1-229) 84 (1-208) 78 (3-198)Abbreviations: Cy= cyclosphosphamide; Bu=Busulfan; TBI=total body irradiation;GVHD=graft vs host disease; TLI= total lymphoid irradiation; flud=fludarabine; Lpam=melphalan; CSA= cyclosporine; MMF= mycophenolate; MTX=methotrexate; FK506= Tacrolimis; BMI=body mass index; HLA= human leukocyte antigen; tx= transplant; mths=months;

89

RRTWC review guidelines for voting on RRT proposals and studies in progress

Proposal objective/Main idea

Is the main purpose and objective(s) of the proposal clearly defined?

Can these objectives be achieved using data from the CIBMTR database?

Does the main idea overlap with an existing or past CIBMTR project?

Does the main idea overlap with a current or published study in the transplant field?

Does this study identify new areas of research?

Will this study impact the transplant community such that it is enough to change current patient practice/treatment or add valuable scientific knowledge to the transplant field?

Patient population/Selection criteria

Is the patient selection criteria appropriate/applicable to stated objectives?

Outcomes and variables to be analyzed

Are the listed outcomes consistent with the stated objectives?

Are additional variables or outcomes needed to achieve the stated objectives?

Are additional data or supplemental data collection needed to achieve the stated objectives of the proposal?

Statistical methodology

Are the stated outcomes measurable and can they be evaluated statistically?

90


Study Proposal 1208-30 Study Title: Comparison of clinical outcomes between Myeloablative And Reduced-Intensity Conditioning for Haploidentical Stem Cell Transplantation Stefan O. Ciurea, MD, The University of Texas, M. D. Anderson Cancer Center,Houston, TX Marcos de Lima, MD, The University of Texas, M. D. Anderson Cancer Center, Houston, TX Hypothesis: Haploidentical stem cell transplantation using reduced-intensity conditioning (RIC) is associated with less treatment-related mortality (TRM) and at least similar outcomes as myeloablative (MA) conditioning.

Specific Aims:

– To describe the outcomes of patients with hematologic malignancies (myeloid and lymphoid) treated with haploidentical stem cell transplantation (≥ 2 antigens mismatch), and identify variables associated with improved survival. Outcomes to be evaluated include: transplant-related mortality, leukemia recurrence leukemia-free survival and overall survival.

– To compare the outcomes of patients treated with a T-cell depleted as compared with a T-cell replete haploidentical graft.

– To determine whether RIC is associated with reduced toxicity and overall at least as effective as MA conditioning for haploidentical stem cell transplantation.

Background: Hematopoietic stem cell transplantation is an effective treatment for advanced hematologic malignancies, both myeloid and lymphoid. An HLA-identical donor is preferred; however a matched sibling or unrelated donor is unavailable for many patients. Mismatched relatives represent a potential donor source of stem cells for such patients, and virtually all patients will have an available haploidentical donor. Historically, haploidentical stem cell transplantation has been limited by the high rates of graft rejection and acute graft-versus-host disease (aGVHD). T-cell depletion decreased the rate of GVHD at the expense of a higher risk of rejection and, in some settings, a reduced graft-versus-leukemia effect with an increased relapse rate and severe infections. Reisner and colleagues reported that “megadoses” of purified CD34+ cells administered with a T-cell depleted graft can overcome major HLA incompatibility and achieve an acceptable rate of engraftment. Aversa et al. demonstrated the feasibility of using high doses of CD34+ cells in patients undergoing myeloablative HaploSCT and concluded that the optimal composition of the haploidentical graft should contain more than 10x106 CD34+ cells/kg and less than 5x104 CD3+ cells/kg body weight. T-cell replete haploidentical transplantation with the use of post transplant high-dose cyclophosphamide for GVHD prophylaxis has been explored by researchers from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. Early clinical studies form this group and the group from Fred Hutchinson Cancer Research Center, indicate favorable outcomes at least for patients with lymphoma. Most studies have used a myeloablative, total body irradiation-based preparative regimens for haploidentical transplants. We and others were concerned about the severe toxicity in this setting with a high rate of transplant-related mortality, particularly in adult patients. A recent review identified median non-relapse mortality (NRM) of approximately 50% in haploidentical stem cell transplant patients treated with myeloablative conditioning. For the purpose of this study MA conditioning is defined as TBI > 6 Gy, Busulfan > 8mg/kg or Melphalan > 140mg/m2. Reduced-intensity preparative regimens have been developed to decrease regimen-related toxicities and allow treatment of older or patients with concurrent medical conditions. The experience with such regimens for haploidentical transplantation, where a more profound immune suppression is required to prevent rejection, has been limited. The purpose of this study is to evaluate the outcomes of RIC

91


preparative regimens for haploidentical stem cell transplantation and to compare these with outcomes of patients treated with MA conditioning in this setting. Significance: This proposal relates to the Bone Marrow Transplantation Cancer Center Program Area goal of improving the efficacy and safety of marrow and stem cell transplantation. This study aims to improve the outcome of patients receiving haploidentical transplants by utilizing data collected by the IBMTR. The large database of the IBMTR will allow estimation of transplant outcomes in these patients with much greater precision than currently available. Additionally, transplant-related complications contributing to morbidity and mortality, commoner in this group of patients, will be identified. Analysis of prognostic factors will likely identify patients most likely to benefit from different types of haploidentical transplantation. The ability to compare diverse transplant strategies should identify those regimens with the highest likelihood of success for certain diseases. Analysis Plan: Eligibility Criteria: This study will include patients with hematologic malignancies who received a haploidentical stem cell transplant from a related donor with ≥ 2 antigen mismatch and reported to the IBMTR. Study period: January 1st 1990 to December 31st 2007. Endpoints: The primary endpoints of these analyses are:

– Hematopoietic recovery:

– Time to neutrophil engraftment - ANC > 0.5 x 109/L for three consecutive days will be the primary measure for comparisons of hematopoietic recovery.

– Time to platelet engraftment - platelet count ≥ 20 x 109/L – Time to platelet count ≥ 100 x 109/L

– Incidence of acute and chronic GVHD: grade II-IV acute GVHD and limited and extensive chronic GVHD.

– Treatment-related mortality: time to death without evidence of disease recurrence. Patients are censored at time of relapse or at last follow-up.

– Disease recurrence: time to onset of disease relapse. Patients will be censored at death in continuous CR or, for patients surviving in continuous complete remission, at the last contact.

– Disease free survival: time to treatment failure (death or relapse). Patients are censored at time of last follow-up.

– Overall survival: time to death. Patients are censored at time of last follow-up. Variables to be Analyzed:

– Continuous variables – Categorical variables

Patient related:

– Age at transplant (A) – Gender (female vs male) (B) – Karnofsky performance score at transplant (<90% vs ≥ 90%) (B)

92


Disease-related (at initial diagnosis): – Leukemias/MDS:

– Cytogenetics (AML, MDS) (good, intermediate, poor prognosis) (B) – Cytogenetics (ALL) (Philadelphia positive vs negative) (B) – AML: Prior hematological disorder (MDS or secondary/therapy-related) (yes/no) (B) – Extramedullary disease (yes/no) (B) – CNS disease? (yes/no) (B)

Disease-related (at the time of transplant): – Disease status transplant (B) – Time from diagnosis to transplant (A) – Ever achieved a first remission? (yes/no) (B) – Time to achieve complete remission (A) – Duration of complete remission (B) – Number of cycles of induction therapy to achieve first complete remission (1 vs >1) for

patients with acute leukemia (B) – Number of chemotherapy courses for patients with lymphoid malignancies (A)

Treatment-related: – Donor age (A) – Donor-recipient gender match (F-M vs M-F vs M-M vs F-F) (B) – Donor type (child/parent/sibling/other) (B) – Donor-recipient HLA-match (# of antigen mismatches) (A) – Donor-recipient CMV status: (-/- vs others) (B) – Conditioning regimen (TBI vs non-TBI) (B) – Conditioning regimen (RIC vs MA) (B) – Conditioning regimen type (A) – Donor-recipient KIR-ligand mismatch (y/n) (B) and direction (HvG or GvH) (B) (if data

available) – Maternal source of mismatched haplotype (yes/no) (B) (if data available) – Infused number of nucleated and CD34+ cells: n/kg recipient weight (A) – Infused number of CD3+ cells: n/kg recipient weight (A) – Source of stem cells: (BM vs PBSC vs both) (B) – Year of transplant (1990-1999 vs 2000-2007) – GVHD prophylaxis (yes/no) (B) – T-cell depletion (yes/no) (B) – Growth factors post transplant: G-CSF or GM-CSF: (yes/no) (B)

Treatment-related - Second transplant (if applicable):

– Second transplant for graft failure? (y/n) (B) – Second transplant - same donor? (y/n) (B) – Disease status at transplant (remission vs not) (B) – Relapse after transplant? (y/n) (B) – GVHD present at time of second BMT? (y/n) (B) – Time from relapse post transplant (A) – Time from transplant (A)

Statistical Methods: Descriptive tables of patient, disease and transplant characteristics will be created. Continuous variables will be reported as medians with ranges, while categorical variables will be reported as absolute numbers and percent of total patients. Whenever applicable, univariate comparisons will be done using Chi-square test for categorical variables and Wilcoxon test for continuous variables. Survival curves for overall survival and leukemia –free survival will be calculated for all patients using the Kaplan-Meier estimator

93


and the variance estimated by Greenwood’s formula. Cumulative incidence rates for leukemia recurrence and transplant-related mortality will be calculated and plotted. The data will be analyzed using Cox proportional hazards models. This method shall build a single model for the outcome of interest as dependent variable and all the relevant exposure variables as adjusting variables. The main effect term for specific aim shall be forced into each model. This will include a term delineating an appropriate cut-off point for duration of remission after first transplant. The proportional hazards assumption for all the variables will be examined using time-varying covariate and graphical approaches. Constructions of stratified proportional variables are identifies. First order interactions between main effect term and other confounding variables will be explored. If this interaction term is significant, then the final model will have an interaction term between the factor and the main effect term and separate inferences about the effect the comparing groups will be made for each level of the confounding factor. The final model constructed by this technique will include all the factors found prognostic of the outcome plus a term for the main effects of interest. The proportional hazards assumption will again be examined and adjustments made for non-proportional hazards as necessary. Due to a considerable number of confounding variables entered in the model, a p value of < 0.01 would be considered significant for any confounder. Likewise, this p-value would be retained in determining significant interaction between main effect term and a significant confounder found. Due to the multi-center nature of the data, test for significant center differences will be tested using random effects of probability models. Analyses will be performed using the procedure PHREG, SAS statistical software program.

References:

1. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354:1813-1826. 2. Powles RL, Morgenstern GR, Kay HE, et al. Mismatched family donors for bone marrow

transplantation as treatment for acute leukemia. Lancet. 1983;8325:612-615. 3. Marmont AM, Horowitz MM, Gale RP, et al. T-cell depletion of HLA-identical transplants in

leukemia. Blood. 1991;78:2120-2130. 4. Aversa F, Tabilio A, Terenzi A, et al. Successful engraftment of T-cell-depleted haploidentical

“three-loci” incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood. 1994; 84:3948-3955.

5. Giralt S, Estey E, Albitar M, et al. Engraftment of allogneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood. 1997;89:4531-4536.

6. Szydlo R, Goldman JM, Klein JP, et al. Results of allogeneic bone marrow transplant for leukemia using donors other then HLA-identical sibling. J Clin Oncol. 1997;15:1767-1777.

7. Aversa F, Tabilio A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA Haplotype. N Eng J Med. 1998;339:1186-1193.

8. Handgrettinger R, Klingebiel T, Lang P, et al. Megadose transplantation of purified peripheral blood CD34(+) progenitor cells from HLA-mismatched parental donors in children. Bone Marrow Transplant. 2001;27:777-283.

9. Aversa F, Terenzi A, Felicini R et al. Haploidentical stem cell transplantation for acute leukemia. Int J Hematol. 2002;76 Suppl(1):165-168.

10. Champlin R, Hesdorffer C, Lowenberg B et al. Haploidentical ‘megadose’ stem cell transplantation in acute leukemia: recommendations for a protocol agreed upon at the Perugia and Chicago meetings. Leukemia. 2002;16:427-428.

11. Kato S, Yabe H, Yasui M, et al. Allogeneic hematopoietic transplantation of CD34+ selected cells from an HLA haploidentical related donor. Along-term follow-up of 135 patients and a comparison of stem cell source between the bone marrow and the peripheral blood. Bone Marrow Transplant. 2000;26:1281-1290.

94


12. Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood. 2001;98:3456-3464.

13. O'Donnell PV, Luznik L, Jones RJ, et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2002;8:377-386.

14. Dobyski WR, Klein J, Flomenberg N, et al. Superior survival associated with transplantation of matched unrelated versus on-antigen mismatched unrelated or highly human-leukocyte antigen-disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: establishinga treatment algorithm for recipients of alternative donor grafts. Blood. 2002;99:806-814.

15. Ruggeri L, Capanni M, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097-2100.

16. van Rood JJ, Loberiza Jr. FR, Zhang MJ, et al. Effect of tolerance to noninherited maternal antigens on the occurrence of graft-versus-host disease after bone marrow transplantation from a parent or and HLA-haploidentical sibling. Blood. 2002;99:1572-1577.

17. Lacerda JF, Martins C, Carmo JA et al. Haploidentical stem cell transplantation with purified CD34+ cells after a chemotherapy-alone conditioning regimen. Biol Blood Marrow Transplant. 2003;9:633-642.

18. Kanda Y, Chiba S, Hirai H, et al. Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (1991-2000). Blood. 2003;102:1541-1547.

19. Spitzer TR, McAfee SL, Dey BR, et al. Nonmyeloablative haploidentical stem-cell transplantation using anti-CD2 monoclonal antibody (MEDI-507)-based conditioning for refractory hematologic malignancies. Transplantation. 2003;75:1448-1751.

20. Mehta J, Singhal S, Gee AP, et al. Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients. Bone Marrow Transplant. 2004; 33:389-396.

21. Aversa F, Terenzi A, Tabilio A ,et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005;23:3447-3454.

22. Bethge WA, Haegele M, Faul C, et al. Haploidentical allogeneic stem cell transplantation in adults with reduced-intensity conditioning and CD3/CD19 depletion: fast engraftment and low toxicity. Exp Hematol. 2006;34:1746-1752.

23. Rizzieri DA, Koh LP, Long GD, et al. Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol. 2007;25:690-697.

24. Koh, LP, Rizzieri DA, Chao NJ. Allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors. Biol Blood Marrow Transplant. 2007; 13:1249-1267.

25. Handgretinger R, Chen X, Pfeiffer M et al. feasibility and outcome of reduced-intensity conditioning in haploidentical transplantation. Ann N Y Acad Sci. 2007;1106:279-289.

26. Ciurea SO, Quareshi SR, Rondon G, et al. Sustained Engraftment Using Fludarabine, Melphalan and Thiotepa Conditioning for Haploidentical Stem Cell Transplantation. Blood. 2007;110;5081a.

27. Ciurea SO, Quareshi SR, Rondon G, et al. Improved outcomes of patients with AML/MDS undergoing haploidentical stem cell transplantation using fludarabine, melphalan and thiotepa (FMT) conditioning chemotherapy. Biol Blood Marrow Transplant. 2008;14:132a.

28. Ciurea SO, de Lima M, Cano P, et al. High Risk of Graft Failure in Patients with Anti-HLA Antibodies Undergoing Haploidentical Stem Cell Transplantation. Submitted for publication.

29. Luznik L, O’Donnell PV, Symons HJ et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008; 14:641-650.

95


30. Burroughs LM, O’Donnell PV, Sandmaier BM, et al. Comparisson of outcomes of HLA-matched related, unrelated, or HLA-haploidentcila related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed of refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2008;14:1279-1287.

31. Ciceri F, Lobopin M, Aversa F, et al. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood. 2008;112:3574-3581.

32. Kaplan EL, Meier P. Nonparametric estimation for incomplete observations. J Am Stat Assoc.1958;53:457-481.

33. Prentice RL, Kalbfleisch JD, Peterson AV, Jr. et al. The analysis of failure times in the presence of competing risks. Biometrics 1978;34(4): 541-554.

34. Cox DR. Regression models and life tables [with discussion]. J R Stat Soc B. 1972;34:187-202.

96


Characteristics of RIC/NMA* vs myeloablative patients with hematologic malignancies who received a haploidentical stem cell transplant from a related donor with ≥ 2 antigen mismatch and reported to

the CIBMTR or John Hopkins transplant center between 1990 and 2009.

Characteristics of patients MA/TCD MA/Non TCD RIC/NST

N% N % N% Number of patients 507 180 99Age at transplant, median (range), years 22 (1 - 60) 29 (1 - 66) 38 (1 - 77)

0-10 134 (26) 25 (14) 8 ( 8)11-20 107 (21) 38 (21) 12 (12)21-30 82 (16) 30 (17) 14 (14)31-40 86 (17) 33 (18) 19 (19)41-50 59 (12) 27 (15) 19 (19)51-60 34 ( 7) 20 (11) 13 (13)>60 5 (<1) 7 ( 4) 13 (13)

Karnofsky score at transplant < 90 303 (60) 103 (57) 68 (69)≥ 90 202 (40) 76 (42) 31 (31)

Missing 2 (<1) 1 (<1) 0Male sex 185 (36) 72 (40) 36 (36)Disease

AML 189 (37) 63 (35) 40 (40)ALL 155 (31) 50 (28) 18 (18)CLL and other leukemia 17 ( 4) 2 ( 1) 6 ( 6)CML 81 (16) 32 (18) 5 ( 5)MDS 40 ( 8) 16 ( 9) 12 (12)

NHL 21 ( 4) 14 ( 8) 18 (18) HD 1 (<1) 0 0 MM 3 (<1) 3 ( 2) 0Donor relationship

Sibling not identical twin 153 (30) 91 (51) 48 (48)Parent of recipient 240 (47) 57 (32) 32 (32)Child of recipient 83 (16) 25 (14) 17 (17)Other relative not specified 31 ( 6) 7 ( 4) 2 ( 2)

Graft type Bone marrow 298 (59) 93 (52) 14 (14)

Peripheral blood 187 (37) 84 (47) 84 (85) BM + PB 22 ( 4) 3 ( 2) 1 ( 1)ATG use?

No 203 (40) 116 (64) 53 (54)Yes 304 (60) 64 (36) 46 (46)

97


Continued.

Characteristics of patients MA/TCD MA/Non TCD RIC/NST

N% N % N% Campath use?

No 7 ( 1) 2 ( 1) 4 ( 4) Yes 26 ( 5) 10 ( 6) 5 ( 5) Missing 474 (93) 168 (93) 90 (91) Year of transplant

1990-1999 352 (69) 92 (51) 20 (20)2000-2009 155 (31) 88 (49) 79 (80)

Conditioning regimen Cy + TBI ± other 363 (72) 72 (40) 19 (19)Cy + Bu ± other 32 ( 6) 57 (32) 3 ( 3)TBI ± other 63 (12) 17 ( 9) 9 ( 9)Cy ± other 5 (<1) 3 ( 2) 20 (20)

Bu ± other 7 ( 1) 10 ( 6) 15 (15) Fludara + Lpam ± other 21 ( 4) 3 ( 2) 20 (20) Fludara + Atg ± other 8 ( 2) 6 ( 3) 2 ( 2)

Fludara ± other 4 (<1) 3 ( 2) 0 Lpam +-other 1 (<1) 0 0 Other 3 (<1) 9 ( 5) 11 (11)GVHD prophylaxis

None (will be checked with teams) 92 (18) 19 (11) 13 (13)CSA + MMF ± other 1 (<1) 9 ( 5) 7 ( 7)CSA + MTX ± other 50 (10) 97 (54) 26 (26)CSA ± other (not MTX) 253 (50) 15 ( 8) 5 ( 5) CSA alone 65 (13) 16 ( 9) 4 ( 4)FK506 + MMF ± other 2 (<1) 11 ( 6) 15 (15)FK506 ± other (not MTX) 3 (<1) 9 ( 5) 17 (17)

FK506 alone 10 ( 2) 0 9 ( 9) MTX alone 0 1 (<1) 0 MTX ± other 3 (<1) 1 (<1) 0 Other 0 2 ( 1) 0 Missing 0 2 ( 1) 0Median follow-up of survivors, median, range months 59 (3-201) 61 (1-195) 31 (3-170)Abbreviations: MTX=methotrexate; TBI= total body irradiation; Bu=busulfan; Cy=cyclophosphamide; Lpam CSA= Cyclosporine; MTX= Methotrexate; FK506=Tacrolimus; LPAM= melphalan; MMF= Mycophenolate; CORT= corticosteroids; HLA= human leukocyte antigen; GVHD=graft vs host disease; RIC=reduced intensity conditioning; NMA=non myeloablative; TCD=t-cell depletion.

98


Characteristics of RIC patients with hematologic malignancies who received a haploidentical stem cell transplant from a related donor with ≥ 2 antigen mismatch and reported John Hopkins

transplant center between 2000 and 2009. Patient characteristics N (eval) Number of patients 203 Age, median (range), years 51 (1-73) Gender

Male 131 Female 72

Disease Acute leukemia

ALL 14 AML 37

Chronic leukemia CLL 19 CML 10

Lymphoma HL 25 NHL 67

Myeloproliferative disorder CMML 4 PV 2

Myelodysplastic syndrome 17 Multiple myeloma 8

Donor relationship Child 66 Sibling or half-sibling 97 Parent

Father 19 Mother 17

Grandparent 1 **None (conditioned but no BMT) 3

Graft source Bone marrow 200

Year of transplant 2000 3 2001 10 2002 10 2003 15 2004 27 2005 28 2006 25 2007 23 2008 44 2009 18

Conditioning Flu 150 mg/m2, Cy 29 mg/kg, TBI 200 203

99


Continued.

Patient characteristics N (eval) GVHD prophylaxis

Cy 50 mg/kg x 1, MMF bid 20 Cy 50 mg/kg x 2, MMF tid 180 None 3

100


Study Proposal 0909-01 Study Title: Survival after second allografting following aMyeloablative Conditioning in patients with relapsed Hematologic malignancies: a CIBMTR report Gorgun Akpek, MD, MHS, FACP, University of Maryland, Greenebaum Cancer Center, Baltimore, MD 21201 Specific Objectives: 1.1 The primary objective of the study is to evaluate overall survival at day 100 and at one-year after

second allogeneic stem cell transplantation following myeloablative conditioning. 1.2 Secondary objectives include rate of complete remission after second allografting, relapse-free

survival, the cumulative incidence of acute and chronic GVHD.

Scientific Justification: Hematopoietic stem cell transplantation (HCT) from related or unrelated donors is a potentially curative treatment modality for patients with malignant hematologic diseases. However, relapse of underlying disease remains a major cause of transplant failure after myeloablative and non-myeloablative allogeneic stem cell transplantation. I just had a young patient with AML in CR-1 who fully relapsed in 3 months following myeloablative perfect HLA-matched allogeneic peripheral stem cell transplantation. I discussed the case in our group. There was no consensus on the most appropriate approach to this patient who still has excellent performance status. I believe we need to re-visit the role of second myeloablative allogeneic stem cell transplantation in patients with hematologic malignancies by analyzing the CIBMTR database. The use of donor lymphocyte infusion (DLI) with or without prior chemotherapy has been the standard treatment approach in post-transplant relapse setting since the initial encouraging data were reported in patient with chronic myelogenous leuekemia. Since then, the scope of DLI application has been expanded and many patients with various hematologic malignancies who relapsed after allogeneic HCT have been treated with DLI. However, it was realized that DLI is not effective in many instances in patients with full blown relapsed disease. The lack of efficacy was much more evident in patients with acute leukemias. Second allogeneic bone marrow transplantation has the reputation of not being very effective because of unacceptable high-toxicity, especially when it is perfomed shortly after the initial transplantation. However, most of the negative results were reported in the era when bone marrow was the only source of stem cell transplantation, the HLA-typing was being performed using low or intermediate resolution techniques. The advances in HLA-typing, understanding the biology and complications of allogeneic stem cell transplantation along with significant improvement in supportive care over the past decade have been the major factors improving the transplant outcome throughout the world. Recent retrospective analyses suggest that second allogeneic stem cell transplantation have a potential therapeutic role in certain group of patients. In 1993, Seattle group evaluated the impact of a second marrow transplant on long-term disease-free survival (DFS) on 77 consecutive patients aged 2 to 51 years who relapsed subsequent to allogeneic marrow transplantation after high-dose chemotherapy and total-body irradiation (TBI). Patients received a second transplant for recurrent chronic myelogenous leukemia (CML) (n = 28), acute myelogenous leukemia (AML) (n = 32), and acute lymphoblastic leukemia (ALL) (n = 15) or lymphoma (n = 2) that used the same marrow donor as the initial transplant. High-dose chemotherapy was used as a preparative regimen for the second transplant. Various GVHD prophylaxis was used. Engraftment occurred in the 74 assessable patients. Severe veno-occlusive disease (VOD) was the most frequent cause of grades 3 and 4 regimen-related toxicity (RRT); it occurred in 20 patients. The probability of death before day 100 from non-leukemic causes was 36%. The probability of relapse after second transplant was 70%, and the DFS rate was 14% (median DFS, 36 months; range, 22 to 87). The DFS rates for ALL, AML, and CML were 8%, 10%, and 25%, respectively. Multivariate analysis showed that the risk of relapse was inversely associated with acute GVHD (relative risk [RR] of relapse = 0.2; P = .0009). No other factor was associated with relapse. DFS was associated with the presence of acute

101


GVHD (RR of treatment failure = 0.5; P = .0085), and a reduction of DFS was associated with severe VOD (RR = 10.6; P = .0001) and those patients older than 10 years (RR = 2.5; P = .0337). It was suggested that younger patients and patients with CML especially should be considered as potential candidates for a second transplant.1 Recently, Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation recently reported the outcome of 170 patients who received second HSCTs for acute leukemia. Engraftment occurred in 97% of patients. Forty-two patients were alive at last follow-up, with a 5-year OS rate of 26%. The 5-year probability for TRM, LFS, and relapse was 46%, 25%, and 59%, respectively. Grade > or = 2 aGVHD occurred in 59% of patients, and chronic GVHD occurred in 32%. In multivariate analysis, diagnosis, interval to relapse after first HSCT > 292 days, aGVHD at first HSCT, complete remission status at second HSCT, use of total-body irradiation at second HSCT, acute GVHD at second HSCT, and use of bone marrow as source of stem cells at second HSCT were associated with better outcome.2 In a very recent analysis of outcome in 144 patients who underwent 2 or more allo-SCT for various reasons including relapse/persistent disease, graft rejection or engraftment failure, 20% patients transplanted survived more then a year with treatment-related mortality of 45.5% as the leading cause of death. Fifty-one (35%) and 16 (11%) of the patients developed acute and chronic GVHD respectively. Factors indicating higher likelihood for survival were nonmalignant disease, a nonrelapse indication for the second SCT, full HLA-matching, and the use of reduced-intensity conditioning (RIC). With a median follow-up of 4.5 years, 25 patients (17.2%) are alive, and 18 are disease-free. 3 Based on the above and other published studies, the second allogeneic stem cell transplantation certainly has a role in achieving durable remissions in some patients. However, the indications of DLI versus second allogeneic HCT following myeloablative conditioning remains to be determined. Our comprehensive analysis will likely to enlighten the transplant community in their decision making process. Study Population: The study population will include all patients who received allogeneic HCT transplant following myeloablative or non-ablative conditioning for the treatment of underlying hematologic malignancies that include AML, ALL, CML, CLL, MDS, MPD, Non-Hodgkin and Hodgkin’s lymphoma, Multiple myeloma between 1989 and 2009. We will identify those who relapsed following the initial transplant and received second allografting from a 6/6 A, B, DRB1 matched related or unrelated donor after a myeloablative conditioning regimen. Myeloablative conditioning regimen will be classified according to the CIBMTR working definition:

– CY+TBI (TBI dose > 500 cGy single dose or TBI dose >800 cGy fractionated) – CY+VP16+TBI (TBI dose > 500 cGy) – BU+CY

GVHD prophylaxis will include a calcineurin inhibitor and second immunosuppressive such as methortrexate, or sirolimus, or ATG. Outcomes: The primary endpoint will be

– Overall survival – Time to death from any cause. Event will be summarized by Kaplan-Meier estimate. Cases will be analyzed at the time of last follow-up. There are no competing risks.

The secondary outcomes to be studied are:

– Neutrophil engraftment - Achievement of a continued absolute neutrophil count (ANC) >500 x 106/L for 3 consecutive days. Death is a competing risk.

– Platelet engraftment - Achievement of a continued platelet count of greater than 20,000 and 50,000 x 109/L. Death is a competing risk.

102


– 30 day early transplant mortality -This is defined as death on or before 30 days post transplant. Patients alive at last observation with fewer than 30 days of follow-up are not considered censored for this event.

– 100 day mortality (TRM) - This is defined as death on or before 100 days post transplant. Patients alive at last observation with fewer than 100 days of follow-up are not considered censored for this event.

– Acute GVHD - Development of Grades II-IV and Grades III – IV acute GVHD using Glucksberg system which grades GVHD based on the pattern and severity of abnormalities in skin, gastrointestinal and liver. Event will be summarized by the cumulative incidence estimate. Cases will be analyzed at time of last follow-up. Death is a competing risk.

– Chronic GVHD - Development of symptoms in any organ system fulfilling the criteria of limited vs. extensive chronic GVHD. The event will be summarized by the cumulative incidence estimate. Patients will be analyzed at last follow-up. Death is a competing risk.

– Relapse-free survival - Time to relapse. Event will be summarized by Kaplan-Meier estimate. Cases will be analyzed at the time of last follow-up. Deaths due to transplantation will be competing risks.

Variables to be Analyzed:

Patient-related: – Age – Gender: female vs male – Karnofsky score at second transplant: <90 vs ≥ 90

Disease-related: – Disease at transplant – Disease status at transplant: CR, PR, Persistent disease

Transplant-related: – Year of second transplant (5-year interval periods between 1989 and 2009) – Graft type: BM vs PBSC – Donor type: Related or unrelated – Donor: Same donor or different donor – Conditioning at initial transplant: Myeloablative or non-myeloablative – GvHD prophylaxis: Standard vs. non-standard – Donor/recipient sex match: M-M vs. M-F vs. F-M vs. F-F – Donor/recipient CMV status: -/- vs. others. – HLA match status: well matched vs. partially matched – Nucleated cell dose, CD34 cell dose.

Study Design and Statistical Considerations: The study proposed here will analyze CIBMTR data to address the working hypothesis that second allografting following myeloablative conditioning is associated with durable (>1 year) remission and survival in certain group of patients. Recent transplants (after year 1999), HLA-match sibling donor, peripheral blood stem cells may yield better survival and lower transplant-related mortality as compared to those done before 1999, matched unrelated donor, and bone marrow stem cells, respectively. Medians and ranges will be tabulated for continuous demographic variables and percentages for categorical demographic variables. Time to neutrophil and platelet engraftment will be described using cumulative incidence estimates. Overall survival will be calculated using Kaplan Meier estimates. Acute and chronic GVHD will be described using cumulative incidence estimates. We will calculate 95% confidence intervals for each outcome at specified time points separately for the two groups. We will adjust for covariates that may influence the study endpoints using Cox proportional hazards regression models. The proportional hazards assumption will be assessed for each variable using time-dependent or graphical approach. Time-dependent covariates will be used when non proportional hazards are detected, where the best-fitting model with time-varying risk coefficients will be found by

103


maximizing the partial likelihood. Forward (I would use backward if it is okay with you) stepwise regression with alpha=0.05 will be used to build models. Two way interactions will be checked between the main effect and all other variables in the model. References:

1. Radich JP, Sanders JE, Buckner CD, et al. Second allogeneic marrow transplantation for patients with recurrent leukemia after initial transplant with total-body irradiation-containing regimens. JCO 1993 Feb;11(2):304-13.

2. Bosi A, Laszio D, Labopin M. Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. JCO 2001 Aug 15;19(16):3675-84.

3. Kedmi M, Resnick IB, Dray L. et al. A retrospective review of the outcome after second or subsequent allogeneic transplantation. Biology of Blood and Marrow Transplantation 2009 Apr;15(4):483-9.

104


Characteristics of patients who received a second allogeneic transplant from an unrelated or related donor as treatment for relapse or persistent disease following a first allogeneic transplant

between 1989 and 2008 and reported to the CIBMTR.

Characteristics of patients 1st transplant 2nd transplant

N% N % Number of patients 1056Patient age, median (range), years 32 (<1 - 64)

<10 151 (14) 151 (14)11-20 159 (15) 159 (15)21-30 182 (17) 182 (17)31-40 227 (21) 227 (21)41-50 209 (20) 209 (20)51-60 104 (10) 104 (10)>60 24 ( 2) 24 ( 2)

Male sex 627 (59) 627 (59)Karnofsky score

<90 255 (24) 533 (50)≥90 786 (74) 483 (46)Missing 15 ( 1) 40 ( 4)

Disease Acute myelogenous leukemia or anll 426 (40) 426 (40)Acute lymphoblastic leukemia 185 (18) 185 (18)CLL 14 ( 1) 14 ( 1)Chronic myelogenous leukemia 250 (24) 250 (24)Myelodysplastic-myeloprolif.disorder 100 ( 9) 100 ( 9)Other acute leukemia 8 (<1) 8 (<1)Non hodgkin lymphoma 38 ( 4) 38 ( 4)Hodgkin lymphoma 9 (<1) 9 (<1)Plasma cell disorder/multiple myeloma 26 ( 2) 26 ( 2)

Reason for second transplant Persistent malignancy 90 ( 9)Recurrent malignancy 966 (91)

Donor type HLA identical sib 938 (89) 927 (88)Unrelated Donor 118 (11) 129 (12)

Graft type BM 733 (69) 299 (28)PB 306 (29) 741 (70)CB 17 ( 2) 16 ( 2)

105


Continued.


N% N % Year of transplant

1989-1993 263 (25) 151 (14)1994-1998 458 (43) 428 (41)1999-2003 266 (25) 368 (35)2004-2009 69 ( 7) 109 (10)

Donor/recipient sex match Male/male 405 (38) 399 (38)Male/female 221 (21) 223 (21)Female/male 231 (22) 223 (21)Female/female 195 (18) 201 (19)

Missing 4 (<1) 10 (<1)Donor/recipient CMV match

Negative 342 (32) 252 (24)Positive 403 (38) 365 (35)+ve/-ve 108 (10) 77 ( 7)-ve/+ve 151 (14) 154 (15)Unknown 52 ( 5) 208 (20)

GVHD prophylaxis T-cell depletion 136 (13) 36 ( 3)CSA + MTX +- other 649 (61) 166 (16)CSA + MMF +-other 31 ( 3) 15 ( 1)CSA +CORT +-other (not mtx) 60 ( 6) 51 ( 5)CSA +- Other 3 (<1) 4 (<1)CSA alone 76 ( 7) 141 (13)MTX + FK506 47 ( 4) 23 ( 2)MTX + CORT +-other 4 (<1) 7 (<1)Fk506 + other (not mtx) 22 ( 2) 21 ( 2)MTX +-other 15 ( 1) 29 ( 3)Other 7 (<1) 53 ( 5)None (Includes DLI patients) 4 (<1) 504 (48)Missing 2 (<1) 6 (<1)

Conditioning regimen intensity Traditional ablative 841 (80) 403 (38)RIC 78 ( 7) 89 ( 8)Non-myeloblative 37 ( 4) 36 ( 3)Non-traditional ablative 81 ( 8) 93 ( 9)Other 18 ( 2) 146 (14)

No conditioning regimen listed 289 (27)

106


Continued.


N% N % Conditioning regimen

CY + TBI 415 (39) 97 ( 9)Bu + CY 450 (43) 119 (11)TBI +- other 67 ( 6) 66 ( 6)Cy +- other 25 ( 2) 55 ( 5)Bu +-other 61 ( 6) 53 ( 5)Fludara + Lpam ±other 14 ( 1) 20 ( 2)Fludara + Atg ±other 4 (<1) 3 (<1)Fludara ±other 4 (<1) 54 ( 5)Lpam ±other 3 (<1) 36 ( 3)Cytarabine ±other 1 (<1) 69 ( 7)VP16 ±other 0 18 ( 2)Other not specified 11 ( 1) 36 ( 3)No conditioning drugs listed 1 (<1) 430 (41)

Patients received DLI as second transplant? No N/A 653 (62)Yes, .DCI reported in registration N/A 96 ( 9)Yes By algorithm N/A 255 (24)

No GvHD prohylaxis used (needs to be checked) N/A 52 ( 5)Median follow-up of survivors, range, months 108 (9-225) 75 (2-217)Abbreviations: CSA= Cyclosporine; MTX= Methotrexate; FK506=Tacrolimus; GVHD= graft vs host disease ; HLA= human leukocyte antigen.

107


Study Proposal 1009-05

Study Title: C-reactive Protein (CRP) To Predict Non-relapse Mortality after Allogeneic Hematopoietic Cell Transplantation (HCT) Andrew Artz, MD, MS, University of Chicago, Chicago, IL

Specific Aims: – To determine the variability in c-reactive protein (CRP) levels prior to allogeneic hematopoietic cell

transplant (HCT) conditioning. – To evaluate the prognostic significance of pre-HCT CRP levels on non-relapse mortality (NRM) – To quantify the prognostic impact of pre-HCT CRP levels HCT related toxicity and acute GVHD – To assess the influence of pre-HCT CRP levels on overall survival – To establish an optimal cutpoint for pre-HCT CRP levels to independently predict NRM

Scientific Justification: Numerous advances including reduced intensity conditioning, better supportive care, and older recipients have promoted HCT for older and less fit individuals 1. However, toxicity and non-relapse mortality remain a considerable if not the largest obstacle in expanding recipient eligibility 2-6. Non-recipient factors strongly influence HCT toxicity such as the conditioning regimen 7 and immunosuppression as well as donor factors of HLA matching 8, donor source 9, and stem cell yield 10. In the modern era of HCT for older and less fit individuals, emerging data have highlighted the importance of recipient health on tolerance. Although age is the most frequently used measure of recipient health, comorbidity and performance status (PS) are surrogates of health status that may predict toxicity 3,4,11,12. Unfortunately, comorbid measures have limited discriminative capacity and have not been easily reproducible 11-17 and significantly impaired PS (e.g. karnofsky <80%) is found in less than 10% of patients undergoing RIC HCT 11,18. Thus, simple and readily available validated measures of recipient health that predict HCT tolerance remain sorely needed. Serum inflammatory biomarkers hold tremendous promise as novel and reproducible prognostic factors for HCT tolerance. C-reactive protein (CRP) and interleukin-6 (IL-6) are two readily assayed and widely studied biomarkers. CRP is a hepatically synthesized acute phase reactant and IL-6 is a pro-inflammatory cytokine that mediates systemic inflammation 19. Outside of HCT, higher CRP and IL-6 have consistently predicted poor outcomes of impaired functional status 20-24, increased risk of cardiovascular outcomes 25,26 and death 27-29. Rising or increased inflammatory biomarkers after HCT conditioning may predict for HCT related complications30-33 and relapse 34. Available cryopreserved sera allowed us to study the impact of CRP and IL-6 levels among 81 and 79 patients respectively who underwent a uniform RIC regimen 13,35. CRP values ranged from 0.17 to 180 mg/L with a median of 18.5 mg/L. IL-6 values ranged from 10 to 2258 pg/mL, with a median of 78.3 pg/mL. Using a dichotomous variable, CRP values above the median predicted for more grade 3 to 4 hepatic toxicity (P = 0.01), longer HCT hospital stay (P = 0.005), more aGVHD (P = 0.003), greater non-relapse mortality (NRM) (P =0.01) and inferior overall survival (P =0.02). CRP showed a non-significant association with infection (P = 0.09). Pre-conditioning IL-6 levels were not statistically significant associated with morbidity or mortality after HCT. After adjusting for age, HCT-CI, PS, and active disease at transplantation, elevated CRP levels predicted for worse NRM (P = 0.04) but were not statistically associated with inferior OS (P = 0.09). Fortunately, these inflammatory biomarkers are quite stable and ideally suited for observational studies using cryopreserved samples. For example, CRP was stable for 5 days at 4 and 21 °C in plasma and whole blood and for 5 freeze-thaw cycles 36. Moreover, epidemiologic studies have analyzed CRP from sera after around one decade of freezing and still detected clinically significant differences in outcomes by CRP levels29.

108


These data strongly support performing a validation study in the CIBMTR. Confirming elevated CRP as an independent marker of HCT related toxicity would promote risk stratification of recipients which could be instrumental not only for individual decision making but for all registry and comparative analyses. Patient Eligibility: We recognize the availability of cryopreserved samples for CRP analysis will dictate the study population. We propose creating a fairly homogenous study population of adults 18 years or older who received an allogeneic HCT for AML or MDS between 2001 and 2008. We will consider AML patients in any remission at the time of transplantation and MDS patients with a blast count < 5%. Peripheral blood stem cell (PBSC) and bone marrow (BM) will be acceptable. Both reduced intensity and myeloablative conditioning will be of interest. Cord blood transplants, syngeneic donors, and patients having a prior autologous or allograft will be excluded. Variables to be collected included age, recipient sex, karnofsky PS, disease, disease, disease status, time from diagnosis to HCT, year of transplant, donor relation, HLA match, PBSC or BM, Ablative versus reduced intensity/non-ablative, and T-cell depletion or not. Outcome variables include NRM, specific causes of death of NRM (e.g., infection), acute GVHD, disease free survival (DFS), and overall survival (OS)

Data Collection: The information requested is routinely collected on the data submission forms.

Sample Requirements: CRP analysis requires 25 uL of either sera or plasma cryopreserved at -20 C. Because this is a protein based assay, no DNA or specific number of cells is required.

Study Design: – CRP analysis. The CRP ELISA will follow the manufacturer’s recommendations. In our laboratory,

we have used the Invitrogen Immunoassay Kit (Camarillo, CA) for human CRP (catalog KHA0032/KHA0031). The assay requires 25 uL of sample (per patient). Accounting for dilutions and the CRP optical standard, samples can be analyzed from 23 patients with a 96 well plate. We have extensive experience at the University of Chicago performing CRP analysis on cryopreserved samples in the Wickrema laboratory. However, this is a standard ELISA and we are amenable to having the test performed elsewhere to minimize shipping and transportation costs. Many commercially available CRP kits are available and this could be ideally performed at the time of analysis of samples for other studies. Although CRP is a highly validated assay and frequently used in retrospective studies, we are also performing a matched pair analysis to ensure no deterioration with cryopreservation after 1 – 2 years.

– Statistical Analysis: Descriptive analysis of CRP levels will be performed. CRP will be correlated with each covariate. We will test CRP thresholds on unadjusted NRM, specifically at 10 mg/L, 18 mg/L, the median, and tertiles to define the optimal cutpoints. In our initial analysis, a cutpoint of 10 mg/L was similar to the median value of 18.5 mg/L. The primary outcome will be whether elevated CRP levels as a dichotomous variable are associated with increased day 2 year NRM. Hazard ratios (HR) will be compared by log-rank test. Univariate models will be created to assess the impact of CRP levels on NRM at day 100, NRM at 2 years, specific causes of NRM, acute GVHD, DFS, and OS. Multi-variate models for 2 year NRM will be created with CRP. A stepwise forward method will be used to build the regression model. The cumulative incidence of 2 year NRM by conditioning regimen (ablative versus not) will be created for low versus high CRP and the difference assessed by the log-rank test. We also will assess whether recipient age, performance status, or CRP levels best predict NRM using the c-statistic.

– Sample size estimates have been devised with the assistance of CIBMTR staff. In our initial report, elevated CRP was associated with a HR of 3.1 (95% CI: 1.3 – 7.5) and the cumulative incidence day 180 NRM was 32% for CRP above the median as opposed to only 10% for those with lower CRP

109


levels (P = 0.013). We are seeing similar effect sizes in a recent analysis of 60 more patients. In the registry setting, a larger sample will be required as we expect less pronounced differences in outcome by CRP, lower median CRP values as we will exclude active disease, and we plan on multivariable adjustment and stratified analysis. Based on our pilot data of 81 patients with CRP levels, the non-relapse mortality (NRM) rate @ year 2 after HCT CRP values below the median group is approximately 20% and HCT for high CRP values is approximately 40%. The total required sample sizes using 2-sided Log-rank test to detect the same difference in NRM @ year 2 after HCT with a significance level of 0.05 for various power levels is given below.

Power (%) Total sample size

48 79 77 158 90 240 97 316

Overall survival is a secondary endpoint as our primary interest rests on evaluating CRP as a predictor of transplant toxicity via NRM. Overall survival (OS) will be explored as well. We assume OS @ year 3 after HCT is approximately 60% for low CRP patients and 40% for high CRP patients based on our own data. The total required sample sizes using 2-sided Log-rank test to detect the same difference in survival rates @ year 3 after HCT with a significance level of 0.05 for various power levels is given below.

a. b. c. d.

Power (%) Total sample size 43 79 70 158 85 240 95 316

– Limitations. The largest limitation will be availability of cryoproserved samples. Samples also may

have been obtained at different intervals which may influence results. The analysis will require interrogation of CRP values and could benefit from a test set and validation set, should the sample size allow. Nevertheless, even without a validation set, the analysis is highly relevant and worth investigating. The EBMTR could perform a validation study. One could limit the analysis to older recipients (e.g., age 40 and greater) of reduced intensity/non-myeloablative regimens. To the extent toxicity remains problematic across ages and conditioning regimens and we lack robust measures of recipient health, we believe a simple, reproducible, inexpensive assay such as CRP warrants evaluation in a representative sample. Comorbidity would be useful as a covariate but will not be available. However, our own data support CRP as independent of comorbidity in predicting NRM and this will clearly be relevant in future analysis. Finally, additional biomarkers are emerging such as ferritin that warrant comparison to CRP and other biomarkers.

References: 1. van Besien K, Artz A, Stock W: Unrelated donor transplantation over the age of 55. Are we

merely getting (b)older? Leukemia 19:31-3, 2005 2. Yanada M, Emi N, Naoe T, et al: Allogeneic myeloablative transplantation for patients aged 50

years and over. Bone Marrow Transplant 34:29-35, 2004 3. Sorror ML, Maris MB, Storer B, et al: Comparing morbidity and mortality of HLA-matched

unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities. Blood 104:961-8, 2004

110


4. Diaconescu R, Flowers CR, Storer B, et al: Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood 104:1550-8, 2004

5. Alyea EP, Kim HT, Ho V, et al: Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood 105:1810-4, 2005

6. Aoudjhane M, Labopin M, Gorin NC, et al: Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia 19:2304-12, 2005

7. Wong R, Giralt SA, Martin T, et al: Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years. Blood 102:3052-9, 2003

8. Lee SJ, Klein J, Haagenson M, et al: High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 110:4576-83, 2007

9. Schmitz N, Beksac M, Hasenclever D, et al: Transplantation of mobilized peripheral blood cells to HLA-identical siblings with standard-risk leukemia. Blood 100:761-7, 2002

10. Pulsipher MA, Boucher KM, Wall D, et al: Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood 114:1429-36, 2009

11. Artz AS, Pollyea DA, Kocherginsky M, et al: Performance status and comorbidity predict transplant-related mortality after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 12:954-64, 2006

12. Sorror ML, Maris MB, Storb R, et al: Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106:2912-9, 2005

13. Artz AS, Wickrema A, Dinner S, et al: Pretreatment C-reactive protein is a predictor for outcomes after reduced-intensity allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 14:1209-16, 2008

14. Lim ZY, Ho AY, Ingram W, et al: Outcomes of alemtuzumab-based reduced intensity conditioning stem cell transplantation using unrelated donors for myelodysplastic syndromes. Br J Haematol 135:201-9, 2006

15. Guilfoyle R, Demers A, Bredeson C, et al: Performance status, but not the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), predicts mortality at a Canadian transplant center. Bone Marrow Transplant, 2008

16. Majhail NS, Brunstein CG, McAvoy S, et al: Does the hematopoietic cell transplantation specific comorbidity index predict transplant outcomes? A validation study in a large cohort of umbilical cord blood and matched related donor transplants. Biol Blood Marrow Transplant 14:985-92, 2008

17. Sorror ML, Giralt S, Sandmaier BM, et al: Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood 110:4606-13, 2007

18. Gomez-Nunez M, Martino R, Caballero MD, et al: Elderly age and prior autologous transplantation have a deleterious effect on survival following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results from the Spanish multicenter prospective trial. Bone Marrow Transplant 33:477-82, 2004

19. Gauldie J, Richards C, Harnish D, et al: Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci U S A 84:7251-5, 1987

111


20. Mantovani G, Madeddu C, Gramignano G, et al: Association of serum IL-6 levels with comprehensive geriatric assessment variables in a population of elderly cancer patients. Oncol Rep 11:197-206, 2004

21. Penninx BW, Kritchevsky SB, Newman AB, et al: Inflammatory markers and incident mobility limitation in the elderly. J Am Geriatr Soc 52:1105-13, 2004

22. Ridker PM, Hennekens CH, Buring JE, et al: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836-43, 2000

23. Reuben DB, Judd-Hamilton L, Harris TB, et al: The associations between physical activity and inflammatory markers in high-functioning older persons: MacArthur Studies of Successful Aging. J Am Geriatr Soc 51:1125-30, 2003

24. Ferrucci L, Harris TB, Guralnik JM, et al: Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc 47:639-46, 1999

25. Ridker PM, Rifai N, Stampfer MJ, et al: Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101:1767-72, 2000

26. Vasan RS, Sullivan LM, Roubenoff R, et al: Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation 107:1486-91, 2003

27. Shlipak MG, Wassel Fyr CL, Chertow GM, et al: Cystatin C and mortality risk in the elderly: the health, aging, and body composition study. J Am Soc Nephrol 17:254-61, 2006

28. Reuben DB, Cheh AI, Harris TB, et al: Peripheral blood markers of inflammation predict mortality and functional decline in high-functioning community-dwelling older persons. J Am Geriatr Soc 50:638-44, 2002

29. Harris TB, Ferrucci L, Tracy RP, et al: Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 106:506-12, 1999

30. Schots R, Kaufman L, Van Riet I, et al: Proinflammatory cytokines and their role in the development of major transplant-related complications in the early phase after allogeneic bone marrow transplantation. Leukemia 17:1150-6, 2003

31. Min CK, Lee WY, Min DJ, et al: The kinetics of circulating cytokines including IL-6, TNF-alpha, IL-8 and IL-10 following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 28:935-40, 2001

32. Pihusch M, Pihusch R, Fraunberger P, et al: Evaluation of C-reactive protein, interleukin-6, and procalcitonin levels in allogeneic hematopoietic stem cell recipients. Eur J Haematol 76:93-101, 2006

33. Fuji S, Kim SW, Fukuda T, et al: Preengraftment serum C-reactive protein (CRP) value may predict acute graft-versus-host disease and nonrelapse mortality after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 14:510-7, 2008

34. Min CK, Kim SY, Eom KS, et al: Patterns of C-reactive protein release following allogeneic stem cell transplantation are correlated with leukemic relapse. Bone Marrow Transplant 37:493-8, 2006

35. van Besien K, Artz A, Smith S, et al: Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 23:5728-38, 2005

36. Hartweg J, Gunter M, Perera R, et al: Stability of soluble adhesion molecules, selectins, and C-reactive protein at various temperatures: implications for epidemiological and large-scale clinical studies. Clin Chem 53:1858-60, 2007

112


Characteristics of patients (≥ 18) with pre-transplant serum samples in the NMDP repository who received an allogeneic HCT for AML or MDS from an URD between 2001 and 2008 and

reported to the NMDP. Characteristics of patients N%Total number of patients 497Age at transplant, median (range), years 45 (18 - 66)

18-20 16 ( 3)21-30 63 (13)31-40 89 (18)41-50 146 (29)51-60 143 (29)>60 40 ( 8)

Male sex 260 (52)Karnofsky score

<90 183 (37)≥90 258 (52)Missing 56 (11)

Disease Acute myelogenous leukemia 352 (71)Myelodysplastic/myeloprolif.disordersa 145 (29)

Graft type Bone Marrow 266 (54)Peripheral blood 231 (46)

Year of transplant 2000 33 ( 7)2001 249 (50)2002 208 (42)2003 4 (<1)2006 2 (<1)2007 1 (<1)

Donor/recipient sex match Male/male 178 (36)Male/female 82 (16)Female/male 147 (30)Female/female 90 (18)

Donor/recipient CMV match Negative 143 (29)Positive 117 (24)+ve/-ve 67 (13)-ve/+ve 148 (30)Unknown 22 ( 4)

113


Continued. Characteristics of patients N%HLA match status

Well matched 280 (56)Partially matched 147 (30)Mismatch 69 (14)Unknown 1 (<1)

Conditioning regimen CY + TBI 231 (46)Bu + CY 95 (19)TBI +- other 55 (11)Cy +- other 18 ( 4)Bu +-other 52 (10)Flud + Lpam +-other 23 ( 5)Flud + Atg +-other 2 (<1)Fludara +- other 6 ( 1)Cytarabine +-other 5 ( 1)Other drug not specified 5 ( 1)No drugs given (will be checked with teams 5 ( 1)

GVHD prophylaxis T-cell depletion 49 (10)CSA + MTX +- other 179 (36)CSA + MMF +-other 56 (11)CSA +CORT +-other (not mtx) 9 ( 2)CSA +- Other 1 (<1)CSA alone 7 ( 1)MTX + FK506 133 (27)MTX + CORT +-other 3 (<1)Fk506 + other (not mtx) 41 ( 8)MTX +-other 2 (<1)Other 2 (<1)None (Will be checked with teams) 15 ( 3)

Median follow-up of survivors, range, months 75 (6-102) Abbreviations: CSA= cyclosporine; MMF= mycophenolate; MTX=methotrexate; TBI= total body irradiation; Bu=busulfan; Cy=cyclophosphamide; GVHD= graft vs host disease; Fludara= fludarabine; Lpam=melphalan; FK506= Tacrolimis; Cort=corticosteroids; CMV=cytomegalovirus; HLA=human leukocyte antigen. a MDS disease included subtype: refractory anemia (RA), acquired idiopathic sideroblastic anemia (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEBT), chronic myelomonocytic leukemia (CMMol), proxysmal nocturnal hemoglobinuria (PNH), polycythemia vera; Essential/primary thrombocythemia, myelofiborosis with myeloid metaplasia, Acute myelofibrosis and other MDS/MPD disease.

114


Study Proposal 1009-01 Study Title: Effect of ATG and TBI on outcomes in patients receiving reduced intensity allogeneic transplants. Jack W. Hsu, MD, Shands Cancer Center, University of Florida, Gainesville, FL Specific Aims: To determine the role of ATG and TBI on outcomes in patients who underwent allogeneic stem cell transplant. Primary outcomes to be studied include:

– Day 100 mortality – Non-relapse mortality at 1 year – Cumulative incidence of acute and chronic GVHD

Secondary outcomes will include: – Time to progression – Event free survival – Overall survival

If enough data is available, the following outcomes will also be investigated: – Cumulative incidence of graft failure (primary and secondary) – Time to neutrophil engraftment – Time to platelet engraftment – Day 30 Chimerism (if available)

Scientific Justification: Allogeneic transplant has emerged as a potentially curative approach for many hematologic diseases. Unfortunately, the procedure is associated with considerable toxicity and has usually been reserved for younger patients with no comorbidities. Reduced intensity conditioning (RIC) regimens have been developed to allow older patients and those with comorbidities to proceed towards transplantation and have been used with success.1,2,3,4,5 Currently, it is thought that there are no significant differences in engraftment and survival among the various types of RIC regimens. However, there are some reports that indicate this may not be the case. A retrospective analysis of 59 patients who underwent reduced intensity allogeneic transplant found patients who received a TBI based RIC had a higher percentage of early donor chimerism compared to those who did not (98.8% vs. 87.5% on day 21; 99.3% vs. 84.3% on day 28).6 Another study of 36 patients undergoing RIC for various diseases revealed a higher incidence of mixed chimerism at day 28 after transplant in patients who did not receive a TBI containing RIC regimen.7 In the unrelated setting, an analysis of 20 patients who underwent a matched umrelated donor RIC transplant found an ATG-containing RIC transplant was associated with a higher risk of graft failure compared to a TBI-containing regimen (30 vs. 0%).8 There was no difference in transplant related mortality between the two groups and there was a higher incidence of acute GVHD in the TBI group compared to the ATG group, however, this was not statistically significant. A larger retrospective analysis of 77 patients who underwent RIC transplant revealed in univariate and multivariate analyses, an ATG-containing regimen was significantly associated with a decreased risk of the onset of grades II–IV acute GVHD.9 No statistically significant differences in transplant related mortality or disease progression were seen between the two groups and overall survivals were similar. They did, however, report a late graft failure rate of 20% in the ATG group and cautioned the use of ATG in RIC with unrelated donors. Currently, it is unclear whether the differences in engraftment kinetics and GVHD translate into differences in progression free, event free, and overall survival. This study will attempt to further characterize the differences among regimens which contain TBI versus regimens which contain ATG and

115


regimens which contain neither. If enough data is available, it will also examine the effect of TBI and ATG on the establishment of full donor chimerism. Patient Eligibility Population: The study will include all patients reported to the CIBMTR who underwent reduced intesity allogeneic transplant between 1993 and 2008 for hematologic malignancy. Eligible disease types will include: AML, ALL, CML, CLL, MDS, MPD, NHL, HD, and aplastic anemia. Related, unrelated, and cord blood donor transplants will be included. Syngeneic transplants will be excluded. Outcome Definitions:

– Time to engraftment: Defined as time between day of transplantation and recovery of neutrophils and or platelets.

– Time to progression: Defined as time between day of transplantation and documentation of disease recurrence/progression. Patients alive and disease free will be censored at last follow up. Patients will be stratified according to disease type and donor source.

– Event free survival: event is defined as progression/recurrence, development of GVHD, or death. – Acute/chronic GVHD: cumulative incidence will be estimated. – TRM: time to death without recurrence of disease – Overall survival: time to death. Patients are censored at last follow-up.

Predictor Variables to be Analyzed:

Patient-related – Age at transplantation (≤60 vs. >60) – Karnofsky performance status (<70 vs. ≥70) – Gender (male vs. female)

Disease-related – Disease type (the guiding principle will be inclusion of diseases for which there are sufficient

data) – Initial differentiation will be between lymphoid and myeloid disease. – If enough data is available, analysis will occur among more specific disease categories

(AML vs. ALL vs. CML vs. CLL vs. NHL etc.). – Disease status at time of transplant

Transplant-related – Conditioning regimen (ATG containing vs. Low dose TBI containing vs. both vs. neither)

– Regimen will be restricted to reduced intensity conditioning regimens. – Low dose TBI is defined as ≤ 200 cGy. – If enough data is available, we will also look at alemtuzumab containing regimens both in

general (ATG vs. low dose TBI vs. alemtuzumab) and separately (alemtuzumab vs. alemtuzumab + TBI).

– Donor type (related vs. unrelated vs. cord blood) – HLA matching: Donors will be restricted to HLA identical sibling or unrelated donors. – Stem cell source: PB vs. BM – GVHD prophylaxis (MTX vs. no MTX) – Donor-Recipient CMV status: +/+ vs. +/- vs. -/+ vs. -/- – Donor-Recipient gender match: M-M vs. M-F vs. F-M vs. F-F – Donor chimersim at time of engraftment or day +30: full vs. mixed (provided there is

sufficient data)

116


Data Collection: Patients, disease and transplant related characteristics will be obtained from the CIBMTR database. No additional supplemental data collection is anticipated. Study Design: This is a comparative study to determine whether outcomes of reduced intensity transplant regimens which contain TBI are similar to regimens which contain ATG and those which contain neither. The expectation is no statistically significant differences exist among the three groups. Univariate and multivariate analyses will be performed using the predictor variables for the outcomes to ensure control of potential confounding factors such as donor source, disease type, disease status and GVHD prophylaxis. References:

1. Champlin R, Khouri I, Shimoni A, Molldrem J, et al. Harnessing graft-versus-malignancy: nonmyeloablative preparative regimens for allogeneic haematopoietic transplantation, an evolving strategy for adoptive immunotherapy. Br J Haematol. 2000; 111: 18–29.

2. Childs R, Clave E, Contentin N, et al. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood. 1999; 94: 3234–3241.

3. Giralt S, Thall PF, Khouri I, et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood. 2001; 97: 631–637.

4. McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001; 97: 3390–3400.

5. Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998; 91: 756–763.

6. Junichi Sugita & Junji Tanaka & Aya Hashimoto, et al. Influence of conditioning regimens and stem cell sources on donor-type chimerism early after stem cell transplantation. Ann Hematol. 2008; 87:1003–1008.

7. Miura Y, Tanaka J, Toubai T, et al. Analysis of donor-type chimerism in lineage-specific cell populations after allogeneic myeloablative and nonmyeloablative stem cell transplantation. Bone Marrow Transplantation. 2006; 37: 837–843.

8. Kusumi E, Kami M, Yuji K, et al. Feasibility of reduced intensity hematopoietic stem cell transplantation from an HLA-matched unrelated donor. Bone Marrow Transplantation. 2004; 33: 697–702.

9. Kim W, Matsuo K, Fukuda T, et al. Reduced-intensity unrelated donor bone marrow transplantation for hematologic malignancies. International Journal of Hematology. 2008; 88: 324–330.

117


Characteristics of patients with malignant and non malignant disease who received RIC/NMA conditioning for an allogeneic transplant from an URD or related donor between 1989

and 2008 and reported to the CIBMTR.

Characteristics of patients RIC (N%) NMA (N%)Total number of patients 5817 2524Age at transplant, median (range), years 48 (<1 - 70) 51 (<1 - 73)

<10 317 ( 5) 129 ( 5)11-20 503 ( 9) 223 ( 9)21-30 577 (10) 175 ( 7)31-40 700 (12) 232 ( 9)41-50 1058 (18) 434 (17)51-60 1654 (28) 805 (32)>60 1005 (17) 523 (21)

Missing 3 (<1) 3 (<1)Male Sex 3388 (58) 1545 (61)Karnofsky score

<90 1849 (32) 810 (32)≥90 3689 (63) 1575 (62)

Missing 279 ( 5) 139 ( 6)Disease

AML-acute myelogenous leukemia or anll 1940 (33) 586 (23)ALL-acute lymphoblastic leukemia 385 ( 7) 135 ( 5)CLL 296 ( 5) 325 (13)CML-chronic myelogenous leukemia 631 (11) 158 ( 6)MDS-myelodysplastic-myeloprolif.disorder 937 (16) 260 (10)Other Acute leukemia 7 (<1) 1 (<1)NHL-non hodgkin lymphoma 798 (14) 464 (18)HD-hodgkin lymphoma 76 ( 1) 11 (<1)MYE-plasma cell disorder,multiple myelom 135 ( 2) 71 ( 3)SAA-severe aplastic anemia 612 (11) 513 (20)

Year of transplant 1990-1993 474 ( 8) 39 ( 2)1994-1997 369 ( 6) 101 ( 4)1998-2001 1031 (18) 504 (20)2002-2005 2537 (44) 1267 (50)2006-2008 1406 (24) 613 (24)

Donor type HLA identical sib 2129 (37) 925 (37)Other related 273 ( 5) 103 ( 4)Unrelated Donor 3415 (59) 1496 (59)

Graft type Bone marrow 2067 (36) 692 (27)Peripheral blood 3591 (62) 1687 (67)Cord blood 159 ( 3) 145 ( 6)

118


Continued. Characteristics of patients RIC (N%) NMA (N%)Donor/recipient sex match

Male/male 2172 (37) 965 (38)Male/female 1209 (21) 577 (23)Female/male 1349 (23) 560 (22)Female/female 1060 (18) 411 (16) Missing 27 (<1) 11 (<1)

Donor/recipient CMV match Negative 1404 (24) 625 (25)Positive 2002 (34) 764 (30)+ve/-ve 576 (10) 264 (10)-ve/+ve 1475 (25) 665 (26)

Unknown 360 ( 6) 206 ( 8)GVHD prophylaxis

T cell depletion 490 ( 8) 99 ( 4)CSA + MTX +- other 1789 (31) 573 (23)CSA + MMF +-other 520 ( 9) 844 (33)CSA +CORT +-other (not mtx) 234 ( 4) 70 ( 3)CSA +- Other 22 (<1) 28 ( 1)CSA alone 546 ( 9) 151 ( 6)MTX + FK506 1211 (21) 359 (14)MTX + CORT +-other 15 (<1) 7 (<1)Fk506 + other (not mtx) 679 (12) 261 (10)MTX +-other 27 (<1) 9 (<1)Other 55 (<1) 28 ( 1)None 66 ( 1) 21 (<1)Missing 163 ( 3) 74 ( 3)

HLA match status Well matched 1491 (26) 772 (31)Partially matched 1823 (31) 659 (26)Mismatched 371 ( 6) 167 ( 7)Unknown 3 (<1) 1 (<1)HLA identical sibling 2129 (37) 925 (37)

Conditioning regimen CY + TBI 641 (11) 562 (22)Bu + CY 1149 (20) 0TBI ± other 292 ( 5) 910 (36)Cy ± other 261 ( 4) 1037 (41)Bu ± other 1661 (29) 0Flud + Lpam ± other 1443 (25) 0Flud + Atg ± other 13 (<1) 5 (<1)Fludara ± other 160 ( 3) 9 (<1)

119


Continued. Characteristics of patients RIC (N%) NMA (N%)Conditioning regimen continued

Lpam ± other 174 ( 3) 0 Other regimen not specified 22 (<1) 1 (<1) Cytarabine ± other 1 (<1) 0Campath given?

No 5413 (93) 2328 (92)Yes 404 ( 7) 196 ( 8)

ATG given? No 3893 (67) 1833 (73)Yes 1924 (33) 691 (27)

TBI given? No 4688 (81) 1051 (42)Yes 1129 (19) 1473 (58)

Median follow-up of survivors, range, months 108 (9-225) 75 (2-217)Abbreviations: CSA= Cyclosporine; MTX= Methotrexate; FK506=Tacrolimus; GVHD= graft vs host diseas HLA= human leukocyte antigen.

120


Study Proposal 1209-36 Study Title: Cancers, conditioning, and outcome of patients Li-Fraumeni Syndrome (LFS) receiving blood and marrow transplant. Joshua Schiffman, MD, University of Utah, Salt Lake City, UT Michael Pulsipher, MD, University of Utah, Salt Lake City, UT Specific Aims:

1. To document the cancers of patients with Li-Fraumeni Syndrome who have received blood and marrow transplants who are enrolled in the Center for International Blood and Marrow Transplant Research (CIBMTR).

2. To document the conditioning regimens received by patients with Li-Fraumeni Syndrome who have received blood and marrow transplants who are enrolled in the Center for International Blood and Marrow Transplant Research (CIBMTR).

3. To document the outcome of patients with Li-Fraumeni Syndrome who have received blood and marrow transplants who are enrolled in the Center for International Blood and Marrow Transplant Research (CIBMTR). These outcomes will include both secondary cancers, event-free survival, and over-all survival.

Scientific Justification: Li-Fraumeni Syndrome (LFS) is a rare hereditary cancer syndrome characterized by dominantly inherited susceptibility to diverse neoplasms from infancy throughout life. The “component” cancers of LFS include brain tumors, adrenal cortical carcinomas, leukemias, bone and soft tissue sarcomas, and breast cancer, but almost every type of neoplasm has been shown to occur excessively and at young ages in LFS families.1 Germline mutations in the TP53 gene are identified in 70% of classic families, and about 30% of less dramatically affected kindreds.2 Li and Fraumeni first described the syndrome in 1969, after identifying 4 small families in which siblings or first cousins with childhood soft tissue or bone sarcomas were identified: one parent of each also had early onset cancer of various types.3 LFS kindreds meeting classic criteria include at least one member with sarcoma before age 45, and two other closely related individuals with sarcoma or another cancer before age 45 years. Three variants of LFS have been described that permit some loosening of these criteria, by reducing the required number of relatives or ages at cancer diagnosis, in kindreds designated Li-Fraumeni-like (summarized in Table 1).4

Table 1: Clinical Criteria for LFS and LFL

Classic LFS Criteria (all) LFL Criteria by Birch & Eeles Chompret Criteria

• Proband diagnosed with sarcoma before age 45 years

• A first-degree relative with cancer diagnosed before age 45 years

• Another first- or second- degree relative in the lineage with any cancer before this age or sarcoma at any age.

• Proband with any childhood tumor or sarcoma, brain tumor, or adrenal cortical tumor before age 45 years

• First- or second- degree relative with typical LFS tumors at any age

• First- or second- degree relative with any cancer before age 60 years.

•Proband with LFS tumor before age 36 and

•At least 1 FDR with early cancer or multiple primaries

•OR Proband with ACC at any age regardless of family history

121


Detailed studies of families with LFS have provided information about specific cancer risk associated with the syndrome, whether defined clinically or by documented TP53 mutation. These observations have expanded the tumor spectrum associated with the syndrome to include a wide range of carcinomas (particularly choroid plexus, but also colorectal, thyroid, pancreatic), germ cell tumors, neuroblastomas, and Wilms’ tumor. The UTMD Anderson group has done outstanding work clarifying the effect of gender on cancer risk (penetrance) through two decades of study of their prospective cohort of kindreds identified through a child with childhood sarcoma.5, 6 Hwang et al. estimated the age-specific cancer risks among carriers of germline TP53 mutations. Among the carriers, 12%, 35%, 52%, and 80% developed

cancer by ages 20, 30, 40, and 50 years, respectively, compared with the corresponding cumulative risks of 0.7%, 1.0%, 2.2%, and 5.1% for the 3,201 non carriers at the same ages. Age at first cancer diagnosis was earlier for female carriers than for male carriers (mean age at diagnosis, 29 vs. 40 years). By ages 20, 30, 40, and 50 years, the female carriers had respective cumulative risks of 18%, 49%, 77%, and 93% for the development of cancer, compared with respective cumulative risks of 10%, 21%, 33%, and 68% in the male carriers at the same ages.5 Cancer incidence in the prospectively collected UTMD Anderson LFS families has been shown to increase with succeeding generations, though no obvious explanation has been identified.7 Data from Hisada et al showed that 15% of individuals with LFS had a second cancer, 4% had a third cancer, and 2% had a fourth cancer.8 The authors found that the excess risk of additional primary cancers was mainly for cancers occurred within classic LFS families, with the highest risk observed for survivors of childhood cancers, suggesting that cancer survivors should be closely monitored for early manifestations of new primary cancers.

There have never been any studies specifically investigating the role of blood or marrow transplant in this population of very high risk cancer patients. The only published literature to describe blood or marrow transplant in LFS patients is limited to two single case reports. Mutafoğlu et al. (2000) described a case of extraosseous Ewing's sarcoma that developed 8 years after allogeneic bone marrow transplantation performed for beta-thalassemia major, and the patient's family was found to fulfill the criteria for Li-Fraumeni syndrome.9 Chao et al. (2007) described a 3-year-old boy with a malignant triton tumor (MTT) with detection of a novel germline TP53 mutation; the tumor could not be resected and the patient was successfully treated with intensive induction chemotherapy, irradiation, and high-dose chemotherapy with autologous stem cell transplantation.10

Clinically, patients with LFS are a challenge in the consideration of blood or marrow transplant. Their underlying TP53 mutation makes them more sensitive to conditioning regimens, and would theoretically put them at extremely high risk for secondary malignancies should they survive the transplant. LFS patients do develop cancers that may require treatment. There is currently no standard of care for this minority group of patients. Only by studying their natural history (including the experience of other transplant physicians), will the blood and marrow transplant community be in the position to accurately council and advise appropriate recommendations when patients with LFS require transplant therapy. The area of transplant and LFS remains completely unexplored in the literature.

Patient Eligibility Population: This study would include everyone in the CIBMTR registry, regardless of age, disease, disease stage, years of transplant, graft and donor type, prior treatment, or specific transplant regimens. The only eligibility requirement would include the diagnosis of Li-Fraumeni, clinically or by TP53 mutation testing, either before or after the transplant. A first-degree family member with known LFS would also qualify the patient for inclusion in this study. In addition, we would randomly select 5 matched "controls" for every LFS case in the CIBMTR database. Variables to be included in this study would include: patient age, disease, disease stage, graft and donor type, prior treatment, transplant regimen (including conditioning), graft vs. host disease status, event-free survival, over-all survival, secondary malignancies, and if available, the specific TP53 mutation.

122


Data Collection: This study will not require additional data collection besides the currently collected data on the existing data collection forms available through the CIBMTR Statistical Center. The only exception will be the TP53 mutation which may need to be abstracted from the medical record through supplemental data collection.

Study Design (Scientific Plan): The specific aims of this retrospective study will be addressed through both a descriptive and statistical analysis of the LFS patients. The descriptive portion would provide detailed information about which cancers occur and what conditioning regimens are used in LFS patients. For the statistical analysis, we would use 5:1 controls. These controls would be non-LFS patients selected from the CIBMTR registry who match the clinical parameters of the LFS patients as close as possible for the following variables: age, diagnosis, disease stage, graft and donor type, prior treatment, transplant regimen. We would use two-tailed Fisher's Exact test in order to calculate any differences in outcome (event-free survival, over-all survival, and secondary malignancies). This study will be the first of its kind to provide very important clinical information for LFS patients who may be in need or are considering the possibility of blood or marrow transplant for cure of their cancer. References:

1. Nichols KE, Malkin D, Garber JE, Fraumeni JF, Jr., Li FP. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev 2001;10:83-7.

2. Varley JM, Evans DG, Birch JM. Li-Fraumeni syndrome--a molecular and clinical review. Br J Cancer 1997;76:1-14.

3. Li FP, Fraumeni JF, Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 1969;71:747-52.

4. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009;27:1250-6.

5. Hwang SJ, Lozano G, Amos CI, Strong LC. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet 2003;72:975-83.

6. Wu CC, Shete S, Amos CI, Strong LC. Joint effects of germ-line p53 mutation and sex on cancer risk in Li-Fraumeni syndrome. Cancer Res 2006;66:8287-92.

7. Brown BW, Costello TJ, Hwang SJ, Strong LC. Generation or birth cohort effect on cancer risk in Li-Fraumeni syndrome. Hum Genet 2005;118:489-98.

8. Hisada M, Garber JE, Fung CY, Fraumeni JF, Jr., Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 1998;90:606-11.

9. Mutafoglu Uysal K, Olgun N, Sarialioglu F, Kargi A, Cevik N. A case with extraosseous Ewing's sarcoma: a late effect related to bone marrow transplantation for thalassemia or a component of a familial cancer syndrome? Pediatr Hematol Oncol 2000;17:415-9.

10. Chao MM, Levine JE, Ruiz RE, et al. Malignant triton tumor in a patient with Li-Fraumeni syndrome and a novel TP53 mutation. Pediatr Blood Cancer 2007;49:1000-4.

123


Characteristics of patients with Li-Fraumeni syndrome or with TP53 mutation who received a first allogeneic transplant and reported to the CIBMTR

Characteristics of patients* N%Number of patients 12Age, median (range), years 45 (7 - 64)Male sex 7 (58)Karnofsky score

<90 4 (33)≥90 7 (58)Missing 1 ( 8)

Disease AML-Acute myelogenous leukemia 8 (67)ALL-Acute lymphoblastic leukemia 2 (17)MDS-Myelodysplastic/myeloprolif.disorders 2 (17)

Donor type HLA identical sib 4 (33)Unrelated Donor 8 (67)

Graft type Bone marrow 3 (25)Peripheral blood 8 (67)Cord blood 1 ( 8)

Year of transplant 2001 1 ( 8)2004 2 (17)2005 2 (17)2006 3 (25)2007 4 (33)

GVHD prophylaxis CSA + MTX +- other 2 (17)CSA + MMF +-other 1 ( 8)CSA +CORT +-other (not mtx) 2 (17)MTX + FK506 3 (25)Fk506 + other (not mtx) 2 (17)Other 2 (17)

124


Continued.

Characteristics of patients N%Conditioning regimen

CY + TBI 3 (25)Bu + CY 5 (42)Bu ± other 1 ( 8)Fludara ± Lpam ± other 3 (25)

LFS reported on CIBMTR form as Other predisposing syndrome on disease insert form 7 (47) Other co-existing disease 3 (20) Cytogenetic mutation TP53 or Del p53 2 (33)Median follow-up of survivors, range, months 12 (3-24)Abbreviations: CSA= Cyclosporine; MTX= Methotrexate; FK506=Tacrolimus; GVHD= graft vs host disease ; Bu=busulfan; Cy=cyclophosphamide; LPAM= melphalan; Fludara=fludarabine; LFS= Li-Fraumeni syndrome.

* There were no autologous patients with Li-Fraumeni syndrome.

125


Study Proposal 1209-47 Study Title: Assessment of pulmonary complications post-transplant in association with A1B8DR3 haplotype in allogeneic hematopoietic cell transplant recipients Hong Liu, MD, PhD, Roswell Park Cancer Institute, Buffalo, NY Philip L. McCarthy, MD, Roswell Park Cancer Institute, Buffalo, NY Theresa Hahn, PhD, Roswell Park Cancer Institute, Buffalo, NY 14263

Objectives: – To examine the incidence of pulmonary complications and their association with A1B8DR3

haplotype. – To examine the overall incidence of any pulmonary complications and its association with

A1B8DR3 haplotype. – To examine the incidence of the following pulmonary complication subtypes and their association

with A1B8DR3 haplotype. – bronchiolitis obliterans/lung graft vs. host disease (BO/GvHD), – viral or fungal pneumonia (VFPn), – diffuse alveolar hemorrhage (DAH), – interstitial pneumonitis/ARDS/other non-infectious pulmonary toxicities (IP/ARDS))

– Secondary objectives will include incidence and severity of acute and chronic GvHD, progression-free survival (PFS) and overall survival (OS) and their association with A1B8DR3 haplotype.

Scientific Justification: A1B8DR3 is one of the 3 most common ancestral haplotypes in people of European descent (A1B8DR3 (5.2%), A2B44DR4 (2.1%) and A3B7DR15 (2.6%))1. A1B8DR3 has a known association with autoimmune diseases such as sarcoidosis, Wegener’s granulomatosis2, MPGN, and SLE3; as well as immunodeficiency such as IgA deficiency and common variable immunodeficiency4. We and others have described patients who have developed sarcoidosis post allotransplant with this haplotype 5,6. This may be an unusual manifestation of GvHD. Tumor necrosis factor alpha (TNF-a) is the cytokine most frequently implicated in the pathobiology of acute GvHD and pulmonary complications after HCT and TNF-a polymorphisms are strongly associated with the A1B8DR3 haplotype. We hypothesize that A1B8DR3 haplotype is associated with increased immune-mediated toxicities including GvHD and infection.

Previous retrospective studies from our group have shown that A1B8DR3 haplotype is associated with increased pulmonary toxicities including BO/lung GvHD and VFPn7; increased incidence of acute GvHD8; decreased leukemia free-survival (LFS) and OS9. We propose to investigate the association of A1B8DR3 haplotype with pulmonary complications and other post-transplant outcomes after allogeneic HCT using the CIBMTR database. Investigating the relationship between HLA haplotype and outcome may improve our understanding of the pathogenesis of pulmonary complications, infections, GvHD and provide preliminary data for additional studies.

Study Population: The study population will include adult (>18 yrs) patients reported to the CIBMTR who received at least a 10/10 HLA-matched (high-resolution A, B, C, DRB1, DQB1) unrelated or a 6/6 HLA-matched (A, B, DRB1) related donor allogeneic peripheral blood or bone marrow transplant from 1999 to 2008 (we could make this 2007 if there is not enough follow-up) for any of the following indications: AML, ALL, and MDS. We chose well matched unrelated and related donor allogeneic HCT in order to control for the known effects of HLA mismatches on risk of GvHD and infectious outcomes. This will also yield a

126


donor-recipient pair who are matched on the HLA haplotype. We are limiting the study population to the 3 most common diseases treated with allogeneic HCT in order to reduce disease heterogeneity.

Patients with a prior allogeneic transplant will be excluded. (We can discuss if prior autologous transplants should be excluded.) Patients <18 years will be excluded. Patients receiving umbilical cord blood grafts will be excluded. Ex vivo T-cell depleted transplants will be excluded.

Outcomes: Univariate and multivariate analysis:

– Pulmonary complications: occurrence of any pulmonary complication. Specific Pulmonary complications:

– VFPn: viral or fungal pneumonia documented by positive culture. – DAH: diffuse alveolar hemorrhage – Lung GvHD: bronchiolitis obliterans or other documented lung involvement – IP/ARDS/other non-infectious pulmonary toxicity

– Acute GvHD: Occurrence of overall grade II - IV fulfilling the Consensus criteria for acute GvHD.

– Chronic GvHD: Occurrence of symptoms in any organ system fulfilling the diagnostic criteria for chronic GvHD.

– Progression-free survival: time to treatment failure (death or disease progression). Patients are censored at time of last follow-up if no disease progression occurred post-HCT.

– Overall survival: time to death. Patients are censored at time of last follow-up.

Data Collection: Patient related:

– Age at transplant: continuous – Gender: female vs. male – Karnofsky performance score: <90% vs. ≥90% – HLA haplotype: A1B8DR3 vs. A2B44DR4 vs. A3B7DR15 vs. others

Disease-related: – AML vs. ALL vs. MDS – CIBMTR Disease risk category: low, intermediate, high

Transplant related: – Type of donor: HLA-identical sibling vs. matched unrelated – Conditioning regimen:groups will be defined based on frequency – Source of stem cells: BM vs. PBSC – Donor age: continuous – Donor-recipient gender match: F-M vs. M-F vs. M-M vs. F-F – Donor parity: parous female vs. non-parous female vs. male – Donor-recipient CMV serostatus: -/- vs. -/+ vs. +/- vs. +/+ – GvHD prophylaxis: groups will be defined based on frequency – Planned or unplanned DLI

Study Design: Descriptive tables of patient-, disease-, and transplant-related factors will be prepared and stratified by related vs. unrelated matched donor transplants. These tables will list median and range for continuous variables and percent of total for categorical variables. Probabilities of survival and progression-free survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. Values for other endpoints will be generated using cumulative incidence estimates.

127


The primary outcome measure is time to occurrence of any pulmonary complication. This will be further analyzed as time to occurrence of specific pulmonary complications (ie., GvHD, infectious, hemorrhagic, toxicity). A modified Cox proportional hazard model will be used to determine if these pulmonary outcomes are associated with the presence of A1B8DR3 haplotype stratified by related vs. unrelated matched donor transplants. Other clinically significant covariates, such as age, KPS, disease risk, etc will be tested in the Cox model for statistical significance.

The secondary outcomes measures (time to acute GvHD, chronic GvHD, PFS and OS) will be modeled similar to the primary outcome measure. References:

1. Mori M, Beatty PG, Graves M, Boucher KM, Milford EL. HLA gene and haplotype frequencies in the North American population: the National Marrow Donor Program Donor Registry. Transplantation. 1997 64(7):1017-1027

2. Stassen PM, Cohen-Tervaert JW, Lems SP, Hepkema BG, Kallenberg CG, Stegeman CA. HLA-DR4, DR13(6) and the ancestral haplotype A1B8DR3 are associated with ANCA-associated vasculitis and Wegener's granulomatosis. Rheumatology (Oxford). 2009 Jun;48(6):622-5. Epub 2009 Mar 31

3. Bishof NA, Welch TR, Beischel LS, Carson D, Donnelly PA. DP polymorphism in HLA-A1,-B8,-DR3 extended haplotypes associated with membranoproliferative glomerulonephritis and systemic lupus erythematosus. Pediatr Nephrol. 1993 Jun;7(3):243-6

4. Schroeder HW Jr, Zhu ZB, March RE, Campbell RD, Berney SM, Nedospasov SA, Turetskaya RL, Atkinson TP, Go RC, Cooper MD, Volanakis JE. Susceptibility locus for IgA deficiency and common variable immunodeficiency in the HLA-DR3, -B8, -A1 haplotypes. Mol Med. 1998 Feb;4(2):72-86

5. Sundar KM, Carveth HJ, Gosselin MV, Beatty BG, Colby TV and Hoidal JR. Granulomatous pneumonitis following bone marrow transplantation. Bone Marrow transplantation 2001; 28; 627-630

6. McCarthy PL et al. Sarcoidosis-Associated MHC antigens and the development of cutaneous and nodal granulomas following allogeneic hematopoietic cell transplant. Manuscript in preparation.

7. Liu J, Pukiat S, Hahn TE, Battiwalla M and McCarthy PL. The ancestral haplotype A1B8DR3 is associated with increased incidence of pulmonary complications after allogeneic hematopoietic cell transplantation (HCT). ASBMT 2010 abstract

8. Gupta S, Aggarwal C, McCarthy PL, Padmanabhan S, Battiwalla M, and Hahn TE. Influence of Human Leukocyte Antigen Haplotypes on Acute Graft Versus Host Disease Incidence after Allogeneic Hematopoietic Stem Cell Transplantation. Blood (ASH Annual Meeting Abstracts), Nov 2006; 108: 2887.

9. Aggarwal C, Gupta S, McCarthy PL, Battiwalla M, and Hahn TE. Human leukocyte antigen (HLA) haplotype and single HLA antigen expression in HLA-matched allogeneic hematopoietic stem cell transplantation (alloHSCT) for myeloid diseases: analysis of overall (OS) and progression free survival (PFS). ASBMT 2007 abstract

128

http://www.ncbi.nlm.nih.gov/pubmed/9381524?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1

http://www.ncbi.nlm.nih.gov/pubmed/9381524?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Stassen%20PM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Cohen-Tervaert%20JW%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lems%20SP%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hepkema%20BG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kallenberg%20CG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Stegeman%20CA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Bishof%20NA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Welch%20TR%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Beischel%20LS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Carson%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Donnelly%20PA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Schroeder%20HW%20Jr%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Zhu%20ZB%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22March%20RE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Campbell%20RD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Berney%20SM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Nedospasov%20SA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Turetskaya%20RL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Turetskaya%20RL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Atkinson%20TP%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Go%20RC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Cooper%20MD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Volanakis%20JE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract


Characteristics of AML, ALL & MDS patients with A1B8DR3 haplotype who received a matched bone marrow or peripheral graft from an unrelated donor and reported to the NMDP between

2000 and 2007 Characteristics of patients N (%)Number of patients 812Age at transplant, median (range), years 46 (18 - 71)

18-19 19 ( 2)20-30 146 (18)31-40 130 (16)41-50 196 (24)51-60 200 (25)≥61 121 (15)


<90 257 (32)≥90 478 (59)

Missing 77 ( 9)Disease

AML-acute myelogenous leukemia or anll 459 (57)ALL-acute lymphoblastic leukemia 158 (19)MDS-myelodysplastic-myeloprolif.disorder 195 (24)

Disease status pre transplant AML/ALL early 246 (30)AML/ALL intermediate 238 (29)AML/ALL advanced 129 (16)MDS early 54 ( 7)MDS advanced 82 (10)Other 63 ( 8)


Regimen intensity Ablative 561 (69)RIC 172 (21)NMA 73 ( 9)Other/TBD 6 (<1)

Donor/recipient sex match Male/male 366 (45)Male/female 72 ( 9)Female/male 275 (34)Female/female 99 (12)

129


Continued. Characteristics of patients N (%)Donor/recipient CMV match

Negative 269 (33)Positive 135 (17)Positive/Negative 77 ( 9)Negative/Positive 314 (39)Unknown 17 ( 2)

Condition regimen at transplant CY + TBI 297 (37)Bu + CY 181 (22)TBI +- other 100 (12)Cy +- other 22 ( 3)Bu +-other 125 (15)Flud + Lpam +-other 70 ( 9)Fludara +- other 13 ( 2)Lpam +-other 2 (<1)Other 2 (<1)

GVHD prophylaxis None ( Will be checked with teams) 9 ( 1)T-cell depletion 17 ( 2)CSA + MMF +-other 57 ( 7)CSA + MTX +- other 113 (14)CSA +-other (not mtx) 11 ( 1)CSA alone 4 (<1)FK506 + MMF +- other 114 (14)FK506 + MTX +- other 329 (41)FK506 +- other (not mtx) 59 ( 7)MTX alone 1 (<1)MTX +- other 44 ( 5)

Other/ Missing 54 ( 6)Race/ Ethnicity

White 776 (96)African-American 15 ( 2)Hispanic 4 (<1)Asian 1 (<1)Unknown 2 (<1)Missing 14 ( 2)

130


Continued. Characteristics of patients N (%)Number of match at A, B, C, DRB1, DQ1,

7/10 2 (<1)8/10 11 ( 1)9/10 93 (11)10/10 554 (68)

Missing 152 (19)Number of match at A B DRB1

6/6 full allele match 682 (95)5/6 single allele level mismatch 32 ( 4)5/6 single antigen level mismatch 2 (<1)Two or more mismatch- at lease one allele level mismatch 1 (<1)

Missing Matching groups

10/10 high resolution at A, B, C, DRB1, DQ1, 455 (56)6/6 full allele match 227 (28)Other 130 (16)

Year of transplant 1999 33 ( 4)2000 63 ( 8)2001 61 ( 8)2002 79 (10)2003 96 (12)2004 107 (13)2005 125 (15)2006 127 (16)2007 121 (15)

T-cell depletion No 768 (95) Yes 44 ( 5)Median follow-up of survivors, range, months 37 (3-110)Abbreviations: MTX=methotrexate; TBI= total body irradiation; Bu=busulfan; Cy=cyclophosphamide; CSA= Cyclosporine; MTX= Methotrexate; FK506=Tacrolimus; LPAM= melphalan; MMF= Mycophenolate; CORT= corticosteroids; HLA= human leukocyte antigen; GVHD=graft vs host disease; res=resolution.

131


Characteristics of AML, ALL & MDS patients with A1B8DR3 haplotype who received a matched bone marrow or peripheral graft from a related donor and reported to the CIBMTR

between 2000 and 2007 Characteristics of patients N (%)Number of patients 212Age at transplant, median (range), years 48 (18 - 69)

18-19 4 ( 2)20-30 36 (17)31-40 25 (12)41-50 57 (27)51-60 67 (32)≥61 23 (11)


<90 68 (32)≥90 134 (63)

Missing 10 ( 5)Disease

AML-acute myelogenous leukemia or anll 116 (55)ALL-acute lymphoblastic leukemia 40 (19)MDS-myelodysplastic-myeloprolif.disorder 56 (26)

Disease status pre transplant AML/ALL early 88 (42)AML/ALL intermediate 38 (18)AML/ALL advanced 29 (14)MDS early 9 ( 4)MDS advanced 20 ( 9)Other 28 (13)


Regimen intensity Ablative 155 (73)RIC 44 (21)NMA 10 ( 5)Other/TBD 3 ( 1)

Donor/recipient sex match Male/male 84 (40)Male/female 51 (24)Female/male 46 (22)Female/female 29 (14)

132


Continued. Characteristics of patients N (%)Donor/recipient CMV match

Negative 51 (24)Positive 70 (33)Positive/Negative 32 (15)Negative/Positive 55 (26)Unknown 4 ( 2)

Condition regimen at transplant CY + TBI 64 (30)Bu + CY 72 (34)TBI +- other 19 ( 9)Cy +- other 7 ( 3)Bu +-other 34 (16)Flud + Lpam +-other 13 ( 6)Fludara + Atg +-other 1 (<1)Lpam +-other 1 (<1)Other 1 (<1)

GVHD prophylaxis None ( Will be checked with teams) 2 (<1)T-cell depletion 14 ( 7)CSA + MMF +-other 6 ( 3)CSA + MTX +- other 90 (42)CSA +-other (not mtx) 7 ( 3)CSA alone 10 ( 5)FK506 + MMF +- other 11 ( 5)FK506 + MTX +- other 42 (20)FK506 +- other (not mtx) 9 ( 4)MTX +- other 11 ( 5)

Other/ Missing 10 ( 4)Race/ Ethnicity

White 202 (95)African-American 1 (<1)Native Hawaiian 1 (<1)Native Indian/alaskan 1 (<1)Other/ Unknown 2 (<1)Missing 5 ( 2)

Donor type HLA identical sibs 189 (89)Other related 23 (11)

133


Continued. Characteristics of patients N (%)T-cell depletion No 195 (92) Yes 17 ( 8)Year of transplant

1999 18 ( 8)2000 33 (16)2001 24 (11)2002 28 (13)2003 18 ( 8)2004 40 (19)2005 32 (15)2006 9 ( 4)2007 10 ( 5)

Median follow-up of survivors, range, months 44 (3-120)Abbreviations: MTX=methotrexate; TBI= total body irradiation; Bu=busulfan; Cy=cyclophosphamide; CSA= Cyclosporine; MTX= Methotrexate; FK506=Tacrolimus; LPAM= melphalan; MMF= Mycophenolate; CORT= corticosteroids; HLA= human leukocyte antigen; GVHD=graft vs host disease; res=resolution.

134

Not for publication or presentation Attachment 16 Study Proposal 1208-49 Study Title: Assessment of Genetic Polymorphisms and Transplant-Related Mortality in Relation to Conditioning Regimen before HLA-Matched Unrelated Donor Allogeneic SCT Theresa Hahn, PhD, Roswell Park Cancer Institute, Buffalo, NY Lara Sucheston, PhD, Roswell Park Cancer Institute, University at Buffalo, Buffalo, NY Marcelo Pasquini, MD, MS, CIBMTR, Medical College of Wisconsin, Milwaukee, WI Objectives:

1. To test for a genetic association with transplant-related and overall mortality in recipients of myeloablative and reduced intensity conditioning matched unrelated donor allogeneic SCT. This will allow an assessment of the unique and common genetic contributions to survival in each treatment arm.

2. To compare the type of transplant-related mortality (infection, toxicity, GVHD, hemorrhage, etc) by conditioning regimen.

3. To test for a genetic association with type of transplant-related mortality by conditioning regimen. Scientific Justification: Transplant-related mortality (TRM) is the largest barrier to successful unrelated donor allogeneic stem cell transplant. While transplant-related mortality has been declining for the past 2 decades due to better patient selection and advances in HLA-typing, supportive care, GVHD and infection prophylaxis, it remains the main cause of death post-unrelated allogeneic transplant. Among the causes of TRM, GVHD, infection, interstitial pneumonitis and organ toxicity account for 50% of all deaths after unrelated allogeneic transplant 1.

Several studies have assessed candidate gene polymorphisms in relation to TRM, particularly in cytokine genes and their receptors and genes involved in redox metabolism. Several of these candidate genes have been significantly associated with transplant-related mortality after unrelated donor allogeneic transplant, including GSTM12-4, donor IL7 receptor-α 5, IL-10 and TNF-α 6, IL-1-α and IL-1-β 7, and IL-2 8, however one study did not find an association of IL-1-α genotype and outcome after unrelated donor allogeneic transplant for CML9.

Other studies evaluated acute GVHD and/or TRM after related allogeneic transplant with polymorphisms in the following genes: NOD2/CARD15 10-12, VDR 13, 14, IL-10 15-17, TNF-α17, CTLA4 18, MTHFR 19, VEGFA 20 and others.

In addition, pharmacogenetic studies evaluating toxicity after allogeneic transplant have demonstrated risk of mucositis by MTHFR genotype 21, 22 and risk of hepatic VOD/SOS by GSTM1 genotype 3, 4. There are a multitude of pharmacogenetic and pharmacogenomic studies demonstrating association of toxicity with genotype after exposure to various chemotherapeutic agents or combinations outside the stem cell transplantation setting.

We propose to analyze the impact of these genetic polymorphisms on treatment related and overall mortality after myeloablative or reduced intensity conditioning matched unrelated donor allogeneic transplantation. Furthermore, this study will determine whether certain polymorphisms are associated with a differential effect on outcome according to the conditioning regimen utilized.

135

Not for publication or presentation Attachment 16 Study Population: The study population will include adult (>20 yrs) patients reported to the CIBMTR who received at least a 10/10 HLA-matched (high-resolution A, B, C, DRB1, DQB1) unrelated donor allogeneic peripheral blood or bone marrow transplant from 2000 to 2007 for any of the following indications: AML, ALL or MDS. Patients receiving the following conditioning regimens will be included: Bu+Cy, Cy+TBI, and reduced intensity Fludarabine-based. Patients must have a banked peripheral blood sample at the NMDP repository. Only recipient samples are needed.

Patients with a prior autologous or allogeneic transplant will be excluded. Patients <20 years will be excluded. Patients receiving umbilical cord blood grafts will be excluded. Ex vivo T-cell depleted transplants will be excluded.

Outcomes:

– Transplant-related mortality will be defined as death due to any cause except underlying disease (code 70), pre-existing disease (code 140), accidental death or suicide (110, 115), or unrelated to the transplant (code 900 – identified on an individual basis).

– Type of transplant-related mortality will be coded as infection (codes 20-24, 29, 31, 32), toxicity (codes 30, 39, 40, 80-89), GVHD (codes 50, 60), hemorrhage (codes 100-104, 109), second malignancy (code 90), vascular (codes 120-123, 129), graft rejection/failure (code 10) or ‘other’ cause (code 900 – identified on an individual basis).

Variables to be Analyzed:

Main Effect: – Conditioning Regimen: BuCy vs. CyTBI vs. Flu-based (groups defined based on frequency)

Patient Related: – Age, continuous – Gender: male vs. female – Karnofsky performance score: <80 vs. >80 – Race/Ethnicity – Weight, height (BMI, BSA) – Gene polymorphisms: additive model coding will be used except when MAF is <5%

Disease Related: – Disease: AML vs ALL vs MDS – Disease status: early, intermediate, late (CIBMTR definition) – Time from diagnosis to transplant

Transplant related: – Total Dose of each conditioning regimen drug and TBI, if applicable – Donor Age, continuous – Recipient/Donor CMV status: +/+, +/-, -/+, -/- – Recipient/Donor gender match: MM, MF, FM, FF – Stem cell source: peripheral blood vs bone marrow – GVHD prophylaxis: groups will be defined based on frequency

Study Design: Laboratory Analysis We will utilize the Genotyping Division of the RPCI Microarray and Genomics Core Facility for both sample preparation and genotyping. The RPCI core facilities are sponsored by the NCI Cancer Center Support Grant and are available to all RPCI researchers. Genotyping will be performed using the Illumina® HumanHap610+ Genotyping Chip. This assay includes >610,000 high density tag SNPs covering multiple ethnic groups. In addition, it includes 4,300 copy number polymorphism regions, 7,577

136

Not for publication or presentation Attachment 16 non-synonymous SNPs, 5,728 tag SNPs in the major histocompatibility complex (MHC), and 138 mitochondrial SNPs. The chip can provide data for analyses of copy number variations (CNV), loss of heterozygosity (LOH) and comparative genomic hybridization (CGH).Genomic DNA is first normalized to 50 ng/�l and 250 total ng in 5 �l, it is then is chemically reacted to incorporate biotin. The biotin label is used to attach the DNA to paramagnetic beads treated with streptavidin, which are then used to recover DNA from solution. Three oligonucleotides are designed for each SNP. Two are allele-specific oligonucleotides (ASO) and one is a locus-specific oligonucleotide (LSO). Each ASO has a 3′ base that is complementary to one of the two SNP bases. The LSO hybridizes downstream of the ASOs. Each oligonucleotide contains a generalized primer sequence for PCR – P1 and P2 on the ASOs and P3 on the LSO. The LSO also contains an address sequence that will be used to characterize the PCR product. After extension and ligation, DNA is amplified using polymerase chain reaction (PCR) and labeled P1 and P2 oligonucleotides. One of these is labeled with Cy5, the other with Cy3. PCR products are then separated from unincorporated material using a filter plate. PCR product is then hybridized to a BeadChip Array. Cy5- and Cy3-labeled material binds in proportion to the relative abundance of the two alleles in the sample. Based upon the color distribution at each allele, the genotype of the samples for the designated SNPs is determined.

Genotyping Data Quality Control will be monitored by the inclusion of replicates (1 intra-plate and 1 inter-plate replicate) and CEPH trios (60 total samples; 20 trios from HapMap CEU population). Reproducibility will be evaluated using the replicates and by comparing our CEPH trio genotype frequencies to the HapMap results for overlapping SNPs. The CEPH trios will also allow evaluation of Mendel errors. The cluster definitions for SNPs with a Mendel error will be checked and modified if necessary in order to remove the error. A SNP will be dropped from the analysis if more than 1 Mendel error occurs or it appears that the cluster definitions do not need modification in the face of the error. SNPs with greater than 10% missing data will also be removed from the analysis. Markers and individual DNA samples with mean Illumina® GenCall scores below 0.4 will be removed as will be individual genotypes with GenCall scores below 0.25. We will also remove relatively uninformative SNPs with a minor allele frequency (MAF) in the sample of less than 0.05.

Statistical Analysis Objectives1.1

– Allelic and Haplotypic association with Survival. A modified Cox proportional hazard model23 will be used to determine if transplant-related and/or overall survival are associated with genetic polymorphisms and/or haplotypes. This model is constructed assuming N individuals typed over K SNPs. For the ith case, we assume the following Cox proportional hazards model,

• �ti|Xi,Gi)=�0(ti) exp(� ́F Xi,Gi) 1 to relate the hazard function to the covariates vector Xi and the genotype Gi, where F(Xi,Gi) is a known function to parameterize the covariates and the genotype. While the function F(Xi,Gi) can be parameterized many ways (including accommodating haplotypes), we will parameterize the function as follows: given G0 =major allele at a given SNP then F(Xi,Gi) =��gl= g0) + �gm= g0))+��X1 where (gl,gm) are the alleles at a given SNP (thus the function reflects an additive model) and X1 is the amount of genetic material shared between donor and recipient. Additional demographic and epidemiologic covariates will be included as appropriate. This can easily be used for haplotype analyses with g0 a particular haplotype of interest and (gl,gm) the pair of the haplotype of Gi We will address cryptic population structure (a type of confounding that can severely bias association signals) by implementing the EIGENSTRAT method. The EIGENSTRAT method estimates the relative degree of relatedness between all pairs of individuals in the study using all the available SNPs for a given subject, computing an adjusted covariance between all SNPs genotyped for each pair of subjects and then computing the eigenvectors (principal components)

137


of the resulting matrix of all pairs of individuals. The eigenvectors associated with the largest eigenvalues can then be used as adjustment variables in the analyses.

– Association of Genetic Pathways with Survival– Following single SNP and haplotype significance testing we will use a pathway-based approach, to jointly consider multiple variants in interacting or related genes. This method is based on a pre-existing algorithm, the Gene Set Enrichment Analysis (GSEA) algorithm, with modifications to address the variable number of SNPs per gene genotyped and sensitivity to situations where subtle effects contribute to changes in overall patterns.24 We will assess the significance of SNPs in the following pathways: metabolism (cytochrome p450 for Cy and Bu, deoxycytidine kinase for Flu), reactive oxygen species (all agents and TBI), DNA repair (all agents and TBI) and cytokine genes/receptors (all agents and TBI).

Objective 1.2

– Patient, disease and transplant related factors will be compared between the myeloablative and reduced intensity conditioning regimen groups using the chi-square test for categorical variables and the factorial ANOVA test for continuous variables.

Univariate probabilites of 100-day, 1 yr and 3 yr transplant-related mortality and overall survival will be calculated using Kaplan-Meier curves. 95% confidence intervals will be calculated for all probabilities. The conditioning regimens will be compared using a Cox proportional hazards regression model, similar to that described in equation 1. The proportional hazards assumption will be tested for all covariates. A backward elimination model will be used to determine the best regression model for transplant-related mortality containing the patient, disease and transplant related variables. Sensitivity analyses will be conducted to determine if the significant covariates differ by type of transplant related mortality. If significant differences are demonstrated by type of transplant-related mortality, then separate models will be generated.

Objective 1.3

– The same approach will be used as stated for objective 1.1, but conducted in subgroups of transplant-related mortality.

References:

1. Pasquini MC, Wang Z, Schneider L. Current use and outcome of hematopoietic stem cell transplantation: part I- CIBMTR Summary Slides, 2007. CIBMTR Newsletter. 2007;13:December 15, 2008.

2. Terakura S, Murata M, Nishida T, et al. Increased risk for treatment-related mortality after bone marrow transplantation in GSTM1-positive recipients. Bone Marrow Transplant. 2006;37:381-386.

3. Srivastava A, Poonkuzhali B, Shaji RV, et al. Glutathione S-transferase M1 polymorphism: A risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004;104:1574-1577.

4. Poonkuzhali B, Vidya S, Shaji RV, Chandy M, Srivastava A. Glutathione S-transferase gene polymorphism and risk of hepatic venoocclusive disease in patients with thalassaemia major undergoing allogeneie bone marrow transplantation. Blood. 2001;98.

5. Shamim Z, Ryder LP, Heilmann C, et al. Genetic polymorphisms in the genes encoding human interleukin-7 receptor-alpha: prognostic significance in allogeneic stem cell transplantation. Bone Marrow Transplant. 2006;37:485-491.

138


6. Keen LJ, DeFor TE, Bidwell JL, Davies SM, Bradley BA, Hows JM. Interleukin-10 and tumor necrosis factor alpha region haplotypes predict transplant-related mortality after unrelated donor stem cell transplantation. Blood. 2004;103:3599-3602.

7. MacMillan ML, Radloff GA, DeFor TE, Weisdorf DJ, Davies SM. Interleukin-1 genotype and outcome of unrelated donor bone marrow transplantation. British Journal of Haematology. 2003;121:597-604.

8. Macmillan ML, Radloff GA, Kiffmeyer WR, Defor TE, Weisdorf DJ, Davies SM. High-producer interleukin-2 genotype increases risk for acute graft-versus-host disease after unrelated donor bone marrow transplantation. Transplantation. 2003;76:1758-1762.

9. Mehta PA, Eapen M, Klein JP, et al. Interleukin-1 alpha genotype and outcome of unrelated donor haematopoietic stem cell transplantation for chronic myeloid leukaemia. British Journal of Haematology. 2007;137:152-157.

10. Brenmoehl J, Holler E, Rogler G. Polymorphisms within epithelial receptors: NOD2/CARD15. Methods Mol Med. 2007;134:115-122.

11. Holler E, Rogler G, Brenmoehl J, et al. Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination. Blood. 2006;107:4189-4193.

12. Granell M, Urbano-Ispizua A, Arostegui JI, et al. Effect of NOD2/CARD15 variants in T-cell depleted allogeneic stem cell transplantation. Haematologica. 2006;91:1372-1376.

13. Bogunia-Kubik K, Middleton P, Norden J, Dickinson A, Lange A. Association of vitamin D receptor polymorphisms with the outcome of allogeneic haematopoietic stem cell transplantation. Int J Immunogenet. 2008;35:207-213.

14. Middleton PG, Cullup H, Dickinson AM, et al. Vitamin D receptor gene polymorphism associates with graft-versus-host disease and survival in HLA-matched sibling allogeneic bone marrow transplantation. Bone Marrow Transplant. 2002;30:223-228.

15. Socie G, Loiseau P, Tamouza R, et al. Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplantation. 2001;72:699-706.

16. Karabon L, Wysoczanska B, Bogunia-Kubik K, Suchnicki K, Lange A. IL-6 and IL-10 promoter gene polymorphisms of patients and donors of allogeneic sibling hematopoietic stem cell transplants associate with the risk of acute graft-versus-host disease. Hum Immunol. 2005;66:700-710.

17. Middleton PG, Taylor PR, Jackson G, Proctor SJ, Dickinson AM. Cytokine gene polymorphisms associating with severe acute graft-versus-host disease in HLA-identical sibling transplants. Blood. 1998;92:3943-3948.

18. Perez-Garcia A, De la Camara R, Roman-Gomez J, et al. CTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors. Blood. 2007;110:461-467.

19. Kim I, Lee KH, Kim JH, et al. Polymorphisms of the methylenetetrahydrofolate reductase gene and clinical outcomes in HLA-matched sibling allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2007;86:41-48.

20. Kim DH, Lee NY, Lee MH, Sohn SK. Vascular endothelial growth factor gene polymorphisms may predict the risk of acute graft-versus-host disease following allogeneic transplantation: preventive effect of vascular endothelial growth factor gene on acute graft-versus-host disease. Biol Blood Marrow Transplant. 2008;14:1408-1416.

21. Robien K, Schubert MM, Bruemmer B, Lloid ME, Potter JD, Ulrich CM. Predictors of oral mucositis in patients receiving hematopoietic cell transplants for chronic myelogenous leukemia. J Clin Oncol. 2004;22:1268-1275.

139


22. Ulrich CM, Yasui Y, Storb R, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood. 2001;98:231-234.

23. Chen J, Peters U, Foster C, Chatterjee N. A haplotype-based test of association using data from cohort and nested case-control epidemiologic studies. Hum Hered. 2004;58:18-29.

24. Wang K, Li M, Bucan M. Pathway-Based Approaches for Analysis of Genomewide Association Studies. Am J Hum Genet. 2007;81.

140


Characteristics of AML, ALL & MDS patients with repository samples who received a high resloution10/10 HLA matched bone marrow or peripheral graft from an unrelated donor and

reported to the NMDP between 2000 and 2007. Patient characteristics N (%) Number of patients 2156 Age at transplant, median (range), years 46 (1 - 69)

0-19 289 (13) 20-30 301 (14) 31-40 270 (13) 41-50 434 (20) 51-60 560 (26) >61 302 (14)

Male sex 1180 (55) Karnofsky score

<90 594 (28) >= 90 1310 (61) Missing 252 (12)

Disease AML-acute myelogenous leukemia or anll 1145 (53) ALL-acute lymphoblastic leukemia 477 (22) MDS-myelodysplastic-myeloprolif.disorder 534 (25)

Graft type Bone marrow 718 (33) Peripheral blood 1438 (67)

Patients ethnicity White 2020 (94) African-American/Black 48 ( 2) Hispanic 8 (<1) Asian 14 (<1) Native Hawaiian 1 (<1) Pacific Islanders 6 (<1) Native Indian Alaskan 4 (<1) Other 5 (<1) Unknown 4 (<1) Missing 46 ( 2)

141

Not for publication or presentation Attachment 16 Continued. Patient characteristics N (%) Year of transplant

2000 115 ( 5) 2001 145 ( 7) 2002 150 ( 7) 2003 215 (10) 2004 341 (16) 2005 438 (20) 2006 439 (20) 2007 313 (15)

Donor/recipient sex match Male/male 848 (39) Male/female 332 (15) Female/male 590 (27) Female/female 386 (18)

Donor/recipient CMV match Negative 669 (31) Positive 414 (19) Positive/Negative 252 (12) Negative/Positive 767 (36) Unknown 54 ( 3)

Regimen intensity Ablative 1489 (69) Reduced intensity conditioning 459 (21) Non myeloablative 176 ( 8) Other ( to be determined) 32 ( 1)

Condition regimen at transplant CY + TBI 737 (34) Bu + CY 527 (24) TBI +- other 260 (12) Cy +- other 40 ( 2) Bu +-other 369 (17) Flud + Lpam +-other 171 ( 8) Flud + Atg +-other 1 (<1) Fludara +- other 27 ( 1) Lpam +-other 4 (<1) Other 20 (<1)

142

Not for publication or presentation Attachment 16 Continued. Patient characteristics N (%) GVHD prophylaxis

None ( Will be checked with teams) 33 ( 2) CSA + MMF +-other 192 ( 9) CSA + MTX +- other 344 (16) CSA +-other (not mtx) 27 ( 1) CSA alone 16 (<1) FK506 + MMF +- other 298 (14) FK506 + MTX +- other 827 (38) FK506 +- other (not mtx) 140 ( 6) MTX alone 6 (<1) MTX +- other 123 ( 6) Other 37 ( 2)

Missing 113 ( 5) Median follow-up of survivors, range, months 24 (<1-90) Abbreviations: MTX=methotrexate; TBI= total body irradiation; Bu=busulfan; Cy=cyclophosphamide; CSA= Cyclosporine; MTX= Methotrexate; FK506=Tacrolimus; LPAM= melphalan; MMF= Mycophenolate; CORT= corticosteroids; HLA= human leukocyte antigen; GVHD=graft vs host disease.

a Selection criteria # Excluded Total N # AML, ALL, MDS patients who received a first allogeneic transplant 7447

between 2000 and 2005 Patients with no previous allo or auto transplant 12 7435 Include BM and PB graft type only 595 6840 Included patients with 10/10 matching only at (a,b,c drb1, dqb1) 3749 3091 High resolution retro typing only 712 2379 Exclude patients who received T-cell depletion 70 2309 Patients with consented samples 19 2290 Patients with samples in the NMDP repository 95 2195 Cap modelled data set 39 2156

143

2010 meeting agenda - cibmtr working committee for regimen ...€¦ · not for publication or...

Documents