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AGENDA CIBMTR WORKING COMMITTEE FOR REGIMEN-RELATED TOXICITY / SUPPORTIVE CARE San Diego, California Wednesday, February 1, 2012, 2:45 pm –4:45 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: Vincent T. Ho, MD, Dana-Farber Cancer Institute Telephone: 617-632-5938; Fax: 617-632-5168; E-mail: [email protected] Co-Chair: Philip M. McCarthy, MD, Roswell Park Cancer Institute Telephone: 716-845-4074; Fax: 716-845-3272; E-mail: [email protected] Statisticians: Xiaochun Zhu, MS, CIBMTR, Medical College of Wisconsin Telephone: 414-805-0649; Fax: 414-805-0714; E-mail: [email protected] Sandy Korman, MS, CIBMTR, Medical College of Wisconsin Telephone: 414-805-0682; Fax: 414-805-0714; E-mail: [email protected] Brent Logan, PhD, CIBMTR Medical College of Wisconsin Telephone: 414-955-8849; Fax: 414-955-6513; E-mail: [email protected] CIBMTR Sci. Dir: Marcelo Pasquini, MD, MS, CIBMTR, Medical College of Wisconsin Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

1. Introduction

Minutes of February, 2011 meeting (Attachment 1)

2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers

a. 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. BMT, 46:34-43, 2011.

b. RT05-02 Barker CC, Agovi MA, Logan B, Gupta V, Lazarus HM, Ballen K, Hale G, Frangoul H, Rizzo D, Pasquini MC. Obesity Adversely Affects Survival of Pediatric Patients with Severe Aplastic Anemia after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant, 17:737-744, 2011.

c. RT06-02 Horan J, Logan B, Agovi MA, Lazarus H, Bacigalupo A, Ballen K, Martino R, Juckett M, Khoury H, Bredeson C, Gupta V, Smith F, Hale G, Carabasi M, McCarthy P, Rizzo D, Pasquini MC. Reducing the Risk for Transplant Related Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation: How Much Progress Has Been Made? JCO, 29:805-813, 2011.

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Not for publication or presentation

d. RT09-01 Olsson R, Logan B, Schriber J, Zhu X, Ringden O, Cook K, Ho V, McCarthy P, Agovi M, Chaudhry S, Pasquini MC. Patients at risk for primary graft failure after allogeneic hematopoietic cell transplantation with myeloablative conditioning. EBMT presentation. Paris, April 2011.

4. Studies in progress (Attachment 3)

a. RT06-01s TGF-B1 promoter polymorphysms in renal dysfunction with CSA (R Shah)

Manuscript preparation

b. RT08-02 Effect of Splx on engraftment after ablative allo HCT (G Akpek)


c. RT09-01 Patients at risk for primary graft failure after allogeneic hematopoietic cell transplantation with myeloablative conditioning (R Olsson)


d. RT07-01 Comorbidities/Aging impact on HCT (M Sorror) Data File Preparation e. RT08-01 End-stage renal disease in HCT recipients (Trivedi/Hari) Data File Preparation f. RT09-02 Effects of body mass in children with leukemias

undergoing allogeneic HCT (N Bunin) Analysis in Progress

g. RT09-04 Genetic polymorphism’s and HCT related mortality RE: pre HCT conditioning in MUD HCT (T Hahn)

Protocol Development

h. RT10-04 Pre-HCT risk factors for relapse after RIC (F Baron) Protocol Development i. RT09-03 Ablative vs RIC for haplo HCT (S Ciurea) Protocol Development j. RT10-01 CRP for predicting non-relapse mortality in allo HCT

(A Artz) Protocol Development

k. RT11-01 Risk fxs for IPS post auto HCT for lymphoma using BCNU based regimen (A Lane/ B Chen)


5. Approved studies but not initiated

a. RT10-02 2nd allo post ablative conditioning for relapsed heme-malignancy (G Akpek) (Attachment 4)


b. RT11-02 Chimerism as predictor for secondary failure/relapse post allo HCT with RIC HCT in AML (R Olsson) (Attachment 5)


c. RT10-03 Pulmonary complications in a/w A1B8DR3 post haplo allo HCT (P McCarthy/H Liu/G Akpek)

Deferred

6. Future/ Proposed studies

a. PROP 0211-01 The role of Tyrosine Kinase Inhibitors on cardiovascular risk in survivors of hematopoietic stem cell transplantation (W Vaughan) (Attachment 6)

b. PROP 1111-66 Outcomes of patients with transplant-associated thrombotic microangiopathy (TA-TMA) (S Jodele/B Laskin) (Attachment 7)

c. PROP 1111-06 Factors predicting treatment-related mortality in pediatric autologous transplant (E Perez-Albuerne) (Attachment 8)

d. PROP 1111-56 Total body irradiation and radiation therapy prior to hematopoietic cell transplant: a survey of transplant specialists associated with the center for international bone and marrow transplant research (C Barker) (Attachment 9)

e. PROP1211-01 Sequence of cyclophosphamide and total body irradiation in evaluation of relapse, mortality, and graft versus host disease in patients with AML undergoing hematopoietic stem cell transplantation (J Chakrabarty) (Attachment 10)

f. PROP1011-06 Transplant in Older Adults: Is it feasible in those 70 years and older? (L Muffly/A Artz) (Attachment 11)

7. Other Business

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Not for publication or presentation Attachment 1

MINUTES FROM THE CIBMTR WORKING COMMITTEE FOR REGIMEN-RELATED TOXICITY / SUPPORTIVE CARE Honolulu, Hawaii Thursday, February 17, 2011, 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: Vincent T. Ho, MD, Dana-Faber Cancer Institute Telephone: 617-632-5938; Fax: 617-632-5168; E-mail: [email protected] Co-Chair: Philip M. McCarthy, MD, Roswell Park Cancer Institute Telephone: 716-845-4074; Fax: 716-845-3272; E-mail: [email protected] Statisticians: Xiaochun Zhu, MS, CIBMTR, Medical College of Wisconsin Telephone: 414-805-0649; Fax: 414-805-0714; E-mail: [email protected] Brent Logan, PhD, CIBMTR, Medical College of Wisconsin Telephone: 414-955-8849; Fax: 414-955-6513; E-mail: [email protected] CIBMTR Sci. Dir: Marcelo Pasquini, MD, MS, CIBMTR, Medical College of Wisconsin Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

1. Introduction

Vincent Ho (VH) started the meeting at 12:15 pm and introduced the new MS statistician, Xiaochun Zhu, to the committee members. All attendees were asked to fill the evaluation form. VH explained the new voting this year and instructed all members that they should assign a priority score for each study or proposal being presented. This score will be used for ranking studies in the next academic year.

Minutes from the 2010 Tandem meeting in Orlando were accepted and approved by the chairs and committee members.

2. Accrual summary

No formal presentation on the accrual summary. The number of cases was referenced for the committee to review.

3. Presentations, published or submitted papers

VH updated the group on studies recently published or presented in 2010, included 5 publications and one presentation in ASH 2010.

4. Studies in progress

Marcelo Pasquini (MCP) updated studies in progress.

a. RT06-01 TGF-B1: Promoter polymorphisms in renal dysfunction with Cyclosporin A (CSA) (R Shah): Manuscript was received from PI, plan for submission by June 2011.

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b. RT08-02: Effect of Splenectomy on engraftment after ablative allo HCT (G Akpek): Results were presented at ASH 2010. Manuscript draft submitted by the PI, plan for submission by June 2011.

c. RT09-01: Predictors for primary graft failure (S Chaudhury/R Olsson): This study

combined three proposals that focused on graft failure, risk factors, risk factors in pediatric and likelihood of engraftment incorporating risk factors and lack of engraftment at days 14 and 21 after transplantation. Richard Olsson worked on the analysis as part of his statistical training in Milwaukee. He has completed the identification risk factors and analysis. This was submitted and accepted for oral presentation in the 2011 EBMT. The plan is to complete all the analyses and report in two separate publications.

d. RT07-01: Comorbidities/Aging impact on HCT (M Sorror): This study initiated with

implementation of the HCT CI in the pre-TED forms in late 2007. The objectives are mainly to validate the score and assess whether there is an impact of age. The study accrued greater than 15,000 patients from the end of 2007 to 2009. This year the data set will be cleaned for analysis. Mohamed Sorror presented demographic information according to conditioning regimen intensity for allogeneic transplant. MS also presented some modifications to the study including assessing the score to predict early mortality in patients with nonmalignant diseases and an assessment of the how reliable is the overall score determination when collected through CIBMTR forms.

e. RT08-01: End-stage renal disease in HCT recipients (Trivedi/Hari): This study requires

matching CIBMTR with USRDS database in order to identified recipients of unrelated donor transplants who started chronic renal replacement therapy after transplantation. The first matching attempt identified 60 out more than 9,000 patients who are in both databases. USRDS recommended using first and last names on the matching in addition to social security numbers. We needed to request approval from NMDP IRB to release this information. We expect to finalize the matching and start data cleaning by June 2011.

f. RT09-02: Effects of body mass in children with leukemias undergoing allogeneic HCT

(N Bunin): This study will assess the impact of weight on transplant outcome in children with acute leukemia. Additionally, this study will attempt to assess whether chemotherapy dose adjustment based on weight has any impact on outcome. This study is currently in data cleaning phase and the plan is to move to analysis in July 2011.

g. RT09-04: Genetic polymorphisms and HCT related mortality RE: pre HCT conditioning

in MUD HCT (T Hahn): This study is being in collaboration with the Immunobiology Working Committee and has the main objective of using genome wide association screening (GWAS) to identify determinants of transplant related mortality. The PIs were awarded NIH funding to run this study. Patient population was selected and the project is under data file cleaning.

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5. Approved studies but not initiated a. RT09-03: Ablative vs RIC for haplo HCT (S Ciurea): The objective of this study is to

compare outcomes of patients who received Haploidentical transplantation for any indication. The groups being compared are based on conditioning regimen intensity and T-cell depletion. This study will be done in collaboration with John’s Hopkins group to add a cohort of patients who received a haplo-identical transplant with posttransplant cyclophosphamide. There are approximately 1,000 patients since 1990 for this analysis.

b. RT10-01: CRP for predicting non-relapse mortality in allo HCT (A Artz): This study was

approved last year and has the objective of assessing C-reactive protein in unrelated donor transplant recipients and study how it impacts on transplant-related mortality. The investigator plans to analyze 500 patient samples stored at the NMDP repository. The investigator is currently seeking funds to cover cost of analysis and utilization of samples. The investigator is interested in adding other assays, such as serum ferritin. Combining these analyses with HCT-CI were discussed, however the samples would need to be from after 2007 and the implementation of the pre-TED form. Another suggestion was to broaden this study to include related donors, which are now being collected by the NMDP repository.

c. RT10-02: 2nd allo post ablative conditioning for relapsed heme malignancy (G Akpek):

This study has the objective of assessing outcomes of second transplant for acute leukemia. This is an update on a previous study published by Eapen et al. Some members commented that this study could generate a skewed result because it includes only relapsed patients who actually get to a second transplant, and not the other patients who were either not a candidate for or died before a second transplant.

d. RT10-03: Pulmonary complications in associated with MHC haplotype A1B8DR3 post-

allo HCT (P McCarthy/H Liu): The objective of this study is to confirm single center observations that patients with certain haplotypes experience higher rates of lung toxicity. Dr. Liu presented unrelated donor recipients, separated according to the haplotypes of interest. The same will need to be done in related donor recipients. The outcomes described were all lung toxicity collected in CIBMTR forms from IPn to GVHD related lung involvement. Some of these events are missing for the forms and would require go back to centers to inquire more information.

e. RT10-04: Pre-HCT risk factors for relapse after RIC (F Baron): The study is to develop a

relapse score based on a scoring system developed by Kahl et al using Seattle data. The study by Kahl et al, utilized disease indication and disease status as a method to predict relapse after HCT using a nonmyeloablative conditioning regimen. Dr. Baron plans to validate this score and assess it in transplants with reduced intensity conditioning regimen. He also plans to modify the score by including additional factors.

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6. Future/ Proposed studies a. PROP 1210-23: Risk factors for the development of idiopathic pneumonitis after

autologous stem cell transplantation for lymphoma using BCNU-containing regimens (A Lane/YB Chen): This proposal has the objective of assessing acute lung injury in recipients of BCNU as part of autologous HCT conditioning regimen. Dr. Chen presented the protocol. One point discussed was the use of high dose corticosteroids to prevent BCNU pneumonitis. This practice is done in some centers, but this is not captured in the database. There was discussion regarding the possibility of doing a survey of transplant centers into this practice.

b. PROP 1210-30: Chimerism as predictor of secondary graft failure or relapse following

allogeneic HSCT using reduced intensity conditioning regimens in acute leukemia (R Olsson): This proposal is a follow on of RT 0901, but focus on recipients of reduced intensity and nonmyeloablative conditioning regimens and uses chimerism data in the first 100 days to predict secondary failure. The main concerned discussed during the meeting was related to the quality of chimerism data in the registry. The data is collected but practices across transplant centers are varied regarding how often and the timing of these assessments.

c. PROP 1210-31: Secondary graft failure after myeloablative allogeneic HSCT in the

treatment of hematological malignancies (R Olsson): This proposal is another extension of RT0901 which assess risk factors for secondary graft failure. This was presented by Dr. Olsson.

d. PROP 1210-36: Development of a predictive scoring system for acute lung injury after

hematopoietic stem cell transplantation (G Akpek): This proposal has the objective to build a scoring system for acute lung injury after transplantation. Dr. Akpek presented the study concept. Again the fact of the quality of pulmonary outcome data was raised, which would be crucial for the development of this study.

7. Other business

Post Hoc discussion with Chairs and Decision on Committee hours. All studies not initiated and proposals were ranked according to the priority given by the committee members. Studies that will be proceeding and will have allocated hours for the 2011-2012 year:

a. RT10-04 b. RT09-03 c. PROP 1210-23 (now RT11-01) d. RT 10-02 e. PROP 1210-30 (now RT 11-02)

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Deferred studies: a. RT 10-01: Despite high priority, this study is deferred pending PI funding. Also other

issues regarding incorporation of related donor samples and other assays will need to be clarified.

b. RT-10-03 and PROP 1210-36: Both studies received similar priority. There were a total

of three studies looking lung toxicity as an outcome. All three PI’s will be invited to work together on these studies starting at RT11-01, since the autologous SCT population is more homogeneous.

c. RT 10-03 and PROP 1210-36: These will be combined as one study (RT 10-03) with

two Co-PIs. This study will be presented next Tandem one more time.

Rejected studies: a. PROP 1210-31

7. Meeting Adjourned at 2:15 PM

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Accrual Summary for Regimen-Related Toxicity/Supportive Care Working Committee

Characteristics of recipients of allogeneic transplant reported to the CIBMTR between 2000 and 2011

Characteristics of patients Registration only ResearchNumber of patients 46627 37969Number of centers 460 355Age, median (range), years 37 (<1 - 83) 36 (<1 - 83)Sex Male 27084 (58) 22125 (58)

Female 19439 (42) 15835 (42)Missing 104 (<1) 9 (<1)

Disease Acute Leukemia/MDS 26309 (56) 21402 (56)CLL 1761 ( 4) 1497 ( 4)Chronic Leukemia 5066 (11) 3654 (10)lymphoma 5374 (12) 3798 (10)Solid Tumor 452 (<1) 339 (<1)Multiple Myeloma 840 ( 2) 488 ( 1)Non-malignant diseases 6825 (15) 6791 (18)

Graft type Bone marrow 15221 (33) 12165 (32)Peripheral blood 28363 (61) 20509 (54)Cord blood 2178 ( 5) 4903 (13)Missing 865 ( 2) 392 ( 1)

Donor type Twin 394 (<1) 276 (<1)HLA-identical sibling 29410 (63) 11529 (30)Other related 3938 ( 8) 1693 ( 4)Unrelated donor 12197 (26) 24447 (64)Missing 688 ( 1) 24 (<1)

Year of transplant 2000-2001 8898 (19) 5953 (16)2002-2003 8745 (19) 5874 (15)2004-2005 7730 (17) 6804 (18)2006-2007 7561 (16) 6230 (16)2008-2009 5524 (12) 8265 (22)2010-2011 8169 (18) 4843 (13)

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Characteristics of recipients of autologous transplant reported to the CIBMTR between 2000 and 2011

Characteristics of patients Registration only ResearchNumber of patients 75474 14526Number of centers 498 305Age, median (range), years 53 (<1 - 90) 54 (<1 - 83)Sex

Male 44811 (59) 8738 (60)Female 30480 (40) 5784 (40)Missing 183 (<1) 4 (<1)

Disease Acute Leukemia/MDS 3410 ( 5) 765 ( 5)CLL 267 (<1) 35 (<1)Chronic Leukemia 112 (<1) 14 (<1)lymphoma 33204 (44) 5200 (36)Solid Tumor 6150 ( 8) 1379 ( 9)Multiple Myeloma 31905 (42) 7037 (48)Non-malignant diseases 426 (<1) 96 (<1)

Graft type Bone marrow 1275 ( 2) 177 ( 1)Peripheral blood 72166 (96) 14011 (96)Cord blood 11 (<1) 5 (<1)Missing 2022 ( 3) 333 ( 2)

Year of transplant 2000-2001 11203 (15) 2479 (17)2002-2003 12122 (16) 2008 (14)2004-2005 12381 (16) 2889 (20)2006-2007 11935 (16) 2785 (19)2008-2009 12006 (16) 3459 (24)2010-2011 15827 (21) 906 ( 6)

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Characteristics of recipients of allogeneic transplant reported to the CIBMTR between 2000 and 2011 in

research retrieval Characteristics of patients ResearchNumber of patients 32487Number of centers 341Age, median (range), years 35 (<1 - 83)Sex

Male 18927 (58)Female 13557 (42)Missing 3 (<1)

Disease Acute myelogenous leukemia or ANLL 12084 (37)Acute lymphoblastic leukemia 6004 (18)Other leukemia 1148 ( 4)Chronic myelogenous leukemia 3414 (11)Non-Hodgkin lymphoma 2904 ( 9)Hodgkin lymphoma 191 (<1)Plasma cell disorder/Multiple Myeloma 441 ( 1)Other Malignancies 327 ( 1)Severe aplastic anemia 2286 ( 7)Inherited abnormalities erythrocyte differentiation or function 1404 ( 4)SCID and other immune system disorders 1082 ( 3)Inherited abnormalities of platelets 63 (<1)Inherited disorders of metabolism 661 ( 2)Histiocytic disorders 397 ( 1)Autoimmune Diseases 27 (<1)Other, specify 54 (<1)

IPn or ARDS/IPS No 27418 (84)Yes 4819 (15)Missing 250 (<1)

Bronchiolitis obliterans No 2893 ( 9)Yes 677 ( 2)Missing 28917 (89)

Pulmonary hemorrhage No 2889 ( 9)Yes 685 ( 2)Missing 28913 (89)

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Continued. Characteristics of patients ResearchCryptogenic organizing pneumonia

No 1606 ( 5)Yes 83 (<1)Missing 30798 (95)

VOD/SOS No 4521 (14)Yes 2016 ( 6)Missing 25950 (80)

Renal failure severe enough to warrant dialysis No 13344 (41)Yes 3396 (10)Missing 15747 (48)

Year of transplant 2000-2001 5841 (18)2002-2003 5723 (18)2004-2005 6674 (21)2006-2007 6000 (18)2008-2009 6181 (19)2010-2011 2068 ( 6)

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TO: Regimen-Related Toxicity Working Committee Members FROM: Marcelo Pasquini, MD, MS, Scientific Director for the Regimen-Related Toxicity WC RE: Studies in Progress Summary RT06-01s: 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): The objectives of this study are 1) genotype hematopoietic transplant patients treated with CsA for three functional TGF-β1 promoter single nucleotide polymorphisms (SNPs): 1550 AGG insertion, -509C-T and +869T-C; 2) to collect data on serum creatinine and blood urea nitrogen before and after the hematopoietic transplant at predefined time intervals as a measure of renal dysfunction; 3) to evaluate the association(s) of TGF-β1 promoter polymorphisms (SNPs -1550, -509 and +869) on development of renal dysfunction in patients receiving CsA for GVHD prophylaxis. The current status is manuscript preparation. RT08-02: The effect of prior splenectomy on myeloid engraftment after myeloablative allogeneic stem cell transplantation: a CIBMTR analysis (G Akpek): The objectives are 1) to compare engraftment and 100-day survival between transplant recipients with or without splenectomy prior to stem cell transplantation; 2) to compare the cumulative incidence of acute and chronic GVHD and overall survival at 1 year post transplant. Analysis was completed in 2010 and results were presented at the ASH meeting as poster. The manuscript will be finalized soon. RT09-01: Primary graft failure following allogeneic HSCT for the treatment of hematological malignancies (R Olsson): The objective is to identify risk factors for primary graft failure following myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of hematological malignancies, with subset analysis in children. This study will also analyze risk factors for graft failures at day 14 and 21 post transplant. The current status is manuscript preparation. Initial risk factor analysis in all the population was presented at the EBMT 2011 meeting, Paris. RT07-01: Interaction between comorbidities and aging and their combined impact on hematopoietic cell transplantation outcomes (M Sorror): This study are 1) to investigate the interaction between comorbidities, aging and the addition of age intervals to the HCT-CI to form composite scores using retrospective data collected from 6 collaborative academic institutions; 2) to validate the comorbidities ± aging scores on HCT outcomes using data from the Center for International Bone Marrow Transplantation Registry (CIBMTR). The study started data collection in November 2007.The current status is data file preparation. In 2010, the protocol was expanded to validate the HCT-CI in allogeneic transplant for nonmalignant diseases. RT08-01: End-stage renal disease in bone marrow transplant recipients (H Trivedi): The objectives of this study are 1) to describe the incidence of ESRD and the time to development in URD HCT recipients; 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; 3) to describe changes in incidence rates of ESRD after BMT in URD over time; 4) to determine the mortality after ESRD in URD compared to transplant recipients of URD transplants who do not develop ESRD (including subgroup analysis

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according to modality of renal replacement therapy, dialysis vs. kidney transplantation), and to ESRD patients who have not undergone BMT. Data merge with USRDS database was needed to identify cases on chronic renal replacement therapy. Initial attempt to merge the CIBMTR and USRDS databases lead to few cases and another attempt is underway using more identifiers. The current status is data file preparation. RT09-02: Effects of body mass in children with leukemias undergoing allogeneic bone marrow transplant (N Bunin): The objectives are 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; 2) to compare transplant related morbidity and mortality in under, over and normal weight patients; 3) to evaluate the impact of chemotherapy dose intensity on survival by BMI. The current status is analysis in progress. Multivariate analysis was done and the summary will be sent to writing committee. RT09-04: Assessment of genetic polymorphisms and transplant-related mortality in relation to conditioning regimen before HLA-matched unrelated donor allogeneic SCT (T Hahn): The objectives are 1) to identify genetic polymorphisms that are associated with transplant related mortality in recipients of unrelated donor transplants; 2) to test for a genetic association with type of transplant-related mortality (infection, GVHD, organ failure) by conditioning regimen. The current status is protocol development. This study is federally funded to run genome-wide association studies with unrelated donor and recipient samples and associate with clinical outcomes. RT10-04: Pre-transplant risk factors for relapse after RIC allo transplantation (F Baron): The aims are 1) to validate the Kahl scoring system in a large cohort of patients given a truly non-myeloablative conditioning (Flu+2 Gy TBI, Flu-Cy, or TLI-ATG) or a more intense reduced-intensity conditioning regimen (Flu-Bu ≤8 mg/kg, Flu-Mel 140, Flu+4 Gy TBI, or Fluda-Thiothepa ≤10 mg/kg); 2) to calculate the relapse rate per patient year (PY) during the first 2 years after transplantation in each disease stage defined in the Kahl study in the whole study group; 3) to adapt the Kahl scoring system according to the relapse-risk of each disease stage calculated in the first secondary endpoint; 4) to validate the new scoring system (if different from the Kahl scoring system); 5) to compare the Kahl and the new scoring system; 6) to compare the impact of conditioning intensity (nonmyeloablative versus RIC) on relapse risk after adjustment with the disease-risk scoring system. The study is under protocol development stage. RT09-03: Comparison of clinical outcomes between Myeloablative And Reduced-Intensity Conditioning for Haploidentical Stem Cell Transplantation (S Ciurea): The aims are 1) 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; 2) to compare the outcomes of patients treated with a T-cell depleted as compared with a T-cell replete Haploidentical graft; 3) to determine whether RIC is associated with reduced toxicity and overall at least as effective as MA conditioning for Haploidentical stem cell transplantation. The current status is protocol development. RT10-01: C-reactive Protein (CRP) To Predict Non-relapse Mortality after Allogeneic Hematopoietic Cell Transplantation (HCT) (A Artz): The aims are 1) to determine the variability in c-reactive protein (CRP) levels prior to allogeneic hematopoietic cell transplant (HCT) conditioning; 2) to evaluate the prognostic significance of pre-HCT CRP levels on non-relapse mortality (NRM); 3) to quantify the prognostic impact of pre-HCT CRP levels HCT related toxicity and acute GVHD; 4) to assess the influence of pre-HCT CRP levels on overall survival; 5) to establish an optimal cutpoint for pre-HCT CRP levels to independently predict NRM. The current status is protocol development.

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RT11-01 Risk factors for the development of idiopathic pneumonitis after autologous stem cell transplantation for lymphoma (A Lane/YB Chen) The aims are 1) to determine the broader applicability of these risk factors; 2) to examine if they are consistent in other HDC regimens that also utilize BCNU (e.g., BEAM); 3) to study the incidence of pneumonitis in TBI (total body irradiation) and busulfan (Bu) containing ASCT regimens, compare with BCNU-containing regimens, and determine if TBI and Bu regimens have the same predictive factors for development of pneumonitis. Accepted studies, but not initiated RT10-02: Survival after second allografting following a myeloablative conditioning in patients with relapsed hematologic malignancies: a CIBMTR report (G Akpek): The objectives are 1) is to evaluate overall survival at day 100 and at one-year after second allogeneic stem cell transplantation following myeloablative conditioning; 2) to include rate of complete remission after second allografting, relapse-free survival, the cumulative incidence of acute and chronic GVHD. RT11-02 Chimerism as predictor of secondary graft failure or relapse following allogeneic HSCT using reduced intensity conditioning regimens in acute leukemia (R Olsson): The aims are 1) to investigate the predictive value of donor chimerism status at 3, 6, and 12 months post-transplant on subsequent secondary graft failure; 2) to investigate the predictive value of donor chimerism status at 3, 6, and 12 months post-transplant on subsequent relapse. RT10-03: Assessment of pulmonary complications post-transplant in association with A1B8DR3 haplotype in allogeneic hematopoietic cell transplant recipients (P McCarthy/H Liu/G Akpek): The objectives are 1) to examine the incidence of pulmonary complications and their association with A1B8DR3 haplotype; 2) to include incidence and severity of acute and chronic GvHD, progression-free survival (PFS) and overall survival (OS) and their association with A1B8DR3 haplotype. The study is deferred.

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CIBMTR RT10-02

SURVIVAL AFTER SECOND ALLOGRAFTING FOLLOWING A MYELOABLATIVE CONDITIONING IN PATIENTS WITH RELAPSED HEMATOLOGIC MALIGNANCIES:

A CIBMTR REPORT

DRAFT PROTOCOL Study Chair: Gorgun Akpek, MD, MHS, FACP

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]

Study Statisticians: Xiaochun Zhu, MS

CIBMTR Statistical Center Medical College of Wisconsin 9200 W. Wisconsin Ave., Suite C5500 Milwaukee, WI 53226 Telephone: 414-805-0649 Fax: 414-805-0714 E-mail: [email protected]

Brent Logan, PhD

CIBMTR Statistical Center Medical College of Wisconsin

9200 W. Wisconsin Ave., Suite C5500 Milwaukee, WI 53226 Telephone: 414-955-8849 Fax: 414-955-6513 E-mail: [email protected] Scientific Director: Marcelo Pasquini, MD, MS


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Working Committee Chairs: Kenneth R. Cooke, MD Case Western Reserve University School of Medicine Wolstein Research Building 2103 Cornell Road Cleveland, OH 44106-7288 Telephone: 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 Telephone: 617-632-5938 Fax: 617-632-5168 E-mail: [email protected] Philip McCarthy, MD Medical Director, BMT program Roswell Park Cancer Institute Elm and Carlton Street Buffalo, NY 14263 Telephone: 716-845-4074 Fax: 716-845-3272 E-mail: [email protected]

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1.0 SPECIFIC OBJECTIVES:

The primary objective of the study is to evaluate overall survival at one-year after second allogeneic stem cell transplantation (HCT) in patients with hematologic malignancies.

Secondary objectives include day+100 TRM, rate of complete remission, relapse-free

survival, the cumulative incidence of grade II-IV acute and chronic GVHD after second HCT.

2.0 SCIENTIFIC JUSTIFICATION: Allogeneic 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 malignancy remains a major cause of transplant failure especially after non-myeloablative HCT. The issue of how to approach in relapsing patients after transplant, especially in young ones with excellent performance status who relapse following a perfect HLA-matched HCT remains widely controversial. There us no established consensus on the most appropriate approach to these patients. In the modern era of HCT, the role of second HCT is worth to revisit given no good treatment options available for most of these patients, especially those with acute leukemias. The use of donor lymphocyte infusion (DLI) with or without prior chemotherapy has been the mostly accepted treatment approach in post-transplant relapse setting. However, DLI is not effective in many instances in patients with full blown relapsed malignant disease. The lack of efficacy is more evident in patients with relapsed acute leukemias. Second allogeneic bone marrow transplantation (BMT) has been reported to be associated with high-morbidity and mortality, especially when it is performed 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 and the HLA-typing was imperfect. The advances in HLA-typing, understanding the biology and complications of HCT along with significant improvement in supportive care over the past decade have improved the transplant outcome throughout the world. Recent retrospective analyses suggest that second HCT have a potential therapeutic role in certain group of patients (Table 1). Initial comprehensive analysis, using IBMTR data on 114 patients who received BMT between 1978 and 1989, showed 41% TRM at 2 years and 21% leukemia-free survival. Patients who relapsed more than 6 months after the initial BMT, those with CML, in complete remission at second BMT, and those with good performance status did get the most benefit from the second BMT1. In 1993, Seattle group evaluated the impact of a second BMT on long-term disease-free survival (DFS) on 77 consecutive patients aged 2 to 51 years who relapsed subsequent to allogeneic BMT 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

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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 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.2 In 2001, Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation 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.3 Eapen et al. reported an updated CIBMTR data on 279 patients with leukemia who received second HCT from related or unrelated donors between 1990 and 2000. Twenty-one percent received PBSCT. TRM was around 28% and relapse rate was 40%. Probability of 5-year LFS and OS was 28%. Multivariable analyses identified the following variables that were associated with better outcome; patient age <20, time to relapse longer than 6 months, Being in remission and use of myeloablative conditioning at second HCT. Using the same or different donor did not seem to have different impact.

More recent observations were more encouraging but still not conclusive. 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 might well have 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. CT10-x study will compare DLI with second allogeneic stem cell transplantation. Our study will address the role of second allogeneic HCT in four different conditioning regimen pairs.

Our hypothesis is that second myeloablative allogeneic stem cell transplantation prolong survival in patients with relapsed hematologic malignancies following the initial allografting. Our comprehensive analysis will likely to enlighten the transplant community in their decision making process.

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Table 1. Summary of previously published studies and the current study

Mrsic, IBMTR

BMT 1992

Radich, Seattle JCO 1993

Bosi, EBMTR JCO 2001

Eapen, CIBMTR

BMT 2004

Kedmi BBMT 2009

Akpek RT 10-02

1978-1989 1983-1991 1978-1997 1990-2000 1981-2007 1990-2009

114 pts 77 patients 170 patients 279 patients 144 patients >500 pts.

2-51 y/o 22 (1-46) 1/3 <20 y/o All ages

ALL 20 AML 44 CML 39

CML 28 AML 32 ALL 15 NHL 2

AML 85 ALL 83

Undifferentiated 2

AML 45% ALL 26% CML 29%

Relapsed 78 Rejection 37 Graft failure

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Relapsed Malignancies

Median TT second HCT

15 mos

Median TT second HCT

3 mos.

First HCT TBI/Chemo

100%

First HCT TBI-based 68%

First HCT TBI/Chem

54% BU/CY 46%

First HCT Myeloablative or NMA/RIC

Second HCT HD chemo

Second HCT TBI-based 23%

TBI/Chem 33%

BU/CY 41% Other 26% RIC 16%

Second HCT

Myeloablative or NMA/RIC

BM Same donor

BM 74% PBSCT 26%

BM 79% PBSCT 21% Same donor

85%

More PBSCT data

Same or Different donors

Matched Related

Related Unrelated

Related (90%) Unrelated

Related Unrelated

Related Unrelated

Related Unrelated

Other

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Table 1. Continued.

Various GVHD

prophylaxis

Various GVHD

prophylaxis

Various GVHD Prophylaxis 63%

None 27%

None 14% Various 86%

Mostly none Various

Graft failure 2%

Engrafted 96% Engrafted 97% Engrafted 86% To be determined

VOD IP

Severe VOD 20

VOD 48% IP 21%

To be determined

2-year TRM 41%

100 day TRM 36%

5 year TRM 46%,

1-yr TRM 26% 5-yr TRM 30%

1 year TRM 46%

To be determined

aGVHD 27% cGVHD 21%

aGVHD 40% cGVHD 37%

aGVHD 59% cGVHD 32%

aGVHD 29% cGVHD 41%

aGVHD 35% cGVHD 11%

To be determined

Relapse 65% Relapse 70% Relapse 59% 1-yr Rel 36% 5-yr Rel 42%

To be analyzed

LFS 21% DFS 8% ALL DFS 10%

AML DFS 25%

CML Med DFS 3 yr

5-yr LFS 25% 5-yr OS 26%.

5 yr LFS 28% 5 yr OS 28%

5 yr LFS 13% 5 yr OS 17% 20% lived >

1yr Med f/u: 4.5

yrs

To be determined

Multivariate Relapse>6

mo LFS 28% TRM 30% Relapse <6

mo LFS 7%

TRM 69% Favorable

CML CR 2nd BMT Good KPS

Multivariate Lower relapse

aGVHD Short DFS No aGVHD

VOD Age>10

Multivariate Better outcome Relapse > 10 mo.

aGVHD CR at 2nd SCT TBI in 2nd SCT BM in 2nd SCT

Multivariate Better

outcome <20 y/o

Relapse >6 mo CR in 2nd SCT Myeloablative conditioning

Same donor = Different donor

Multivariate Better

Survival Nonmalignant

disease Non-relapse

indication for 2nd HCT

HLA-match RIC

To be determined

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Summary • Second allo-BMT is a feasible treatment consideration in appropriate patients • >90% engraftment • TRM 25-50% • GVHD 30-60% • Relapse 40-70% • 5 yr survival of 15-30% • Favorable predictors for better outcome after second HCT

– Age <20 – Time to relapse > 6 mos – CR at 2nd SCT – GVHD (+) – Full match – Myeloablative conditioning in 2nd SCT – TBI-conditioning in second HCT – RIC (one study)

What will be in RT 10-02?

• We will identify a subgroup of patients who may benefit from 2nd SCT in a larger cohort transplanted b/w 1990-2009.

• All hematologic malignancies will be included • We will assess the outcome after second allografting in 4 different first and second conditioning

regimen pairs – Myeloablative Myeloablative – Myeloablative Non-myeloablative/RIC – Non-myeloablative/RIC non-myeloablative/RIC – Non-myeloablative/RIC Myeloablative

• We will also assess – Decade on outcome (before 2000 and after 2000) – HLA-match – Stem cell source (PBSCT vs. BM) – Donor (related vs. unrelated)

• Revisit/Address – Second MUD transplant – Second cord transplant if any – Same vs. different donor question

• Data to be included in Cox model – Age – KPS at second HCT – Cytogenetic (poor vs. favorable) – Chemosensitive vs. refractory disease prior to second SCT (in those who received chemo

prior to second HCT) – Presence of circulating blast, platelet count at relapse – GVHD prophylaxis (used vs. not used)

3.0 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 1990 and 2009.

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We will identify those who relapsed following the initial transplant and received second allografting from matched related, unrelated or alternative donor after a myeloablative or NMA/RIC regimen.

4.0 OUTCOMES

The primary endpoint will be Overall survival at 1 year – Time to death from any cause after second HCT. 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.

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.

5.0 VARIABLES TO BE ANALYZED (AT THE TIME OF SECOND HCT)

Patient related: Age Gender: female vs male Karnofsky score at second transplant: <80 vs ≥ 80 Donor related: Age Gender: female vs male

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Disease related: Disease at second transplant Disease status at second transplant: CR, PR, Persistent disease Transplant related: Year of second transplant (5-year interval periods between 1990 and 2009) Graft type: BM vs PBSC vs. cord Donor type: Related or unrelated Donor: Same donor or different donor Conditioning at initial transplant: Myeloablative or non-myeloablative/RIC Conditioning at second transplant: Myeloablative or non-myeloablative/RIC GvHD prophylaxis T-cell depletion ATG use at second transplant 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

6.0 STUDY DESIGN AND STATISTICAL CONSIDERATIONS

The study proposed here will analyze CIBMTR data to address the working hypothesis that second allografting is associated with durable (>1 year) remission and survival in at least %25 of patients.. Recent transplants (after year 2000), HLA-match sibling donor, peripheral blood stem cells may yield better survival and lower transplant-related mortality as compared to those done before 2001.

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 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.

7.0 REFERENCES

1. Mrsíc M, Horowitz MM, Atkinson K, Biggs JC, Champlin RE, Ehninger G, Gajewski JL, Gale RP, Herzig RH, Prentice HG, et al. Second HLA-identical sibling transplants for leukemia recurrence. Bone Marrow Transplant. 1992 Apr;9(4):269-75.

2. 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.

3. 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.

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4. Eapen M, Giralt SA, Horowitz MM, Klein JP, Wagner JE, Zhang MJ, Tallman MS, Marks DI, Camitta BM, Champlin RE, Ringdén O, Bredeson CN, Martino R, Gale RP, Cairo MS, Litzow MR, deLima M. Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant. 2004 Oct;34(8):721-7.

5. 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.

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Table 2. 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 2009 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-myeloprolific 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)

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Table 2. Continued.

Characteristics of patients 1st transplant 2nd transplant

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-myeloablative 37 ( 4) 36 ( 3)Non-traditional ablative 81 ( 8) 93 ( 9)Other 18 ( 2) 146 (14)

No conditioning regimen listed 289 (27)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)

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Table 2. Continued.

Characteristics of patients

1st transplant 2nd transplant

N% N %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 prophylaxis 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.

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CIBMTR RT11-02

CHIMERISM AS PREDICTOR OF SECONDARY GRAFT FAILURE OR RELAPSE FOLLOWING ALLOGENEIC HSCT USING REDUCED INTENSITY CONDITIONING

REGIMENS IN ACUTE LEUKEMIA

DRAFT PROTOCOL Study Chair: Richard Olsson, MD, PhD, MMSc

Karolinska University Hospital Centre for Allogeneic Stem Cell Transplantation B87 Stockholm, Sweden Telephone: 46-8-585-800-00 Fax: 46-8-585-878-70 E-mail: [email protected]

Study Statisticians: Xiaochun Zhu, MS


Brent Logan, PhD

CIBMTR Statistical Center Medical College of Wisconsin

9200 W. Wisconsin Ave., Suite C5500 Milwaukee, WI 53226 Telephone: 414-955-8849 Fax: 414-955-6513 E-mail: [email protected] Scientific Director: Marcelo Pasquini, MD, MS


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Working Committee Chairs: Kenneth R. Cooke, MD Case Western Reserve University School of Medicine Wolstein Research Building 2103 Cornell Road Cleveland, OH 44106-7288 Telephone: 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 Telephone: 617-632-5938 Fax: 617-632-5168 E-mail: [email protected] Philip McCarthy, MD Medical Director, BMT program Roswell Park Cancer Institute Elm and Carlton Street Buffalo, NY 14263 Telephone: 716-845-4074 Fax: 716-845-3272 E-mail: [email protected]

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1.0 OBJECTIVES:

1.1 Investigate the predictive value of donor chimerism status at 3, 6, and 12 months post-transplant on subsequent secondary graft failure.

1.2 Investigate the predictive value of donor chimerism status at 3, 6, and 12 months post-

transplant on subsequent relapse.

2.0 SCIENTIFIC JUSTIFICATION: During the last decade both reduced intensity conditioning (RIC) regimens [1-3] and donor chimerism analyses [4] have been introduced to HSCT. In acute leukemia patients, the rationale for reduced-intensity conditioning regimens is to provide a less toxic treatment in elderly patients, who still may benefit from the graft-versus-leukemia (GVL) effect. Donor chimerism is presently used both to monitor relapse and to detect secondary graft failures, which most likely are caused by immunological rejection of the transplanted donor cells. In myeloablative HSCT, where almost all successful transplants have full donor chimerism (>95%), a shift to mixed chimerism (5-95% donor) is much easier to interpret than in RIC transplants, where many patients are mixed chimeras and may stay that for a longer period of time. To date, there are some studies that have reported encouraging data on chimerism to monitor minimal residual disease or secondary graft failure [5-11]. This is an important issue since both secondary graft failure as well as relapse may be treated by donor lymphocyte infusions (DLI). Moreover, donor chimerism analyses are expensive and time consuming. The usefulness of this method has yet not been evaluated in a large patient cohort, and such a study is now proposed using the CIBMTR registry to investigate the feasibility of chimerism analyses.

3.0 STUDY POPULATION:

Inclusion Criteria: Allogeneic HSCT during the time-period 2000 to 2010 Adults (≥ 18 years old) Acute leukemia AML ALL Complete remission (1st or 2nd) Reduced intensity conditioning regimens TBI dose <5 Gy single or TBI dose <8 Gy fractionated L-PAM dose ≤150 mg/m2 BU dose ≤9 mg/kg BEAM (upper limit of RIC) Donor Matched unrelated donor (HLA- match 8/8) HLA-identical sibling Cord blood (HLA-match 4/6) Stem cell source Bone marrow (BM), peripheral blood stem cells (PBSC), or cord blood Engraftment Absolute neutrophil count >0.5x109/l for 3 consecutive days before 48 days post-transplant

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Exclusion Criteria: Myeloablative conditioning (MAC) BU + CY CY + TBI (TBI dose >5 Gy single dose, or fractionated TBI >8 Gy) TBI dose >5 Gy single or TBI dose >8 Gy fractionated BU dose >9 mg/kg

4.0 OUTCOMES:

Primary: Secondary graft failure: <5% donor chimerism without signs of relapse Relapse: As judged by morphology and flowcytometry (FACS) analyses

Secondary: Overall survival Relapse Non-relapse mortality

5.0 VARIABLES TO BE ANALYZED:

Donor chimerism at 3 months post-transplant:

<5% vs. 5-25%, vs. 25-50% vs. >50% donor chimerism Donor chimerism at 6 months post-transplant:

<5% vs. 5-25%, vs. 25-50% vs. >50% donor chimerism Donor chimerism at 12 months post-transplant:

<5% vs. 5-25%, vs. 25-50% vs. >50% donor chimerism Gender:

Male vs. female Disease related:

Disease: ALL vs. AML Disease stage: first vs. second remission

Transplant-related: Donor type: HLA-identical sibling vs. matched unrelated donor Source of stem cells: BM vs. PBSC

Cell dose (continuous variable) CD34+ Total nucleated cells (TNC)

Donor-recipient ABO incompatibilities: no vs. minor vs. major Ex vivo T-cell depleted vs. repleted Unrelated donor age as a continuous variable Donor-recipient gender match: F-M vs. M-F vs. M-M vs. F-F Year of transplant: continuous variable GVHD prophylaxis: cyclosporine ± MTX ± other, Prograf ± MTX ± other vs. other. Thymoglobulin vs. Campath vs. none Cryopreservation yes vs. no Day of engraftment continuous variable Acute graft-versus host disease at 3 months, grades I-II vs. grades III-IV, vs. no acute GVHD Chronic GVHD at 3 months, vs. 6 months, vs. 12 months, vs. 24 months vs. no chronic

GVHD

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6.0 STUDY DESIGN AND STATISTICAL CONSIDERATIONS: To summarize the characteristics of the dataset, descriptive tables of patient, disease and transplant related variables will be reported. 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 the prognostic value of donor chimerism at 3 months, 6 months, or 12 months on subsequent secondary graft failure or leukemic relapse following reduced intensity conditioning regimens for acute leukemia. Secondary objectives include comparison of overall survival and transplant related mortality in patients with different levels of donor chimerism (<5%, 5-25%, 25-50%, or >50%), at 3, 6 or 12 months post-transplant. Landmark analyses will be performed to investigate whether donor chimerism at 3, 6 or 12 months can predict secondary graft failure and/or relapse. The overall survival will be described using survival curves (Kaplan-Meier), whereas TRM will be calculated according to cumulative incidences.

7.0 REFERENCES:

1. Turner, B.E., M. Collin, and A.M. Rice, Reduced intensity conditioning for hematopoietic stem cell transplantation: has it achieved all it set out to? Cytotherapy, 2010. 12(4): p. 440-54.

2. Turner, B.E., et al., Reduced intensity conditioning for allogeneic hematopoietic stem-cell transplant determines the kinetics of acute graft-versus-host disease. Transplantation, 2008. 86(7): p. 968-76.

3. Belkacemi, Y., et al., Reduced-intensity conditioning regimen using low-dose total body irradiation before allogeneic transplant for hematologic malignancies: Experience from the European Group for Blood and Marrow Transplantation. Int J Radiat Oncol Biol Phys, 2007. 67(2): p. 544-51.

4. Perez-Simon, J.A., et al., Chimerism and minimal residual disease monitoring after reduced intensity conditioning (RIC) allogeneic transplantation. Leukemia, 2002. 16(8): p. 1423-31.

5. Bader, P., et al., How and when should we monitor chimerism after allogeneic stem cell transplantation? Bone Marrow Transplant, 2005. 35(2): p. 107-19.

6. Aoudjhane, M., 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, 2005. 19(12): p. 2304-12.

7. Gorner, M., et al., Stable mixed chimerism after T cell-depleted allogeneic hematopoietic stem cell transplantation using conditioning with low-dose total body irradiation and fludarabine. Bone Marrow Transplant, 2002. 29(7): p. 621-4.

8. Misawa, M., et al., Reduced-intensity conditioning followed by unrelated umbilical cord blood transplantation for advanced hematologic malignancies: rapid engraftment in bone marrow. Int J Hematol, 2006. 83(1): p. 74-9.

9. Saito, B., et al., Impact of T cell chimerism on clinical outcome in 117 patients who underwent allogeneic stem cell transplantation with a busulfan-containing reduced-intensity conditioning regimen. Biol Blood Marrow Transplant, 2008. 14(10): p. 1148-55.

10. Valcarcel, D., et al., Chimerism analysis following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant, 2003. 31(5): p. 387-92.

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11. Mattsson, J., et al., Mixed chimerism is common at the time of acute graft-versus-host disease and disease response in patients receiving non-myeloablative conditioning and allogeneic stem cell transplantation. Br J Haematol, 2001. 115(4): p. 935-44.

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Table 1. Characteristic of patients >=18 years of age who underwent an HLA-identical sibling or HLA- 8/8 matched URD non-myeloablative transplant for AML/ALL in first or second complete remission reported to the CIBMTR between 1999 and 2009 Characteristics of patients N (%)Number of patients 1614Number of centers 188Age, median (range), years 56 (18 - 76)

18-29 104 ( 6)30-39 117 ( 7)40-49 250 (15)50-59 571 (35)>=60 572 (35)

Sex Male 892 (55)Female 722 (45)

Karnofsky score <90% 495 (31)90-100% 1027 (64)Missing 92 ( 6)

Disease status at HCT 1st CR 1160 (72)2nd CR 454 (28)

Donor type HLA identical-sibling 806 (50)HLA 8/8 matched URD 808 (50)

D-R sex match M-M 476 (29)M-F 347 (21)F-M 288 (18)F-F 276 (17)Missing 227 (14)

D-R CMV status +/+ 503 (31)+/- 129 ( 8)-/+ 399 (25)-/- 317 (20)Missing 266 (16)

Graft type Bone marrow 195 (12)Peripheral blood 1408 (87)Cord blood 7 (<1)Missing 4 (<1)

34


Table 1. Continued. Characteristics of patients N (%)Year of transplant

1995-1999 20 ( 1)2000-2003 358 (22)2004-2007 780 (48)2008-2009 456 (28)

GVHD prophylaxis T-cell depletion 32 ( 2)FK506+MTX+-other 501 (31)FK506+-other 336 (21)CsA+MTX+-other 262 (16)CsA+-other 421 (26)Other 61 ( 4)Missing 1 (<1)

Median follow-up of survivors, range, months 47 (1 - 123)Chimerism test

@ 100 days No 754 (47)Yes 860 (53)

@ 6 months No 1156 (72)Yes 458 (28)

@ 1 year No 1170 (72)Yes 444 (28)

@ 2 years No 1267 (79)Yes 347 (21)

@ 3 years No 1511 (94)Yes 103 ( 6)

35


Study Proposal 0211-01 Study Title: The Role of Tyrosine Kinase Inhibitors on Cardiovascular Risk in Survivors of Hematopoietic Stem Cell Transplantation William P. Vaughn, MD, MBA, University of Alabama at Birmingham, Birmingham, Alabama Specific Aims:

Hypothesis: the prior use of tyrosine kinase inhibitors is associated with an excess risk of cardiovascular events in patients who undergo hematopoietic stem cell transplantation (HSCT).

Aim 1: determine the incidence of early and late cardiovascular events in patients who received tyrosine kinase inhibitors and undergo HSCT.

Aim 2: identify clinical and treatment related factors associated with excess risk of cardiovascular events in patients who received tyrosine kinase inhibitors and undergo HSCT.

Aim 3: compare the incidence and time of occurrence of cardiovascular events between patients who undergo HSCT and received tyrosine kinase inhibitors and controls matched for age, donor source for the HSCT (autologous vs allogeneic), length of follow up, and factors which in the multivariate analysis of Aim 2 reach statistical significance.

Background and Significance: The introduction of the tyrosine kinase inhibitors in clinical therapeutics has revolutionized the treatment paradigm in many diseases. This has been eloquently shown in the case of chronic myeloid leukemia where the introduction of imatinib resulted in a significant change in the clinical outlook of this entity. [1] By virtue of inhibiting the BCR-ABL1 fusion tyrosine kinase, a “driver” mutation in Philadelphia chromosome positive malignancies, Imatinib, nilotinib, and dasatinib have become an integral therapeutic component of Philadelphia chromosome positive hematologic malignancies, mainly chronic myelogenous leukemia [1-4] and Philadelphia chromosome positive acute lymphoblastic leukemia [5]. As a consequence, many patients with the aforementioned diagnoses referred for HSCT have received tyrosine kinase inhibitors in the pretransplant setting. Despite the relative selectivity of Imatinib, nilotinib, and dasatinib for the BCR-ABL1 fusion protein, other receptor and nonreceptor tyrosine kinases are also inhibited albeit to a lesser extent. In the first report associating Imatinib with cardiotoxicity, ten patients with normal baseline cardiac function developed left ventricular dysfunction during therapy with imatinib. [6] Correlative studies in mice have shown that inhibition of the c-Abl in cardiomyocytes activated the endoplasmic reticulum stress response leading to profound alterations in mitochondrial function and eventually to cardiomyocyte apoptosis. [6] Another tyrosine kinase implicated in the cardiotoxicity associated with tyrosine kinase inhibitors is the Platelet Derived Growth Factor Receptor – beta (PDGFRβ). [7] Experiments in mice have shown that PDGFRβ signaling is an indispensable component of the cardiac response to pressure overload – induced stress. Cardiac – specific PDGFRβ knockout mice have impaired angiogenic response and show evidence of ischemic injury upon exposure to load stress. In response to pressure overload, these mice were also shown to develop ventricular dilation and heart failure. [7] In retrospective studies the incidence of adverse cardiovascular events associated with tyrosine kinase inhibitors appears to be low (reviewed in [8]). Prospective studies in which the cardiac function was evaluated by means of echocardiography or nuclear scanning have reported no evidence of deterioration of the myocardial function in 12 months. [9] However, the role of tyrosine kinase inhibitors in the development of cardiovascular events in patients who undergo HSCT has not been investigated. Moreover, patients who are referred for HSCT may have received tyrosine kinase inhibitors for periods

36


considerably longer than one year (as may be the case in chronic myelogenous leukemia) as well as in combination with known cardiotoxic medications such as anthracyclines (as may be the case in acute lymphoblastic leukemia). Although patients undergoing HSCT represent a selected group as they undergo extensive pretransplant evaluation including cardiologic screening, the process of HSCT by itself may represent a significant cardiovascular stress. Purpose of this study is to identify whether in patients undergoing HSCT prior tyrosine kinase inhibitor administration results in excess cardiovascular risk either early (within the first year) or late (beyond the first year) after HSCT. Research Design and Methods:

Aim 1. Definitions: the term cardiovascular event will be used to include any event reflecting

cardiac dysfunction due to cardiomyopathy, valvular or conduction abnormality leading to subclinical or overt cardiac failure after HSCT. Acute coronary syndromes such as myocardial ischemia or infarction and atherosclerotic coronary artery disease leading to ischemic cardiomyopathy will also be considered as cardiovascular events.

A distinction between early and late cardiovascular events is necessary as the nature of the events that occur early after HSCT is different from the ones that occur in long-term survivors [10]. Also, the risk factors predisposing to early and late cardiovascular events and their relative contribution may be different. Early in the course after HSCT, disease-related factors, pretransplant comorbidities, the type of conditioning regimen and immediate post-HSCT complications may be most influential on the overall cardiovascular risk. Late cardiovascular events may occur after a long latency period and may reflect the cumulative effect of diverse risk factors, primarily the risks imposed by prior treatments. The arbitrary cutoff point of 1 year will be used to differentiate between early and late cardiovascular events, as this cutoff has been used in previous literature. [11, 12] Cardiovascular events occurring within the first year after HSCT will be considered early whereas events occurring after the first feat will be considered late. If a patient has undergone HSCT twice or more, each HSCT will be considered as a separate event.

Tyrosine kinase inhibitors. Hematologic malignancies constitute the predominant indication for HSCT in the adult population and Imatinib, nilotinib, and dasatinib are the most widely used tyrosine kinase inhibitors to treat hematologic malignancies in the pretransplant setting. The major indications of Imatinib, nilotinib, and dasatinib include chronic myelogenous leukemia [2-4] and Philadelphia chromosome positive acute lymphoblastic leukemia (summarized in [5]). The role of the aforementioned tyrosine kinase inhibitors in conferring excess risk of cardiovascular toxicity will be retrospectively investigated in the present study.

To determine the incidence of early and late cardiovascular events, patients who received tyrosine kinase inhibitors prior to HSCT will be identified from the Center for International Blood and Marrow Transplant Research (CIBMTR) database and the nature and incidence of cardiovascular events will be recorded.

Aim 2.

Patients who received tyrosine kinase inhibitors prior to HSCT may constitute a distinct group regarding cardiovascular risk. Factors that have been previously identified to influence the risk for cardiovascular events may be different and their relative contribution may differ significantly compared with the cardiovascular risk factors identified in previous studies. [10-12] No study so far has investigated the relationship between tyrosine kinase inhibitors and cardiovascular risk.

37


In the patients identified from CIBMTR database in Aim 1, the role of the following factors in the development of early and late cardiovascular events will be investigated in a univariate and multivariate analysis:

Demographic factors: age, gender, body mass index (kg/m2). Pretransplant comorbidities: hypertension, hyperlipidemia, renal insufficiency,

diabetes mellitus, chronic lung disease, cardiovascular disease. Pretransplant diagnosis: acute leukemia versus chronic leukemia, leukemia

versus other diagnoses. Pretransplant therapeutic exposures: time of initial diagnosis to HSCT (this

variable may reliably reflect the time of tyrosine kinase inhibitor administration), cycles of pre-HSCT chemotherapy, total lifetime anthracycline exposure, administration of cyclophosphamide, administration of melphalan, and mediastinal radiation therapy.

Conditioning regimen: myeloablative versus nonmyeloablative chemotherapy, radiation therapy versus no radiation therapy.

Immediate posttransplant complications (complications occurring within the first 30 days after HSCT): sepsis requiring pressure support, respiratory failure requiring mechanical ventilation, renal failure requiring hemodialysis, acute and chronic graft versus host disease.

For the univariate analysis the χ2 or Fisher’s exact tests for dichotomous or t test for continuous variables will be used. For the multivariate analysis, a logistic regression model will be used.

Aim 3. In order to compare the incidence of cardiovascular events between patients who undergo

HSCT and received or are receiving tyrosine kinase inhibitors and controls, a nested case-control study design will be used. The cohort of patients who underwent HSCT and received or are receiving tyrosine kinase inhibitors will form the sampling frame for selecting controls from the CIBMTR database matched for age, donor source for the HSCT (autologous vs allogeneic), length of follow up, and factors which in the multivariate analysis of Aim 2 reach statistical significance. The overall incidence of cardiovascular events between the two groups will be compared using the χ2 or Fisher’s exact tests.

The time to occurrence of a cardiovascular event in the two groups will be plotted and compared. The analysis will be conducted with the use of Kaplan-Meier estimates and Cox proportional-hazards models.

Anticipated Problems and Possible Outcomes: This study is retrospective and cardiovascular events may be missed as they are not prospectively recorded. Other factors that have not been recorded or analyzed may as well influence the risk for cardiovascular events. However, all the factors that have been associated with excess risk of cardiovascular events in previous studies [10-12] will be investigated in univariate and multivariate analyses in patients who received or are receiving tyrosine kinase inhibitors and underwent HSCT. Given the nonselective inhibition of “off target” receptor and nonreceptor tyrosine kinases that play important roles in compensatory cardiac responses, we predict that HSCT poses a significant cardiovascular stress in patients who received tyrosine kinase inhibitors prior to HSCT. Consequently, despite the careful pretransplant screening, these patients may experience an excess of cardiovascular events compared with matched controls who did not receive tyrosine kinase inhibitors.

38


References: 1. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib

compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. New Engl J Med. 2003 Mar 13; 348(11):994-1004.

2. O'Brien SM, Kantarjian H, Radich J. Update: chronic myelogenous leukemia clinical practice guidelines. J Natl Compr Canc Netw. 2003 Jan; 1 Suppl 1:S29-40.

3. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus Imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. New Engl J Med. 2010 Jun 17; 362(24):2260-70.

4. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Nilotinib versus Imatinib for newly diagnosed chronic myeloid leukemia. New Engl J Med. 2010 Jun 17; 362(24):2251-9.

5. Fielding AK. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2010 Nov 4; 116(18):3409-17.

6. Kerkela R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, et al. Cardiotoxicity of the cancer therapeutic agent Imatinib mesylate. Nat Med. 2006 Aug; 12(8):908-16.

7. Chintalgattu V, Ai D, Langley RR, Zhang J, Bankson JA, Shih TL, et al. Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress. J Clin Invest. 2010 Feb 1;120(2):472-84.

8. Giles FJ, O'Dwyer M, Swords R. Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia. 2009 Oct; 23(10):1698-707.

9. Estabragh ZR, Knight K, Watmough SJ, Lane S, Vinjamuri S, Hart G, et al. A prospective evaluation of cardiac function in patients with chronic myeloid leukaemia treated with Imatinib. Leukemia Res. 2010 Jan; 35(1):49-51.

10. Tichelli A, Bhatia S, Socie G. Cardiac and cardiovascular consequences after haematopoietic stem cell transplantation. Brit J Haematol. 2008 Jul; 142(1):11-26.

11. Armenian SH, Sun CL, Francisco L, Steinberger J, Kurian S, Wong FL, et al. Late congestive heart failure after hematopoietic cell transplantation. J Clin Oncol. 2008 Dec 1; 26(34):5537-43.

12. Armenian SH, Sun CL, Mills G, Teh JB, Francisco L, Durand JB, et al. Predictors of late cardiovascular complications in survivors of hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2010 Aug; 16(8):1138-44.

39


Characteristic of ALL patients who received an allogeneic HCT with TKI as part of conditioning regimen reported to the CIBMTR between 2001 and 2010.

Characteristics of patients ALL TKI Yes ALL TKI No ALL TKI

missingNumber of patients 353 863 2796Number of centers 3 3 86Age, median (range), years 40 (3 - 69) 26 (<1 - 72) 23 (1 - 69)

0-20 57 (16) 335 (39) 1217 (44)21-30 63 (18) 167 (19) 561 (20)31-40 64 (18) 141 (16) 392 (14)41-50 100 (28) 107 (12) 340 (12)51-60 51 (14) 86 (10) 234 ( 8)61-70 18 ( 5) 26 ( 3) 52 ( 2)>70 0 1 (<1) 0

Sex Male 207 (59) 526 (61) 1725 (62)Female 146 (41) 337 (39) 1071 (38)

Karnofsky score <90% 99 (28) 187 (22) 638 (23)90-100% 240 (68) 645 (75) 1961 (70)Missing 14 ( 4) 31 ( 4) 197 ( 7)

Conditioning regimen Myeloablative 273 (77) 692 (80) 2498 (89)Non-myeloablative 76 (22) 167 (19) 223 ( 8)TBD 4 ( 1) 4 (<1) 75 ( 3)

Donor type HLA-identical sibling 182 (52) 455 (53) 713 (26)Twin 1 (<1) 1 (<1) 8 (<1)Other related 15 ( 4) 64 ( 7) 68 ( 2)Well-matched URD 83 (24) 207 (24) 1237 (44)Partially matched URD 33 ( 9) 48 ( 6) 531 (19)Mismatched URD 5 ( 1) 6 (<1) 229 ( 8)Multi donor 0 0 0HLA match information missing URD 34 (10) 82 (10) 9 (<1)Missing 0 0 1 (<1)

D-R sex match M-M 92 (26) 253 (29) 1079 (39)M-F 58 (16) 138 (16) 578 (21)F-M 79 (22) 151 (17) 628 (22)F-F 54 (15) 120 (14) 479 (17)Missing 70 (20) 201 (23) 32 ( 1)

D-R CMV status +/+ 111 (31) 294 (34) 807 (29)+/- 39 (11) 64 ( 7) 379 (14)-/+ 63 (18) 123 (14) 717 (26)-/- 51 (14) 147 (17) 795 (28)Missing 89 (25) 235 (27) 98 ( 4)

40


Continued.

Characteristics of patients ALL TKI Yes

ALL TKI No

ALL TKI missing

Graft type Bone Marrow 100 (28) 324 (38) 1322 (47)Peripheral blood 253 (72) 539 (62) 1474 (53)

GVHD prophylaxis No GVHD prophylaxis 14 ( 4) 34 ( 4) 39 ( 1)Ex vivo T-cell depletion alone 3 (<1) 9 ( 1) 76 ( 3)Ex vivo T-cell depletion + post-tx immune

suppression 2 (<1) 14 ( 2) 110 ( 4)

CD34 selection alone 3 (<1) 16 ( 2) 9 (<1)CD34 selection + post-tx immune suppression 6 ( 2) 11 ( 1) 24 (<1)Cyclophosphamide alone 0 0 4 (<1)Cyclophosphamide + others 0 2 (<1) 2 (<1)FK506 + MMF +- others 32 ( 9) 71 ( 8) 162 ( 6)FK506 + MTX +- others (except MMF) 121 (34) 270 (31) 796 (28)FK506 + others (except MTX, MMF) 18 ( 5) 32 ( 4) 64 ( 2)FK506 alone 9 ( 3) 4 (<1) 46 ( 2)CSA + MMF +- others (except FK506) 9 ( 3) 23 ( 3) 104 ( 4)CSA + MTX +- others (except FK506, MMF) 113 (32) 322 (37) 1177 (42)CSA + others (except FK506, MTX, MMF) 8 ( 2) 9 ( 1) 62 ( 2)CSA alone 8 ( 2) 32 ( 4) 87 ( 3)Other GVHD prophylaxis 7 ( 2) 14 ( 2) 34 ( 1)

Year of transplant 2001 0 4 (<1) 457 (16)2002 8 ( 2) 7 (<1) 466 (17)2003 32 ( 9) 90 (10) 332 (12)2004 42 (12) 107 (12) 394 (14)2005 35 (10) 106 (12) 402 (14)2006 55 (16) 73 ( 8) 407 (15)2007 37 (10) 62 ( 7) 297 (11)2008 84 (24) 230 (27) 25 (<1)2009 42 (12) 145 (17) 12 (<1)2010 18 ( 5) 39 ( 5) 4 (<1)

Philadelphia chromosome status Ph+ 270 (76) 64 ( 7) 490 (18)Ph- 83 (24) 799 (93) 2306 (82)

Congestive heart failure post-HCT before 2007 (including 2007)

No 38 (18) 83 (18) 472 (17)Yes 1 (<1) 5 ( 1) 13 (<1)Missing 170 (81) 361 (80) 2270 (82)Congestive heart failure post-HCT after 2007 No 77 (53) 189 (46) 15 (37)Yes 4 ( 3) 7 ( 2) 2 ( 5)Missing 63 (44) 218 (53) 24 (59)

41


Continued.

Characteristics of patients ALL TKI Yes

ALL TKI No

ALL TKI missing

Myocardial infarction before 2007 (including 2007) No 102 (49) 215 (48) 1051 (38)Yes 0 4 (<1) 13 (<1)Missing 107 (51) 230 (51) 1691 (61)Myocardial infarction after 2007 No 80 (56) 196 (47) 17 (41)Yes 1 (<1) 0 0Missing 63 (44) 218 (53) 24 (59)Median follow-up of survivors, range, months 36 (3 - 94) 31 (1 - 98) 60 (<1 - 123)** Tyrosine Kinase Inhibitors were defined as receiving Imatinib or dasatinib or nilotinib. The “other specify” field was also checked.

42


Characteristic of CML patients who received an allogeneic HCT with TKI as part of conditioning regimen reported to the CIBMTR between 2001 and 2010.

Characteristics of patients CML TKI Yes CML TKI No CML TKI

missingNumber of patients 1356 141 1179Number of centers 15 2 45Age, median (range), years 39 (1 - 77) 34 (4 - 69) 36 (1 - 76)

0-20 169 (12) 13 ( 9) 182 (15)21-30 240 (18) 39 (28) 226 (19)31-40 315 (23) 49 (35) 310 (26)41-50 322 (24) 24 (17) 271 (23)51-60 251 (19) 11 ( 8) 153 (13)61-70 55 ( 4) 5 ( 4) 35 ( 3)>70 4 (<1) 0 2 (<1)

Sex Male 777 (57) 89 (63) 715 (61)Female 579 (43) 52 (37) 464 (39)

Karnofsky score <90% 278 (21) 10 ( 7) 189 (16)90-100% 1006 (74) 122 (87) 907 (77)Missing 72 ( 5) 9 ( 6) 83 ( 7)

Conditioning regimen Myeloablative 943 (70) 111 (79) 956 (81)Non-myeloablative 359 (26) 25 (18) 197 (17)TBD 54 ( 4) 5 ( 4) 26 ( 2)

Donor type HLA-identical sibling 783 (58) 116 (82) 286 (24)Twin 4 (<1) 2 ( 1) 4 (<1)Other related 46 ( 3) 2 ( 1) 16 ( 1)Well-matched URD 334 (25) 13 ( 9) 552 (47)Partially matched URD 88 ( 6) 7 ( 5) 240 (20)Mismatched URD 23 ( 2) 1 (<1) 80 ( 7)Multi donor 0 0 0HLA match information missing URD 78 ( 6) 0 1 (<1)

D-R sex match M-M 413 (30) 58 (41) 453 (38)M-F 245 (18) 30 (21) 265 (22)F-M 256 (19) 29 (21) 260 (22)F-F 243 (18) 22 (16) 198 (17)Missing 199 (15) 2 ( 1) 3 (<1)

D-R CMV status +/+ 511 (38) 74 (52) 400 (34)+/- 122 ( 9) 12 ( 9) 151 (13)-/+ 189 (14) 19 (13) 285 (24)-/- 283 (21) 29 (21) 314 (27)Missing 251 (19) 7 ( 5) 29 ( 2)

Graft type Bone Marrow 438 (32) 45 (32) 588 (50)Peripheral blood 918 (68) 96 (68) 591 (50)

43


Continued. Characteristics of patients CML TKI Yes

CML TKI No CML TKI

missingGVHD prophylaxis

No GVHD prophylaxis 30 ( 2) 3 ( 2) 13 ( 1)Ex vivo T-cell depletion alone 20 ( 1) 1 (<1) 25 ( 2)Ex vivo T-cell depletion + post-tx immune

suppression 19 ( 1) 1 (<1) 30 ( 3)

CD34 selection alone 4 (<1) 2 ( 1) 1 (<1)CD34 selection + post-tx immune suppression 15 ( 1) 3 ( 2) 15 ( 1)Cyclophosphamide alone 1 (<1) 0 3 (<1)Cyclophosphamide + others 1 (<1) 0 1 (<1)FK506 + MMF +- others 71 ( 5) 0 88 ( 7)FK506 + MTX +- others (except MMF) 390 (29) 14 (10) 331 (28)FK506 + others (except MTX, MMF) 30 ( 2) 2 ( 1) 23 ( 2)FK506 alone 22 ( 2) 0 13 ( 1)CSA + MMF +- others (except FK506) 61 ( 4) 6 ( 4) 76 ( 6)CSA + MTX +- others (except FK506, MMF) 600 (44) 95 (67) 505 (43)CSA + others (except FK506, MTX, MMF) 29 ( 2) 4 ( 3) 23 ( 2)CSA alone 45 ( 3) 9 ( 6) 24 ( 2)Other GVHD prophylaxis 18 ( 1) 1 (<1) 8 (<1)

Year of transplant 2001 51 ( 4) 18 (13) 304 (26)2002 130 (10) 22 (16) 222 (19)2003 144 (11) 37 (26) 175 (15)2004 244 (18) 28 (20) 172 (15)2005 220 (16) 19 (13) 130 (11)2006 138 (10) 13 ( 9) 103 ( 9)2007 53 ( 4) 4 ( 3) 73 ( 6)2008 123 ( 9) 0 02009 153 (11) 0 02010 100 ( 7) 0 0

Congestive heart failure post-HCT before 2007 (including 2007)

No 114 (12) 6 ( 4) 186 (16)Yes 3 (<1) 0 6 (<1)Missing 863 (88) 135 (96) 987 (84)Congestive heart failure post-HCT after 2007 No 180 (48) Yes 3 (<1) Missing 193 (51) Myocardial infarction before 2007 (including 2007) No 377 (38) 39 (28) 477 (40)Yes 3 (<1) 0 9 (<1)Missing 600 (61) 102 (72) 693 (59)Myocardial infarction after 2007 No 178 (47) Yes 5 ( 1) Missing 193 (51) Median follow-up of survivors, range, months 34 (1 - 120) 38 (3 - 108) 71 (1 - 125)

44


Study Proposal 1111-66 Study Title: Outcomes of Patients with Transplant-Associated Thrombotic Microangiopathy. Sonata Jodele, MD and Stella Davies, MBBS, PhD, Children’s Hospital Medical Center, Cincinnati, Ohio Benjamin L Laskin, MD, The Children’s Hospital of Philadelphia, Philadelphia, PA Specific Aims:

Transplant-associated thrombotic microangiopathy (TA-TMA) is a significant complication of hematopoietic stem cell transplantation (HSCT) with high mortality and high potential for acute and chronic kidney injury. Exact incidence of kidney injury with TA-TMA is not known. The aim of the study is test the hypothesis that patients with TA-TMA will have worse renal and overall outcome compared to patients without a history of TA-TMA.

We would like to report renal and overall outcomes (TA-TMA incidence, overall survival, and

incidence of renal replacement therapy) in patients with TA-TMA in comparison to transplant patients without TA-TMA; and evaluate risk factors (such as chemotherapy regimen, GVHD, infections) associated with TA-TMA.

Scientific Justification: Transplant-associated thrombotic microangiopathy (TA-TMA) is a significant complication of hematopoietic stem cell transplantation (HSCT). The reported prevalence of TA-TMA ranges widely (from 0.5% to 76%), reflecting different levels of awareness among institutions, diagnostic uncertainty, and limited prospective data1. TA-TMA belongs to the family of thrombotic microangiopathies (TMAs) including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). TA-TMA occurs when endothelial injury in the context of HSCT causes microangiopathic hemolytic anemia and platelet consumption, resulting in thrombosis and fibrin deposition in the microcirculation2, 3. High dose chemotherapy, radiation, graft versus host disease (GVHD) and infections have been implicated as causative factors for TA-TMA, but exact pathogenesis of TA-TMA is yet unknown1, 4. The kidney is the most commonly affected organ, although injury has been reported elsewhere in the body in rare cases5-7. In its most severe form, mortality rates are very high (60-90%)8, while milder cases have an increased risk of later chronic kidney disease (CKD)2. HSCT patients diagnosed with TA-TMA were 4.3 times more likely to develop CKD, and 9 times more likely to have long term hypertension than those without. Patients surviving acute TA-TMA are left with less than 40% of kidney function two years post-HSCT and many later progress to CKD by retrospective reports9. TA-TMA-associated renal complications such as hypertension lead to significant later heart disease, a major cause of morbidity and mortality in childhood HSCT survivors10. Diagnosing and managing TA-TMA is especially relevant for children, who have a lifetime of increased risk of developing end stage renal disease (ESRD), needing dialysis and kidney transplantation. Considering thousands of HSCTs performed each year around the world, there is a need for better understanding of TA-TMA incidence and effect on kidney function11. Our current knowledge is limited by retrospective reviews. CIBMTR is the organization with a series of cases sufficient to try to draw conclusions about the incidence of TMA and severity of renal injury from it as it captures the data on presence of TA-TMA and the need to renal replacement therapy. It will also allow us to look at risk factor for TA-TMA like conditioning regimen, infections, GVHD.

Patient Eligibility Population: Adult and pediatric patients who meet the following criteria:

Patients who received autologous and allogeneic stem cell transplantation in the past 5 years. Patients who received single, repeated or tandem transplants.

45


Data Requirements: Patient-related variables

- Age: Children <18y, Adults ≥18y - Sex - Race: Caucasian and black, Other

Disease-related variables

- Transplant diagnosis (malignancy, bone marrow failure, immunodeficiency) - Renal function prior to transplant (nucGFR ≥100mL/min/1.73m2, <100mL/min/1.73m2) - Prior history of TA-TMA or renal failure if second transplant or tandem transplant

Transplant-related variables

- Donor/recipient sex match - Viral serology in recipients and donors - Conditioning regimens: TBI, non-TBI; Myeloablative, Reduced intensity - Stem cell source: Bone marrow, Peripheral blood, Cord blood - GVHD prophylaxis: CsA ± MTX ± FK-based regimens - HLA matching

Outcomes to be analyzed

- Overall incidence of TA-TMA at 100-days, 6-months and 2-years post-transplant. - Incidence of TA-TMA by conditioning regimen at 100-days, 6-month and 2-years post-

transplant. - Incidence of TA-TMA by post-transplant infection type (in particular CMV, adeno, BK, EBV

viremia, bacteremia) at 100-days, 6-month and 2-years post-transplant. - Incidence of TA-TMA in patients with acute and chronic GVHD at 100-days, 6-month and 2-

years post-transplant. - Development of grades II-IV acute GVHD will be scored using the using the Gluckberg

system. - Cumulative incidence to be estimated with death as a competing risk.

- Incidence of renal replacement therapy by TA-TMA status at 100-days, 6-month, 1-year, 2-years and 3-years post-transplant.

- Overall survival by TA-TMA status: Time to death from any cause. - No competing risks.

- Need for kidney dialysis by TA-TMA status. - Comparison of overall outcomes for TA-TMA patients by plasmapheresis treatment status (yes,

no). - Incidence of TA-TMA or renal failure as primary cause of death (yes, no).

No supplemental data are expected to be required. Sample Requirements: None

46


Study Design: 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 categorical variables. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. Probability of overall 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. Comparison of survival curves will be done using the log-rank test. Multivariate analyses will be performed using proportional hazards models. These analyses will fit models to determine which risk factors may be related to a given outcome. All variables will first be examined to assure that they comply with the proportional hazards assumption. Factors found to have non-proportional hazards will be adjusted for in subsequent analyses. A stepwise model building approach will then be used to develop models for overall survival References:

1. Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplant associated-thrombotic microangiopathy. Blood. 2011. Changsirikulchai S, Myerson D, Guthrie KA, McDonald GB, Alpers CE, Hingorani SR. Renal thrombotic microangiopathy after hematopoietic cell transplant: role of GVHD in pathogenesis. Clin J Am Soc Nephrol. 4:345-53. 2009.

2. Siami K, Kojouri K, Swisher KK, Selby GB, George JN, Laszik ZG. Thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation: an autopsy study. Transplantation. 85:22-8. 2008.

3. Haines HL, Laskin BL, Goebel J, Davies SM, Yin HJ, Lawrence J, Mehta PA, Bleesing JJ, Filipovich AH, Marsh RA, Jodele S. Blood, and not urine, BK viral load predicts renal outcome in children with hemorrhagic cystitis following hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. as DOI 10.1016/j.bbmt.2011.02.012:Prepublished on March 7, 2011

4. Batts ED, Lazarus HM. Diagnosis and treatment of transplantation-associated thrombotic microangiopathy: real progress or are we still waiting? Bone Marrow Transplant. 40:709-19. 2007.

5. George JN. Hematopoietic stem cell transplantation-associated thrombotic microangiopathy: defining a disorder. Bone Marrow Transplant. 41:917-8. 2008.

6. Kojouri K, George JN. Thrombotic microangiopathy following allogeneic hematopoietic stem cell transplantation. Curr Opin Oncol. 19:148-54. 2007.

7. George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion. 44:294-304. 2004.

8. Glezerman IG, Jhaveri KD, Watson TH, Edwards AM, Papadopoulos EB, Young JW, Flombaum CD, Jakubowski AA. Chronic kidney disease, thrombotic microangiopathy, and hypertension following T cell-depleted hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 16:976-84. 2010.

9. Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, Friedman DL, Marina N, Hobbie W, Kadan-Lottick NS, Schwartz CL, Leisenring W, Robison LL. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 355:1572-82. 2006.

10. Hingorani S. Chronic kidney disease in long-term survivors of hematopoietic cell transplantation: epidemiology, pathogenesis, and treatment. J Am Soc Nephrol. 17:1995-2005. 2006.

47


Characteristic of patients who received a first allogeneic HCT reported to the CIBMTR between 2007 and 2010.

Characteristics of patients N (%)Number of patients 12454Number of centers 249Age, median (range), years 42 (<1 - 80)

0-18 3338 (27)19-29 1405 (11)30-39 1185 (10)40-49 1880 (15)50-59 2740 (22)60-69 1745 (14)>=70 161 ( 1)

Sex Male 7143 (57)Female 5311 (43)

Karnofsky score <90% 3334 (27)90-100% 7853 (63)Missing 1267 (10)

Conditioning regimen Myeloablative 5828 (47)Non-myeloablative 3971 (32)TBD 760 ( 6)Conditioning regimen not applicable to non-malignant/immune deficiency 1895 (15)

Graft type Bone Marrow 2567 (21)Peripheral blood 6768 (54)Cord blood 3007 (24)BM + PB 48 (<1)BM + UCB 28 (<1)PB + UCB 35 (<1)Other tissue 1 (<1)

Disease AML 4750 (38)ALL 1867 (15)Other leukemia 482 ( 4)CML 601 ( 5)MDS 1676 (13)Other acute leukemia 131 ( 1)NHL-non Hodgkin lymphoma 900 ( 7)HD-Hodgkin lymphoma 51 (<1)MYE-plasma cell disorder, multiple myeloma 81 (<1)Other Malignancies 20 (<1)SAA-severe aplastic anemia 657 ( 5)Inherit.abnorm.erythrocyte diff-funct. 400 ( 3)SCID & oth immune system disorders 385 ( 3)Inherit.abnorm. of platelets 17 (<1)Inherit.disord. of metabolism 219 ( 2)

48


Continued.

Characteristics of patients N (%)Histiocytic disorders 179 ( 1)Autoimmune diseases 13 (<1)Other, specify 25 (<1)

Donor type Cord blood 3007 (24)HLA-identical sibling 3526 (28)Twin 17 (<1)Other related 382 ( 3)Well-matched URD 3064 (25)Partially matched URD 952 ( 8)Mismatched URD 111 (<1)Multi donor 3 (<1)HLA match information missing URD 1392 (11)

D-R sex match M-M 2333 (19)M-F 1542 (12)F-M 1633 (13)F-F 1368 (11)Missing 5578 (45)


GVHD prophylaxis No GVHD prophylaxis 591 ( 5)Ex vivo T-cell depletion alone 117 (<1)Ex vivo T-cell depletion + post-tx immune suppression 91 (<1)CD34 selection alone 76 (<1)CD34 selection + post-tx immune suppression 59 (<1)Cyclophosphamide alone 6 (<1)Cyclophosphamide + others 10 (<1)FK506 + MMF +- others 1960 (16)FK506 + MTX +- others (except MMF) 3749 (30)FK506 + others (except MTX, MMF) 595 ( 5)FK506 alone 259 ( 2)CSA + MMF +- others (except FK506) 1932 (16)CSA + MTX +- others (except FK506, MMF) 1673 (13)CSA + others (except FK506, MTX, MMF) 577 ( 5)CSA alone 267 ( 2)Other GVHD prophylaxis 492 ( 4)

TTP-HUS No 5811 (47)Yes 348 ( 3)Missing 6295 (51)

49


Continued.

Characteristics of patients N (%)Received dialysis

No 324 ( 3)Yes 853 ( 7)Missing 11277 (91)

Year of transplant 2007-2008 7036 (56)2009-2010 5418 (44)

Median follow-up of survivors, range, months 25 (<1 - 54)

50


Study Proposal 1111-06 Study Title: Factors Predicting Treatment-Related Mortality in Pediatric Autologous Transplant Evelio D Perez-Albuerne, MD PhD, Children's National Medical Center / George Washington University, Washington, DC Specific Aims: The two aims of the study are to: Analyze the CIBMTR data on pediatric autologous transplant for malignant disease to identify

factors that are associated with an increased risk of treatment-related mortality (TRM) in pediatric autologous transplant for malignant disease.

Report descriptive statistics on rates of TRM, cause of death, early relapse, and patient, disease and transplant characteristics in pediatric autologous transplant for malignant disease.

Scientific Justification: Autologous hematopoietic cell transplant (HCT) is used to treat a variety of pediatric malignancies. Although autologous HCT patients experience a much lower rate of transplant-related mortality (TRM) compared to allogeneic HCT patients, TRM rates of 0 - 9.8% have been reported for pediatric autologous HCT in the last decade1-8. We performed an analysis of 162 autologous PBSC transplants done at Children's National Medical Center (CNMC). There were two episodes of TRM, for a rate of 1.2%. A multivariate analysis of factors including total nucleated cells /kg infused, total CD34+/kg infused, product CD34+ fraction in the infusion, conditioning chemotherapy, diagnosis, and age was carried out. Outcome variables were fever, bacteremia, intensive care requirement, and death (occurring between the time of stem cell infusion and neutrophil recovery). Factors found to have a significant effect on the rate of those transplant toxicity events included a negative association with the patient’s age at transplant (odds ratio 0.88, p = 0.001), and positive relationship with diagnoses of neuroblastoma (odds ratio 2.76, p=0.006) and “other” (not medulloblastoma or supratentorial PNET) CNS tumor (odds ratio 2.55, p=0.011). Patients less than 1 year of age had the highest incidence of toxicity events, and this is the only group that included deaths. A bivariate analysis of the effect of age on toxicity was done to determine the age group at highest risk of toxicity, which was age < 1 year old9, 10. We hypothesize that the larger CIBMTR data set will also show increased rate of TRM in pediatric autologous transplant patients < 1 year old and in those with a diagnosis of neuroblastoma. There are a few other reports published in the last decade that examined age and other risk factors for toxicity after transplant. Some of these studies found an association between very young age at transplant and increased toxicity, but others did not. Analysis of 166 children who received autologous PBSC transplant in Madrid had an overall TRM rate of 6.9% by day 180. Patients not in complete remission at the time of transplant had significantly higher TRM, but this group found no significant association between TRM and age, gender, conditioning, or number of CD34+ cells infused1. A group in Hong Kong analyzed risk factors for sinusoidal obstructive syndrome (SOS) in 144 autologous and allogeneic HCT and found that age < 3 years and busulfan/cyclophosphamide conditioning were significant risk factors for the development of SOS11 Although having a much lower TRM than allogeneic transplant, TRM still does occur in a few percent of autologous transplant patients. A larger fraction of these patients also experience significant transplant-related morbidity. Because TRM is uncommon, the number of patient deaths at any one center will be small, making it difficult for centers to assess the risk factors for TRM. Use of the larger CIBMTR dataset will allow for identification of patterns that would be difficult or impossible to detect in a single center's

51


data. In our study at CNMC, we hypothesized that if a factor truly increased the risk of TRM, it would also increase the risk of at least some less severe toxicities. This hypothesis was confirmed in our data. Identification of factors increasing autologous transplant TRM will allow the intensity of post-transplant care to be appropriately adjusted for low and high-risk populations; this should decrease the risk of TRM. For example, at CNMC, we routinely discharge brain tumor patients home after the HCT, but are now discussing keeping those patients’ < 1 year-old in the hospital until neutrophil count recovery. Patient Eligibility Population:

Age: < 19 years Disease: Any cancer Year of Transplant: 2001-2010 Donor type: Autologous

Data Requirements:

Data collection forms needed: 2400 Pre-Transplant Essential Data 2450 Post-Transplant Essential Data

Pre-Transplant Essential Data required:

Gender Age at transplant Disease Performance status Secondary malignancy (i.e. 'yes' to history of prior solid tumor or therapy-related AML/MDS) Comorbid conditions History of invasive fungal infection Conditioning

Intensity (myeloablative versus non-myeloablative or RIC) Radiation in preparative regimen (none, TBI, other radiation) Chemotherapy (containing busulfan, other agents, none)

Prior HSCT - analyze by number of previous Malignant disease status at last evaluation prior to transplant Transplant Center Time from diagnosis to transplant

Post-Transplant Essential Data required:

Date of relapse Cause of Death Survival status

Supplemental data: No supplemental data are required. The study does not involve combination with an outside database.

Sample Requirements: None

52


Study Design: The proposed study will be a retrospective analysis of information in the CIBMTR database. On the post-TED form, the diagnosis of central nervous system tumors is not subdivided in a way that would allow for an analysis to confirm or not confirm the single-institution result of a higher risk of toxicity with non-medulloblastoma / supratentorial PNET brain tumors. The post-TED forms also, unfortunately, do not capture information on the other post-transplant toxicities examined in the CNMC study: fever, bacteremia, intensive care requirement. Because of this, the proposed study focuses on TRM.

Aim 1 The data will be subjected to multivariate analysis using Cox proportional hazard models for TRM. For the purpose of this study, TRM will be defined as death occurring in first 100 days after transplant (or prior to the next transplant, whichever is shorter), and before relapse / progression. Relapse / progression will be treated as a competing risk. A subsequent transplant will be treated as a censoring event.

One model will be constructed with age and diagnosis dichotomized: age < 1 year versus ≥ 1 year, diagnosis neuroblastoma versus all others. Those were the factors significantly associated with increased toxicity (including TRM) in the CNMC study described above. A second model will be constructed with age as a continuous variable and the full set of categories for diagnosis.

Aim 2 We will report descriptive statistics on the incidence of TRM and the cause of death. We will also report descriptive statistics for the listed predictor variables in the analyzed patient group. References:

1. Foncillas, M. A. et al. Engraftment syndrome emerges as the main cause of transplant-related mortality in pediatric patients receiving autologous peripheral blood progenitor cell transplantation. J Pediatr Hematol Oncol 26, 492-6 (2004).

2. Park, J. E. et al. Efficacy of high-dose chemotherapy and autologous stem cell transplantation in patients with relapsed medulloblastoma: a report on the Korean Society for Pediatric Neuro-Oncology (KSPNO)-S-053 study. J Korean Med Sci 25, 1160-6 (2010).

3. Sung, K. W. et al. Efficacy of tandem high-dose chemotherapy and autologous stem cell rescue in patients over 1 year of age with stage 4 neuroblastoma: the Korean Society of Pediatric Hematology-Oncology experience over 6 years (2000-2005). J Korean Med Sci 25, 691-7 (2010).

4. Spreafico, F. et al. Treatment of high-risk relapsed Wilms tumor with dose-intensive chemotherapy, marrow-ablative chemotherapy, and autologous hematopoietic stem cell support: experience by the Italian Association of Pediatric Hematology and Oncology. Pediatr Blood Cancer 51, 23-8 (2008).

5. Fraser, C. J. et al. Autologous stem cell transplantation for high-risk Ewing's sarcoma and other pediatric solid tumors. Bone Marrow Transplant 37, 175-81 (2006).

6. Lieskovsky, Y. E. et al. High-dose therapy and autologous hematopoietic stem-cell transplantation for recurrent or refractory pediatric Hodgkin's disease: results and prognostic indices. J Clin Oncol 22, 4532-40 (2004).

7. Anak, S. et al. Allogeneic versus autologous versus peripheral stem cell transplantation in CR1 pediatric AML patients: a single center experience. Pediatr Blood Cancer 44, 654-9 (2005).

8. Cesaro, S. et al. High-dose melphalan with autologous hematopoietic stem cell transplantation for acute myeloid leukemia: results of a retrospective analysis of the Italian Pediatric Group for Bone Marrow Transplantation. Bone Marrow Transplant 28, 131-6 (2001).

9. Dubrovsky, L. et al. Pediatric autologous peripheral blood stem cell harvest: factors affecting time to engraftment and transplant toxicity. Biol Blood Marrow Transplant 16, S249 (2010).

10. Dubrovsky, F. et al. Analysis of Pediatric Autologous PBSC Apheresis and Transplant: Age is a Major Factor Affecting Post-Transplant Toxicity. Pediatr Blood Cancer, forthcoming.

53


11. Cheuk, D. K. et al. Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant 40, 935-44 (2007).

12. Ozkaynak, M. F. et al. A pilot study of addition of amifostine to melphalan, carboplatin, etoposide, and cyclophosphamide with autologous hematopoietic stem cell transplantation in pediatric solid tumors-A pediatric blood and marrow transplant consortium study. J Pediatr Hematol Oncol 30, 204-9 (2008).

13. Won, S. C. et al. Autologous peripheral blood stem cell transplantation in children with non-Hodgkin's lymphoma: A report from the Korean society of pediatric hematology-oncology. Ann Hematol 85, 787-94 (2006).

54


Characteristic of patients who received an autologous HCT reported to the CIBMTR between 2000 and 2010 in autologous research retrieval.


0-9 691 (70)10-18 301 (30)


Performance status <90% 203 (20)90-100% 733 (74)Missing 56 ( 6)

Graft type Bone marrow 48 ( 5)Peripheral blood 904 (91)Cord blood 4 (<1)BM + PB 35 ( 4)BM + UCB 1 (<1)

Time from diagnosis to transplant, median (range), months 7 (<1 - 1000)Disease

AML 25 ( 3)ALL 2 (<1)Other leukemia 1 (<1)CML 1 (<1)MDS 1 (<1)NHL-non Hodgkin lymphoma 29 ( 3)HD-Hodgkin lymphoma 68 ( 7)MYE-plasma cell disorder, multiple myeloma 4 (<1)Other Malignancies 861 (87)

Sub-group of other malignancies Head and neck 1 (<1)Lung cancer, small cell 1 (<1)Renal Carcinoma/Kidney 1 (<1)Testicular 9 ( 1)Ovary (epithelial) 5 (<1)Sarcoma, NOS 3 (<1)Soft tissue sarcoma (Include PNET) 8 (<1)Bone sarcoma (excluding Ewing sarcoma) 12 ( 1)Central nervous system tumors 108 (13)Wilms Tumor 24 ( 3)Neuroblastoma 408 (47)Retinoblastoma 10 ( 1)Ewing sarcoma 42 ( 5)Germ cell tumor 9 ( 1)

55


Continued.

Characteristics of patients N (%)Medulloblastoma 141 (16)PNET 12 ( 1)Rhabdomyosarcoma 10 ( 1)Neurogenic sarcoma 1 (<1)Other malignancy, specify 38 ( 4)Soft tissue sarcoma, (excluding Ewing family tumors) 2 (<1)Ewing family tumors of bone (includes PNET) 12 ( 1)Ewing family tumors, extraosseous (includes PNET) 4 (<1)

Year of transplant 2000-2003 337 (34)2004-2007 400 (40)2008-2010 255 (26)

Median follow-up of survivors, range, months 39 (1 - 126)

56


Characteristic of patients who received an autologous HCT reported to the CIBMTR between 2000 and 2010 in registration retrieval.


0-9 3817 (63)10-18 2226 (37)

Sex Male 3539 (59)Female 2504 (41)

Performance status <90% 2973 (49)90-100% 1413 (23)Missing 1657 (27)

Graft type Bone marrow 490 ( 8)Peripheral blood 5441 (90)Cord blood 8 (<1)BM + PB 103 ( 2)BM + UCB 1 (<1)

Time from diagnosis to transplant, median (range), months 8 (<1 - 1000)Disease

AML 230 ( 4)ALL 57 (<1)Other leukemia 2 (<1)CML 3 (<1)MDS 4 (<1)Other acute leukemia 5 (<1)Non-Hodgkin lymphoma 365 ( 6)Hodgkin lymphoma 808 (13)Plasma cell disorder/Multiple Myeloma 60 (<1)Other malignancies 4509 (75)

Sub-group of other malignancies Solid tumor, NOS 5 (<1)Head and neck 2 (<1)Lung cancer, small cell 1 (<1)Mediastinal neoplasms, specify 1 (<1)Hepatobiliary 2 (<1)Renal Carcinoma/Kidney 8 (<1)Testicular 26 (<1)Ovarian (epithelial) 17 (<1)Sarcoma, NOS 19 (<1)Bone sarcoma(excluding Ewing sarcoma) 93 ( 2)Melanoma 1 (<1)Central nervous system tumors, including CNS PNET 405 ( 9)Wilms Tumor 162 ( 4)Neuroblastoma 2278 (51)

57


Continued.

Characteristics of patients N (%)Retinoblastoma 58 ( 1)Ewing sarcoma 225 ( 5)Germ cell tumor, extragonadal 109 ( 2)Medulloblastoma 671 (15)PNET 26 (<1)Rhabdomyosarcoma 70 ( 2)Synovial sarcoma 1 (<1)Neurogenic sarcoma 3 (<1)Other malignancy, specify 225 ( 5)PNET non-CNS 10 (<1)None sarcoma, excluding Ewing family tumors 4 (<1)Soft tissue sarcoma, (excluding Ewing family tumors) 5 (<1)Ewing family tumors of bone (includes PNET) 57 ( 1)Ewing family tumors, extraosseous (includes PNET) 25 (<1)

Year of transplant 2000-2003 2179 (36)2004-2007 2149 (36)2008-2010 1715 (28)

Median follow-up of survivors, range, months 32 (<1 - 126)

58


Study Proposal 1111-56 Study Title: Total Body Irradiation and Radiation Therapy Prior to Hematopoietic Cell Transplant: A Survey of Transplant Specialists Associated with the Center for International Bone and Marrow Transplant Research. Christopher A. Barker, MD, Memorial Sloan-Kettering Cancer Center, New York, NY Specific Aims: The aims of the study are to:

To determine why transplant specialists associated with the CIBMTR use total body irradiation (TBI) or other radiation therapy (RT) as part of hematopoietic cell transplant (HCT).

To characterize how TBI is performed at institutions associated with the CIBMTR. Scientific Justification: Recent research suggests that the use of total body irradiation (TBI) and other forms of radiation therapy (RT) prior to hematopoietic cell transplant (HCT) vary widely in centers associated with the Center for International Bona and Marrow Transplant Research (CIBMTR) (Barker, Hong, et al. submitted; Hong, Barker et al, submitted). Use of TBI varies by patient age, geographic location, human development index, cell source, and disease indications. Moreover, TBI appears to be used less frequently in recent years. RT directed at the central nervous system (CNS), gonads, lymphoid tissues, spleen, residual tumor and other tissues has also been observed in patients undergoing HCT. However, reasons for variations in TBI and RT use are unclear.

Since the early years of HCT, a wide variety of TBI techniques have been described (AAPM 1986). The last report describing the techniques of TBI at several centers in North America and England was over 30 years ago, and it is possible that techniques used now are considerably different (Kim, Khan et al. 1980). CIBMTR data does not accurately reflect the salient details of TBI (Pasquini, personal communication), and therefore a detailed assessment of current techniques employed would be valuable. Moreover, variations in TBI technique are clinically relevant; variations in shielding, boosting, fractionation and dose-rate have demonstrated significant differences in outcome in randomized clinical trials (Labar, Bogdanic et al. 1992) (Clift, Buckner et al. 1998) (Ozsahin, Belkacemi et al. 1994) (Deeg, Sullivan et al. 1986) (Girinsky, Benhamou et al. 2000) (Gratwohl, van Biezen et al. 2000).

Given the considerable variation in use of TBI and RT reported to the CIBMTR, and the possible variation in TBI techniques, and survey of transplant specialists would be informative to transplant community.

Patient Eligibility Population: Transplant specialists associated with the CIBMTR will be surveyed about the use of TBI and RT at their institution. No patient data will be required. Data Requirements: Data will be generated using a web-based survey designed and implemented with the help of the Memorial Sloan-Kettering Cancer Center (MSKCC) Web Survey Core: http://www.mskcc.org/research/web-survey-core

59


Eligible participants in the survey will be identified through the CIBMTR and contacted via electronic mail. Supplemental data: Supplemental data gathering will not be required of the CIBMTR staff. However, analysis of the data with CIBMTR resources would be valuable. Sample Requirements: None Study Design: A web-based survey will be developed with input from transplant specialists in hematologic and radiation oncology. General sections will include respondent information, transplant practice characteristics, transplant strategies, TBI and RT technique details, opinions about TBI and RT.

Surveys will be sent to individuals identified through the CIBMTR by email. Surveys will available on the internet through MSKCC. Non-responders will be contacted again by email every 3 weeks, on 5 occasions, or until a response is received. References:

1. AAPM, T.G.o.R.T.C.o. (1986). The Physical Aspects of Total and Half Body Photon Irradiation. J. V. Dyk. New York, American Institute of Physics: 55.

2. Clift, R. A., C. D. Buckner, et al. (1998). "Long-term follow-up of a randomized trial of two irradiation regimens for patients receiving allogeneic marrow transplants during first remission of acute myeloid leukemia." Blood 92(4): 1455-1456.

3. Deeg, H. J., K. M. Sullivan, et al. (1986). "Marrow Transplantation for Acute Nonlymphoblastic Leukemia in 1st Remission - Toxicity and Long-Term Follow-up of Patients Conditioned with Single Dose or Fractionated Total-Body Irradiation." Bone Marrow Transplantation 1(2): 151-157.

4. Girinsky, T., E. Benhamou, et al. (2000). "Prospective randomized comparison of single-dose versus hyperfractionated total-body irradiation in patients with hematologic malignancies." Journal of Clinical Oncology 18(5): 981-986.

5. Gratwohl, A., A. van Biezen, et al. (2000). "Role of splenic irradiation in patients with chronic myeloid leukemia undergoing allogeneic bone marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation." Biol Blood Marrow Transplant 6(2A): 211-213.

6. Kim, T. H., F. M. Khan, et al. (1980). "A report of the work party - comparison of total-bodyirradiation techniques for bone-marrow transplantation." International Journal of Radiation Oncology Biology Physics 6(6): 779-784.

7. Labar, B., V. Bogdanic, et al. (1992). "Total-Body Irradiation with or without Lung Shielding for Allogeneic Bone-Marrow Transplantation." Bone Marrow Transplantation 9(5): 343-347.

8. Ozsahin, M., Y. Belkacemi, et al. (1994). "Total-Body Irradiation and Cataract Incidence - a Randomized Comparison of 2 Instantaneous Dose-Rates." International Journal of Radiation Oncology Biology Physics 28(2): 343-347.

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Characteristics of recipients in TED database given TBI for the first auto vs. allo transplant between 2000 and 2010

Variable Allogeneic AutologousNumber of patients 36311 3988Number of centers 404 259Age, years <10 yrs 4311 (12) 87 (2) 10-19 yrs 5601 (15) 140 (4) 20-29 yrs 5351 (15) 389 (10) 30-39 yrs 5724 (16) 510 (13) 40-49 yrs 6916 (19) 922 (23) 50-59 yrs 5870 (16) 1298 (33) 60-69 yrs 2335 (6) 589 (15) >= 70 yrs 203 (<1) 53 (1)Sex Male 21465 (59) 2481 (62) Female 14846 (41) 1507 (38)Primary disease Acute myelogenous leukemia 11037 (30) 534 (13) Acute lymphoblastic leukemia 11692 (32) 186 (5) Chronic myelogenous leukemia 3105 (9) 7 (<1) Myelodysplastic disorders 2783 (8) 12 (<1) Non-Hodgkin lymphoma 3218 (9) 2241 (56) Hodgkin lymphoma 181 (<1) 262 (7) Multiple myeloma 457 (1) 431 (11) Other malignancies 2075 (6) 231 (6) Severe aplastic anemia 1067 (3) 0 Other non-malignancies 696 (2) 84 (2)Year of transplant 2000 3994 (11) 835 (21) 2001 3790 (10) 610 (15) 2002 3616 (10) 460 (12) 2003 3232 (9) 324 (8) 2004 3274 (9) 297 (7) 2005 3147 (9) 329 (8) 2006 3101 (9) 255 (6) 2007 2858 (8) 188 (5) 2008 3001 (8) 265 (7) 2009 3120 (9) 211 (5) 2010 3178 (9) 214 (5)WHO region Africa 122 (<1) 8 (<1) Americas 23544 (65) 3412 (86) Eastern Mediterranean 579 (2) 30 (<1) Europe 8363 (23) 434 (11) Southeastern Asia 1531 (4) 77 (2) Western Pacific 2165 (6) 27 (<1) Missing 7 (<1) 0Graft type Bone marrow 12567 (35) 186 (5) Peripheral blood 19663 (54) 3747 (94) Cord blood 3792 (10) 1 (<1) Missing 289 (<1) 54 (1)

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Continued.

Variable Allogeneic AutologousDonor type HLA-identical sibling 14474 (40) 0 Twin 174 (<1) 0 Other relative 2459 (7) 0 Unrelated donor 18571 (51) 0 NA 633 (2) 3988

62


Characteristics of recipients in CRF database given TBI for the first auto vs. allo transplant between 2000 and 2010

Variable Allogeneic AutologousNumber of patients 15112 567Number of centers 288 90Age, years <10 yrs 2125 (14) 8 (1) 10-19 yrs 2545 (17) 16 (3) 20-29 yrs 2143 (14) 37 (7) 30-39 yrs 2183 (14) 58 (10) 40-49 yrs 2659 (18) 123 (22) 50-59 yrs 2450 (16) 192 (34) 60-69 yrs 917 (6) 124 (22) >= 70 yrs 90 (<1) 9 (2)Sex Male 8932 (59) 350 (62) Female 6180 (41) 217 (38)Primary disease Acute myelogenous leukemia 4711 (31) 54 (10) Acute lymphoblastic leukemia 4621 (31) 27 (5) Chronic myelogenous leukemia 1300 (9) 0 Myelodysplastic disorders 1189 (8) 1 (<1) Non-Hodgkin lymphoma 1204 (8) 313 (55) Hodgkin lymphoma 59 (<1) 33 (6) Multiple myeloma 153 (1) 92 (16) Other malignancies 853 (6) 19 (3) Severe aplasitc anemia 602 (4) 0 Other non-malignancies 420 (3) 28 (5)Year of transplant 2000 1558 (10) 111 (20) 2001 1497 (10) 93 (16) 2002 1427 (9) 60 (11) 2003 1364 (9) 27 (5) 2004 1549 (10) 21 (4) 2005 1527 (10) 40 (7) 2006 1556 (10) 38 (7) 2007 1256 (8) 47 (8) 2008 1356 (9) 70 (12) 2009 1211 (8) 37 (7) 2010 811 (5) 23 (4)WHO region Africa 73 (<1) 1 (<1) Americas 11792 (78) 564 (99) Eastern Mediterranean 242 (2) 0 Europe 1807 (12) 0 Southeastern Asia 474 (3) 0 Western Pacific 724 (5) 2 (<1)Graft type Bone marrow 5324 (35) 9 (2) Peripheral blood 7370 (49) 552 (97) Cord blood 2401 (16) 0 Missing 17 (<1) 6 (1)

63


Continued.

Variable Allogeneic AutologousDonor type HLA-identical sibling 3885 (26) 0 Twin 44 (<1) 0 Other relative 407 (3) 0 Unrelated 10741 (71) 0 NA 35 (<1) 567

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Study Proposal 1211-01 Study Title: Sequence of cyclophosphamide and total body irradiation in evaluation of relapse, mortality, and graft versus host disease in patients with AML undergoing hematopoietic stem cell transplantation. Jennifer Holter Chakrabarty, MD, George B. Selby, MD, Robert B. Epstein, MD and Amber M. Borden, MD, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma Specific Aims:

The aim of the study is to evaluate the impact that the sequencing of the conditioning regimen has on the outcome of allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia. Specifically, we would like to evaluate the effect that the sequence of administration of cyclophosphamide and total body irradiation has on the relapse rate, mortality rate, and graft versus host disease incidence and severity in patients with AML who are in a complete remission and undergo either HLA matched sibling or unrelated donor bone marrow transplants. We recently performed a local retrospective review of our bone marrow transplantation patients at OU Health Sciences Center which has been accepted for poster presentation at the national ASBMT meeting in February 2012. We would also like to do a CIBMTR registry evaluation to evaluate the relapse rate, mortality rate, and incidence and severity of graft versus host disease in this selected patient population on a much larger scale.

Scientific Justification: Controversy concerning the optimal pre-transplantation regimen and sequence of modalities for patients with myeloid malignancies still persists. The optimum sequencing of the two agents that will maximize tumor cell kill and minimize normal tissue damage is unknown. Animal preclinical data in the early 1990’s showed that cyclophosphamide given 24 hours after total body irradiation (TBI) caused less lung damage but more bone marrow damage in the mouse model. 1 However, the anti-leukemic effect of cyclophosphamide followed by total body irradiation was better than the reverse in mice with B cell leukemia/lymphoma. 2 Such studies have not been performed in humans to establish the optimal sequencing of cyclophosphamide and total body irradiation. Synergism between chemotherapy and radiation therapy exists. In early studies, total body irradiation was used solely as the pre-transplant conditioning regimen. 3 Cyclophosphamide was later added to the myeloablative regimen as it allowed lower TBI doses to be used which decreased the incidence of pulmonary toxicity and rates of leukemia relapse. The standard regimen used for disease ablation and immunosuppression in patients with leukemia was established in the early 1970’s, and is cyclophosphamide (60 mg/kg/day X 2 days) which is followed 3-4 days thereafter with total body irradiation. A number of modifications to this regimen have been introduced to improve the rates of engraftment and reduce the relapse rate and radiation complications. During the early 1990s, randomized studies evaluated outcomes in patients receiving cyclophosphamide and total body irradiation compared to busulfan and cyclophosphamide as conditioning regimens pre-transplantation. In a French study, the outcomes were better for the cyclophosphamide and total body irradiation group with increased disease free survival and overall survival along with decreased relapse and transplantation-related mortality as compared to the busulfan and cyclophosphamide group. 4 Several randomized studies, as well as retrospective registry data comparing the two types of preparative regimens, report conflicting results concerning outcomes and toxicities. A recent large metaanalysis of randomized controlled trials evaluating 730 patients showed that cyclophosphamide and total body irradiation was associated with a modest but non-significant reduction in all cause mortality, relapse of leukemia, and transplant-related mortality compared to busulfan and cyclophosphamide. The conclusion of the metaanalysis is that although not overly superior, the evidence favors cyclophosphamide and total body irradiation over busulfan and cyclophosphamide as the first choice conditioning regimen in patients with leukemia. 5 For

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these reasons, cyclophosphamide and total body irradiation have largely been chosen as the myeloablative preparative conditioning regimen prior to allogeneic hematopoietic stem cell transplant in patients with AML. To our knowledge, no clinical study has specifically evaluated the sequencing of cyclophosphamide and total body irradiation prior to HST in patients with AML in complete remission and how the sequencing affects the rate of relapse, mortality, and graft versus host disease. The standard pre-transplant conditioning regimen which is accepted by most clinicians is to receive cyclophosphamide followed by hyper-fractionated total body irradiation and then followed by the stem cell infusion. It is not know if total body irradiation starting seven days prior to the stem cell infusion then following with cyclophosphamide may give better outcomes. The bone marrow transplant physicians at our institution believe that the latter may be true although there are presently no clinical studies to confirm this. We did a retrospective analysis of patients treated at our institution with both sequential regimens to see if a suggestion of the optimal sequence of cyclophosphamide and total body irradiation exists. We examined 44 patients with acute myeloid leukemia ages 7 to 56 who underwent HLA matched allogeneic transplantation at our center between 1/2000 and 4/2011. Twenty-six patients were in first complete remission (CR1), sixteen patients were in CR2, and two patients were in CR3 at the time of the stem cell transplantation. Pre-transplant conditioning regimen was myeloablative with two days of cyclophosphamide 60 mg/kg/d followed by four days of hyperfractionated TBI (1200cGy) (n=32) or the reverse sequence of TBI followed by cyclophosphamide(n=12). The conditioning regimen was followed by marrow (n=31) or peripheral blood transplant (n=13) from unrelated or related donors. All patients had graft-versus-host disease (GVHD) prophylaxis with cyclosporine and methotrexate (n=31) or tacrolimus and methotrexate (n=13). Sixteen patients remain alive after a median of 47 months (range, 5 to 134 months), with 29 deaths, mostly from relapse (n=13) and infections (n =9). The relapse rate of patients who received cyclophosphamide followed by TBI was 25% (8 of 32 patients) and 42% (5 of 12 patients) in patients receiving TBI followed by cyclophosphamide. The mortality rate of patients receiving cyclophosphmide followed by TBI was 66% (21 of 32 patients) and 67% (8 of 12 patients) with TBI followed by cyclophosphamide. Severe acute-GVHD appeared in three (25%) patients receiving TBI followed by cyclophosphamide and two (6%) patients receiving cyclophosphamide followed by TBI. Severe chronic-GVHD appeared in one (8%) patient receiving TBI followed by cyclophosphamide as compared to five (16%) patients receiving cyclophosphamide followed by TBI. Therefore, we concluded that patients undergoing allogeneic transplant can receive either cyclophosphamide followed by TBI or the reverse sequence. We were unable to identify a significant difference in the relapse rate, mortality rate, or GVHD between the two sequences of cyclophosphamide and TBI in this small group of patients. A more complete registry analysis examining this issue could shed light on the most optimum schedule of cyclophosphamide and TBI in the pre-transplant regimen. We would like to further evaluate these questions with a larger patient population with a CIBMTR review to specifically evaluate the effect that the timing and sequence of cyclosphosphamide and total body irradiation has on the transplantation outcomes in this population.

Patient Eligibility Population: Sibling and unrelated donor bone marrow transplantation in patients reported to the NMDP who meet the following criteria: (a) patients who received cyclophosphamide 60 mg/kg on two to three consecutive days and hyperfractionated total body irradiation twice daily with total dose (1200cGy-1300 cGy) as conditioning regimen pre-transplant (b) patients between ages of 2 and 60 years of age (c) AML in complete remission only (CR1 or CR2) (d) allogeneic sibling and allogeneic unrelated donor transplants (e) hematopoietic stem cell transplantion occurring between years of 2000 and 2010.

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Data Requirements: Pre-Transplant Essential Data requested:

Acute Myeloid Leukemia in 1st complete remission and 2nd complete remission by cytogenetic or molecular remission.

All cytogenetic abnormalities. Including therapy related AML and AML transforming from MDS or MPS Allogeneic donors including HLA-matched relatives, HLA-identical siblings, and unrelated

donor Bone marrow and peripheral blood stem cells as cell source Myeloablative preparative regimen with cyclophosphamide and total body irradiation including

dosages Sequence of the preparative regimen (was cyclophosphamide or total body irradiation given

first?) Post-Transplant Essential Data at Day 100: Date of relapse Cause of Death Survival status Was donor cellular infusion performed? Was donor cellular infusion planned or not planned? Maximum overall grade of acute graft versus host disease Maximum severity/stage of liver and skin involvement with GVHD Was lung GVHD present?

Post-Transplant Essential Data at 1 year:

Survival status Cause of death Date of relapse Maximum extent of chronic graft versus host disease

Supplemental data: No supplemental data are required.

Sample Requirements: None Study Design: Retrospective review of paired transplants receiving cyclophosphamide and total body irradiation versus total body irradiation and cyclophosphamide. References:

1. Yan et al. Cyclophosphamide 24 hours before or after total body irradiation: effects on lung and bone marrow. Radiotherapy and Oncology. 1991; 21: 149-156 2. Lowenthal et al. Optimization of conditioning therapy for leukemia prior to BMT. I. Optimal synergism between cyclophosphamide and total body irradiation for eradication of murine B

cell leukemia (BCL1). Bone Marrow Transplantation. 1993; 12:109-113 3. Thomas et al. Allogeneic Marrow Grafting for Hematologic Malignancy Using HLA Matched Donor-Recipient Sibling Pairs. Blood. 1971; 38: 267-287. 4. Blaise et al. Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the Groupe d’ Etudes de la Greffe de Moelle Osseuse. Blood. 1992;79:2578-2582.

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5. Gupta et al. Cyclophosphamide plus total body irradiation compared with busulfan plus cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplantation in patients with leukemia: a systematic review and meta-analysis. Hematology/Oncology and Stem Cell Therapy.2011;4(1):17-29.

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Characteristics of patients ≥18 years of age who received cyclophosphamide and fractionated TBI>800 HLA-identical sibling or unrelated donor transplant AML in first complete remission

reported to the CIBMTR between 2003 and 2010

Characteristics of patients: N (%)Number of patients 701Number of centers 98Age at transplant, years

Median (range) 42 (18-63)10-19 yrs 29 ( 4)20-29 yrs 140 (20)30-39 yrs 149 (21)40-49 yrs 217 (31)50-59 yrs 161 (23)>=60 yrs 5 ( 1)



Total Cy dose <55 mg/kg 41 ( 6)55-96 mg/kg 164 (23)97-120 mg/kg 389 (55)121-135 mg/kg 79 (11)>135 mg/kg 22 ( 3)Missing 6 ( 1)

Type of AML denovo AML 581 (83)secondary AML 115 (16)Missing 5 ( 1)

WBC at diagnosis, x109/L <30 420 (60)30-100 130 (19)>100 76 (11)Missing 75 (11)

Cytogenetic test Abnormal 409 (58)Normal 186 (27)Missing 106 (15)

Type of donor HLA-id sibling 293 (42)URD well-matched 221 (32)URD partially matched 62 ( 9)URD mismatched 12 ( 2)URD matching to be classified 113 (16)

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Continued.

Characteristics of patients: N (%)D-R sex match

M-M 178 (25)M-F 167 (24)F-M 107 (15)F-F 119 (17)Missing 130 (19)

D-R CMV status +/+ 174 (25)+/- 77 (11)-/+ 143 (20)-/- 167 (24)Missing 140 (20)

Graft type Bone marrow 165 (24)Peripheral blood 536 (76)

Year of HCT 2003-2004 162 (23)2005-2006 212 (30)2007-2008 139 (20)2009-2010 188 (27)

ATG or Campath ATG alone 92 (13)Campath alone 9 ( 1)No ATG or Campath 598 (85)Missing 2 (<1)

GVHD Prophylaxis No GVHD prophylaxis 14 ( 2)Ex vivo T-cell depletion alone 22 ( 3)Ex vivo T-cell depletion + post-tx immune supression 13 ( 2)CD34 selection alone 8 ( 1)CD34 selection + post-tx immune supression 16 ( 2)FK506 + MMF +- others 46 ( 7)FK506 + MTX +- others (except MMF) 325 (46)FK506 + others (except MTX, MMF) 44 ( 6)FK506 alone 9 ( 1)CSA + MMF +- others (except FK506) 7 ( 1)CSA + MTX +- others (except FK506, MMF) 181 (26)CSA + others (except FK506, MTX, MMF) 2 (<1)CSA alone 11 ( 2)Other GVHD prophylaxis 3 (<1)

Median (range) FU of survivors, months 38 (3-98)*Cord blood were excluded

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Cyclophosphamide date availability is as follows: Cyclophosphamide Date Availability Missing, N (Row %) Available, N (Row

%) Total N

Number of Patients 226 (32) 475 (68) 701Year of Transplant 2003 46 (74) 16 (26) 62 2004 52 (52) 48 (48) 100 2005 45 (42) 63 (58) 108 2006 51 (49) 53 (51) 104 2007 32 (43) 42 (57) 74 2008 0 (0) 65 (100) 65 2009 0 (0) 86 (100) 86 2010 0 (0) 102 (100) 102Note: Start date of TBI has always been collected in CIBMTR data collection forms (TBI date is available for all patients); cyclophosphamide date has been collected since 2003. Order of Cyclophosphamide when given with TBI as part of conditioning regimen. TBI_first Frequency (%) No 219 (31)Yes 253 (36)Same Day 3 (<1)Cy missing date 226 (32)

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Study Proposal 1011-06 Study Title: Transplant in Older Adults: Is it feasible in those 70 years and older? Lori Muffly, MD, University of Chicago, Chicago, IL Andrew S. Artz, MD, MS, University of Chicago, IL Specific Aims:

To describe the baseline characteristics of patients 70 years and older receiving an allogeneic hematopoietic cell transplant (HCT) reported to the CIBMTR

To detail the secular trend in absolute numbers and proportion of all transplanted patients for adults 70 years and older undergoing HCT.

To examine transplant outcomes of day 180 non-relapse mortality (NRM), engraftment, and a GVHD

To assess OS and DFS in patients with standard risk disease: AML or ALL in remission and MDS with < 5% blasts.

To explore prognostic factors associated with increased day 180 NRM including conditioning regimen intensity, PS, disease status, graft source, time period, comorbidity, and T-cell depletion.

Scientific Justification: Allogeneic HCT offers the only potential curative therapy for many hematologic malignancies. In the past, older adults were often denied access to the potentially curative modality of HCT out of concern for increased toxicity and mortality, which thus excluded the majority of patients that may have gained benefit. In recent years, the development of reduced intensity conditioning (RIC) and non-myeloablative regimens, coupled with improvements in supportive care measures and more accurate HLA typing methods, has broadened the application of HCT to include older adults1. According to the CIBMTR database, from 2002-2009, 44% of patients undergoing HCT were older than 50, and 20% were older than 60 years of age2. The feasibility of HCT in adults over 50 years of age, and even older than 65, has been detailed in several recent reports3-7. In a CIBMTR analysis of patients over the age of 40 with AML in first remission or MDS, there was no significant difference seen in relapse rate, NRM, or survival amongst patients aged 40-50 and patients older than 65. Similar results have been reported in European registry studies, where disease status and cytogenetic abnormalities, rather than age, seemed to predict for worse outcomes, suggesting that older age should not be a contraindication to performing allogeneic HCT. Although adults over the age of 65 have been included in these retrospective analyses, the number of patients transplanted in their eighth decade remains small and poorly if ever quantified and little can be gleaned from the current literature regarding characteristics and outcomes of this oldest cohort of patients. For each 5 year increase in age from 65 years and older, the proportion of cancer patients with comorbidity, disability and/or geriatric syndromes increases8. Because 70 has been a traditional inflection point of high risk of geriatric syndromes, it has been a recommendation that a comprehensive geriatric assessment be performed on all patients 70 years and older9. As the population continues to age, with the proportion of people who are 65 and older estimated to be 20% of the total population by 2030, and with 50% of all cancers and 70% of cancer mortality occurring in this age group, it is conceivable that the number of patients eligible for and offered HCT in their eighth decade will continue to grow10.

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Despite the frequent conclusions that older age is not a barrier or contraindication to transplant, almost no data exist on the tolerance of patients 70 years and older. Therefore, we propose an observational study describing the baseline characteristics, outcomes and prognostic factors for older adults having undergone HCT since 2000. We believe that this descriptive analysis will add significantly to the literature regarding transplantation in the elderly, and be of value to transplant physicians as more patients in this age group are referred for transplant. Patient Eligibility Population: We will include all patients who underwent an allogeneic hematopoietic cell transplant (HCT) at 70 years or older for any disease between 2000 and 2010. Variables to be collected include year of transplant, age at transplant, recipient sex, Karnofsky PS, comorbidities as available, prior transplant, disease, interval from diagnosis to HCT, disease status at transplant, year of transplant, donor, donor age, degree of HLA match, donor age, graft type, conditioning regimen, GVHD prophylaxis with or without T-cell depletion (and type ATG vs alemtuzumab) and duration of follow-up. Outcome variables include days to neutrophil engraftment, acute GVHD, chronic GVHD, NRM with specific cause of death, relapse rate, disease free survival, and overall survival.

Data Requirements: The information requested is routinely collected on the data submission forms. Comorbidity has been reported more recently only.

Sample Requirements:* None Study Design:

Describe baseline characteristics. Descriptive statistics will be employed to summarize the baseline characteristics of all adults 70 years and older undergoing allogeneic HCT over the past decade. The number and proportion of adults 70 years and older will be presented for each year and then dichotomized and compared for the time period of 2000- 2005 vs 2006 to 2010.

To determine the non-relapse mortality of older adults undergoing HCT, the cumulative incidence of non-relapse related deaths to day 180 and the appropriate 95% confidence intervals will be calculated. We select day 180 NRM to represent early toxicity from transplant. In our own data, deaths due to NRM tend to be steepest over this period and a better reflection of acute death compared to day 100 in this era of reduced intensity conditioning. We also have noted that deaths after 1 and 2 years, may not be the best measure of early acute toxicity and become difficult to disentangle from relapse, chronic GVHD, and other competing causes of death in this population. No sample size will be required in this descriptive study. Should an adequate sample be detected, additional analysis will be pursued including estimates and 95% CI for the following: NRM at 2 years, cumulative incidence of aGVHD grades II-IV, cumulative incidence of chronic GVHD, and neutrophil and platelet engraftment. To generate estimates of outcomes, we will also report 3 year OS and DFS on the subset of patients with AML, MDS and ALL in remission or (low blast count for MDS) to enable comparison to prior publications such as McClune B et al, JCO. To the extent this prior analysis by McClune contained some of these patients, it may be prudent to compare outcomes for the 70 years and older cohort (divided by 70 to 74 and 75 and older if sample size permits) to younger adults such as 60-64, and 65 to 69). The cytogenetics at diagnosis would be summarized, to the extent available for this group. Finally, we would like to look at the subset of AML, ALL, and MDS not in remission or (blasts 5% or more for MDS) for the same outcome measures.

Prognostic factor analysis: We believe subsets with a day 180 NRM of 20% or less support the application of HCT in these groups. For subsets with an NRM of 50% or more at day 180, transplant should be done with extreme caution or on specific clinical trials. We estimate that to

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have 15% precision for an adverse risk factor would require around 36 to 39 subjects if the actual NRM is 50 to 70%. Therefore, an adverse risk factor with a NRM of 60% in these older adults (such as poor PS) would translate into a 95% CI of 45 to 75%. Should adequate numbers exist, we will analyze the following prognostic factors: myeloablative versus RIC/NMA or RIC vs NMA conditioning on NRM, related versus well-matched unrelated donor (we assume few cords and mismatches adult donors will be done), T-cell depletion versus not, HCT 3 or more versus not (if available), PS of 80% or less or not, BM vs PBSC and donor age for unrelated donors (e.g., <35 years or not). For related donors, donor age is correlated with recipient age and requires more complex modeling that may be pursued if the sample size permits.

Limitations. The largest limitation is the possibility of few patients 70 years and older undergoing HCT. We believe that finding warrants reporting itself and caution against the general conclusion that age alone should not be a barrier to transplant. This might also translate into specific trials, potentially run by the BMT-CTN of older adults 70 years and older exclusively. We expect to have relatively wide confidence intervals that limit prognostic factor analysis. However, certain prognostic factors may have very high day 180 NRM such as poor PS, or disease not in remission (as NRM is higher for active disease). We have not planned to compare the results to younger cohorts as the finding of similar, less or more toxicity does not necessarily appear meaningful in this highly select group. Further, comparisons to non-transplant groups would likely not be meaningful without a method to adjust for baseline characteristics of health and disease.

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. Deeg HJ, Sandmaier BM: Who is fit for allogeneic transplantation? Blood 116:4762-70, 2010 3. Chevallier P, Szydlo RM, Blaise D, et al: Reduced-Intensity Conditioning before Allogeneic

Hematopoietic Stem Cell Transplantation in Patients Over 60 Years: A Report from the SFGM-TC. Biol Blood Marrow Transplant, 2011

4. McClune BL, Weisdorf DJ, Pedersen TL, et al: Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol 28:1878-87, 2010

5. Schetelig J, Bornhauser M, Schmid C, et al: Matched unrelated or matched sibling donors result in comparable survival after allogeneic stem-cell transplantation in elderly patients with acute myeloid leukemia: a report from the cooperative German Transplant Study Group. J Clin Oncol 26:5183-91, 2008

6. Lim Z, Brand R, Martino R, et al: Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol 28:405-11, 2010

7. Wallen H, Gooley TA, Deeg HJ, et al: Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older. J Clin Oncol 23:3439-46, 2005

8. Koroukian SM, Murray P, Madigan E: Comorbidity, disability, and geriatric syndromes in elderly cancer patients receiving home health care. J Clin Oncol 24:2304-10, 2006

9. Extermann M, Aapro M, Bernabei R, et al: Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG). Crit Rev Oncol Hematol 55:241-52, 2005

10. Lichtman SM: Therapy insight: Therapeutic challenges in the treatment of elderly cancer patients. Nat Clin Pract Oncol 3:86-93, 2006

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Characteristic of patients (age≥70) who received an allogeneic HCT reported to the CIBMTR between 2000 and 2010.

Characteristics of patients N (%)Number of patients 268Number of centers 79Age, median (range), years 71 (70 - 83)

70-75 251 (94)76-80 15 ( 6)>80 2 (<1)



Disease AML 159 (59)ALL 2 (<1)Other leukemia 26 (10)CML 9 ( 3)MDS 40 (15)Other acute leukemia 1 (<1)NHL-non hodgkin lymphoma 21 ( 8)MYE-plasma cell disorder, multiple myeloma 5 ( 2)Other Malignancies 1 (<1)SAA-severe aplastic anemia 4 ( 1)

Donor type Cord blood 30 (11)HLA-identical sibling 69 (26)Other related 12 ( 4)Well-matched URD 116 (43)Partially matched URD 19 ( 7)Mismatched URD 3 ( 1)HLA match information missing URD 19 ( 7)

D-R sex match M-M 99 (37)M-F 30 (11)F-M 43 (16)F-F 25 ( 9)Missing 71 (26)


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Continued.

Characteristics of patients N (%)Graft type

Bone Marrow 19 ( 7)Peripheral blood 219 (82)Cord blood 30 (11)

GVHD prophylaxis No GVHD prophylaxis 8 ( 3)Ex vivo T-cell depletion alone 6 ( 2)Ex vivo T-cell depletion + post-tx immune supression 3 ( 1)CD34 selection + post-tx immune supression 4 ( 1)Cyclophosphamide + others 1 (<1)FK506 + MMF +- others 60 (22)FK506 + MTX +- others (except MMF) 66 (25)FK506 + others (except MTX, MMF) 5 ( 2)FK506 alone 14 ( 5)CSA + MMF +- others (except FK506) 57 (21)CSA + MTX +- others (except FK506, MMF) 9 ( 3)CSA + others (except FK506, MTX, MMF) 18 ( 7)CSA alone 12 ( 4)Other GVHD prophylaxis 5 ( 2)

Time from diagnosis to transplant, median (range), months 10 (<1 - 225)Year of transplant

2000 6 ( 2)2001 13 ( 5)2002 11 ( 4)2003 15 ( 6)2004 24 ( 9)2005 16 ( 6)2006 29 (11)2007 39 (15)2008 58 (22)2009 43 (16)2010 14 ( 5)

Median follow-up of survivors, range, months 36 (2 - 121)

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