a g e n d a cibmtr working committee for late effects ... · prop 0811-10 prevalence and associated...

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR LATE EFFECTS (LONG-TERM COMPLICATIONS / SECOND CANCERS) San Diego, CA Thursday, February 2, 2012, 12:15 - 2:15 pm Co-Chair: David A. Jacobsohn, MD, Children’s National Medical Center, Washington DC, Phone: 202-476-6250; E-mail: [email protected] Co-Chair: Mohamed Sorror, MD, Fred Hutchinson Cancer Center, Seattle, WA

Phone: 206-667-2765; Fax: 206-667-6124; E-mail: [email protected] Co-Chair: Christine Duncan, MD; Dana Farber Cancer Institute, Boston, MA Phone: 617-632-6255; E-mail: [email protected] Scientific Director: Navneet Majhail, MD, MS, National Marrow Donor Program, Minneapolis, MN, Phone: 612-884-8676, Fax: 612-884-8549; E-mail : [email protected] Statisticians: Ruta Brazauskas, PhD, CIBMTR Statistical Center

Phone: 414-456-8687, Fax: 414-805-0714, E-mail: [email protected] Jerry (Zhiwei) Wang MS, CIBMTR Statistical Center Phone: 414-805-0640, Fax: 414-805-0714, E-mail: [email protected]

1. Introduction

a. Minutes of February, 2011 meeting (Attachment 1) 2. Accrual summary (Attachment 2) 3. Published or submitted papers a. LE00-02b Majhail NS, Bajorunaite R, Lazarus HM, Wang Z, Klein JP, Zhang M J, Rizzo JD.

High probability of long-term survival in 2-year survivors of autologous hematopoietic cell transplantation for AML in first or second CR. Bone Marrow Transplant. 2011 Mar;46(3):385-92. PMID: 20479710, PMCID: PMC2978251

b. LE07-04 Loren AW, Chow E, Jacobsohn DA, Gilleece M, Halter J, Joshi S, Wang Z, Gupta

V, Hale GA, Marks DI, Stadtmauer EA, Apperley J, Cahn JY, Schouten HC, Lazarus HM, Savani B, McCarthy PL, Jakubowski AA, Kamani NR, Hayes-Lattin B, Maziarz RT, Warwick AB, Sorror ML, Bolwell BJ, Socié G, Wingard JR, Rizzo JD, Majhail NS. Pregnancy after hematopoietic-cell transplantation: A report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR). Biol Blood Marrow Transplant. 2011 Feb;17(2):157-66. PMID: 20659574, PMCID: PMC3017731

c. LE07-03 Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D,

Sorror ML, Horowitz MM, Bolwell B, Rizzo JD, and Socié G. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011 Jun 1;29(16):2230-9. PMID: 21464398, PMCID: PMC3107742

1


d. Majhail NS, Rizzo JD, Lee SJ, Aljurf M, Atsuta Y, Bonfim C, Burns JL, Chaudhri N, Davies

S, Okamoto S, Seber A, Socie G, Szer J, Van Lint MT, Wingard JR, and Tichelli A, Recommended Screening and Preventive Practices for Long-term Survivors after Hematopoietic Cell Transplantation. In press, Biology of Blood and Marrow Transplantation, Bone Marrow Transplantation, Hematology-Oncology and Stem Cell Therapy, Revista Brasilieira de Hematologia e Hemoterapia

e. LE09-01 Danner-Koptik KE, Majhail NS, Brazauskas R, Wang Z, Buchbinder D, Cahn JY,

Dilley KJ, Frangoul HA, Gross TG, Hale GA, Hayashi RJ, Hijiya N, Kamble RT, Lazarus HM, Marks DI, Reddy V, Savani BN, Warwick AB, Wingard JR, Wood WA, Sorror ML, Jacobsohn DA, Second malignancies after autologous hematopoietic cell transplantation in children. Submitted to JCO

4. New study proposals

a. PROP 1111-10 Evaluate the risk of squamous cell CA in patients receiving voriconazole as fungal prophylaxis following allogeneic stem cell transplantation (J Palmer) (attachment 3)

b. PROP 1111-20 Sequential occurrence of new malignancies in donor-recipient pairs after allogeneic HCT: Incidence, characteristics and biologic significance for malignant evolution (G Akpek) (attachment 4)

c. PROP 1111-31 HCT in patients who had a prior solid organ HCT (T Schechter-Finkelstein, D Jacobsohn, H Klingemann) (attachment 5)

d. PROP 1111-44 Late Effects of Children Undergoing Allogeneic HSCT at a Young Age (L Vrooman, C Duncan) (attachment 6)

e. PROP 1111-47 Solid organ transplantation after hematopoietic cell transplantation (M Gupta, P L Abt, M Levine) (attachment 7)

f. PROP 1111-59 Avascular Necrosis of Bone in Adults after Hematopoietic Cell Transplantation (L Burns, B McClune, N Majhail) (attachment 8)

g. PROP 0811-10 Prevalence and Associated Risk Factors for Diabetes Mellitus and Hyperglycemia in Children Following Hematopoietic Stem-Cell Transplantation (J Ho, G Guilcher, T Schechter-Finkelstein) (attachment 9)

5. Studies in progress

a. LE09-01 New malignancies after autologous hematopoietic stem cell transplantation in children (K Danner-Koptik, D Jacobsohn) (Attachment 10)

Submitted

b. LE09-03a National survey of transplant physician practice patterns regarding fertility preservation (A Loren)

Manuscript preparation

c. LE09-03b Review of fertility preservation practice in HSCT patients (S Joshi)


d. LE07-01 Second cancer after RIC transplants (O Ringden) Data file preparation e. LE10-01 Avascular necrosis of bone in children and adolescents

after hematopoietic cell transplantation (X Li) Analysis

f. LE10-02 Late effects in hematopoietic stem cell transplant recipients with non-malignant disease (D Buchbinder, D Nugent) (attachment 11)


h. LE11-01 Long-term survival following second allogeneic HCT for hematologic malignancies (C Duncan, M Sorror)

Protocol development

2


i. LE11-02 Risk factors for secondary CNS tumors in survivors of pediatric HCT (M Gabriel, P Shaw)

Protocol development

6. Approved studies not using active statistical resources (e.g. in data accrual/form development)

a. LE05-01 Bronchiolitis obliterans after HCT (S Mineishi) Form Development b. LE06-01 Single nucleotide polymorphism analysis in patients

who developed AML or MDS after auto SCT for lymphoma (T Fenske)

Dropped

7. Update on LEWC projects that were initiated in response to survey of members in 2007

a. Late liver complications (attachment 12) b. Fertility issues after transplant c. QOL pilot project d. Pulmonary function forms (attachment 13)

8. Tandem Presentations

a. LE10-02: Chronic health conditions in hematopoietic stem cell transplant recipients with non-malignant disease (D Buchbinder). Oral abstract, Session K, Saturday, February 4, 4:45pm-6:45pm

9. Other Business

3

Not for publication or presentation Attachment 1

M I N U T E S CIBMTR WORKING COMMITTEE FOR LATE EFFECTS (LONG-TERM COMPLICATIONS / SECOND CANCERS) Honolulu, Hawaii Saturday, February 19, 2011, 12:15 - 2:15 pm Co-Chair: David A. Jacobsohn, MD, Children’s National Medical Center, Washington DC, Phone: 202-476-6250; E-mail: [email protected] Co-Chair: Mohamed Sorror, MD, Fred Hutchinson Cancer Center, Seattle, WA

Phone: 206-667-2765; Fax: 206-667-6124; E-mail: [email protected] Co-Chair: Christine Duncan, MD; Dana Farber Cancer Institute, Boston, MA Phone: 617-632-6255; E-mail: [email protected] Scientific Director: Navneet Majhail, MD, MS, University of Minnesota, Minneapolis, MN Phone: 612-624-6982, Fax : 612-625-6919, E-mail : [email protected] Statisticians: Ruta Brazauskas, PhD, CIBMTR Statistical Center

Phone: 414-456-8687, Fax: 414-805-0714, E-mail: [email protected] Kathleen Sobocinski MS, CIBMTR Statistical Center

Phone: 414-805-0682, Fax: 414-805-0714, E-mail: [email protected] Jerry (Zhiwei) Wang MS, CIBMTR Statistical Center Phone: 414-805-0640, Fax: 414-805-0714, E-mail: [email protected]

1. Introduction

a. Minutes of February, 2010 meeting (Attachment 1)

The meeting was called to order at 12:15pm by Dr. Christine Duncan. Co-chairs, scientific director and statisticians introduced themselves to the audience. The minutes of February, 2010 meeting were approved. The committee thanked Kathy Sobocinski for all her contribution to LEWC and wished Kathy all the best for her retirement in May this year.

2. Accrual summary (Attachment 2) The audience was referred to the handouts for the annual accrual summary. 3. Published or submitted papers a. LE99-01c Bishop MM, Lee SJ, Beaumont JL, Andrykowski MA, Rizzo JD, Sobocinski KA,

Wingard JR. The preventive health behaviors of long-term survivors of cancer and hematopoietic stem cell transplantation compared to matched controls. Biology of Blood & Marrow Transplantation 16:207-214, 2010.

b. LE99-01d Wingard JR, Huang IC, Sobocinski KA, Andrykowski MA, Cella D, Rizzo

JD, Brady M, Horowitz MM, Bishop MM. Factors associated with self-reported physical and mental health after hematopoietic cell transplantation. Biology of Blood & Marrow Transplantation 16: 1682-92, 2010.

4


c. LE00-02b Majhail NS, Bajorunaite R, Lazarus HM, Wang Z, Klein JP, Zhang M J, Rizzo JD.

High probability of long-term survival in 2-year survivors of autologous hematopoietic cell transplantation for AML in first or second CR. Bone Marrow Transplantation, advance online publication, May 2010.

d. LE07-04 Loren AW, Chow E, Jacobsohn DA, Gilleece M, Halter J, Joshi S, Wang Z, Gupta

V, Hale GA, Marks DI, Stadtmauer EA, Apperley J, Cahn JY, Schouten HC, Lazarus HM, Savani B, McCarthy PL, Jakubowski AA, Kamani NR, Hayes-Lattin B, Maziarz RT, Warwick AB, Sorror ML, Bolwell BJ, Socié G, Wingard JR, Rizzo JD, Majhail NS. Pregnancy after hematopoietic-cell transplantation: A report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR). Biology of Blood & Marrow Transplantation 17:157-66, 2011.

e. LE08-01 Majhail NS, Brazauskas R, Rizzo JD, Sobecks RM, Wang Z, Horowitz MM, Bolwell

B, Wingard JR, and Socie G. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood, 117:316-12, 2011.

f. LE07-03 Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D,

Sorror ML, Horowitz MM, Bolwell B, Rizzo JD, and Socié G. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. Journal of Clinical Oncology (in press).

Christine noted that there were six manuscripts published during the course of last year.

4. New study proposals

a. PROP 1210-22 Risk factors for development of secondary central nervous system (CNS) tumors in survivors of pediatric bone marrow transplantation (M Gabriel/P Shaw) (attachment 3)

Dr. Peter Shaw presented this proposal. The aim of the study is to evaluate the incidence of secondary CNS tumors in survivors of pediatric BMT and identify risk factors for the development of secondary CNS tumors. The main risk factors of interest are prior chemotherapies and conditioning regimens. Dr. Shaw reviewed the characteristics of the patients with and without secondary CNS tumors available in the CIBMTR database. It was noted that patients transplanted for CNS tumors were excluded from the study population. Secondary tumor diagnoses will be confirmed if the study is voted to move forward. It was suggested that patients with post-transplant lymphoproliferative disease of the CNS be excluded.

b. PROP 1210-33 Long-term survival following second allogeneic transplant for hematologic malignancies (C Duncan/M Sorror) (attachment 4)

Christine presented this proposal. The aim of the study is to report the overall survival of patients transplanted for leukemia, MDS and lymphoma who survived for at least one year from transplant and to compare the mortality rates of the study population to that of age, gender and nationality matched general population. Committee members were referred to the table for the characteristics of the patients available in the CIBMTR database. The reasons for second transplants included graft failure and persistent or recurrent disease. It was suggested that the study focus on the second transplants for relapse as that is a key clinical question vs. graft failure where there are not many options besides a second graft infusion. It was suggested to compare the second transplant

5


population to the patients who relapsed after an allogeneic transplant and did not get any other therapies and to patients who had DLI after transplant. It was noted that the DLI data was not very well captured in the CIBMTR database. Definition of second transplant should be further specified in the study protocol. Regimen related toxicity working committee has a study (RT10-02) and pediatric cancer working committee has a study proposal (PROP0710-01) looking at second transplants. We will contact the committees to check if there is any overlap among these studies, and if applicable, any opportunities for collaboration. Other suggestion was to look at quality of life for patients who have survived ten years or longer – although this was noted to be beyond the current capabilities of the database. Audience also asked about variables: same donor vs. different donor, conditioning regimen intensity for second transplant and secondary hematological malignancy prior to second transplant. Data are available for these variables and will be looked at in the study during data file preparation stage.

5. Research opportunities through the LEWC (attachment 5) Dr. David Jacobsohn reviewed the recent publications from LEWC. A few study areas were high-

lighted: Dr. John Wingard led the effort of a large study (LE99-01) looking at various aspects of the quality of life of HCT survivors. This study has published four manuscripts. The second area was non-relapse complications and mortality. Examples were LE07-03 looking at the long-term survival in 2-year survivors of myeloablative HCT; LE10-01: AVN in pediatric HCT patients; and LE10-02: chronic health conditions in pediatric patients with SAA. The third area was secondary malignancy after HCT. Recent publications included LE98-05 looking at solid cancers after allogeneic HCT and LE08-01 looking at solid cancers after Bu-Cy based conditioning regimen. Fertility issues after HCT was a new area of research in this committee. LE07-04 looked at pregnancy after HCT and LE09-03 conducted a national survey looking at the transplant physician practice patterns regarding fertility preservation. David welcomed any new ideas and encouraged the members to submit study proposals to LEWC utilizing the large number of patients in the CIBMTR database.

Navneet reviewed the legacy and current CIBMTR forms and data collection mechanism for late

effects research. Currently, post-transplant data were collected at 100 days, 6 months, once every year up to six years and every other year after the sixth year. Pulmonary functions, liver functions and other organ functions were captured. Newer versions of pulmonary function and liver function forms are under development and will be piloted this year. Pregnancy was captured between 2002 and 2007. Secondary malignancies were also captured. There are some limitations of the data, including under reporting, missing onset dates and missing covariates such as pre- and post- transplant treatment.

6. Studies in progress

a. LE09-01: New malignancies after autologous hematopoietic stem cell transplantation in children (K Danner-Koptik/D Jacobsohn): (Attachment 6)


David presented this study. This is a retrospective cohort study evaluating the incidence of new malignancies in children who have undergone autologous transplant for lymphoma or malignant solid cancers. Pediatric HCT patients have an increased risk of developing new malignancies compared to general population. Patient age was identified as a risk factor. This study is at manuscript preparation stage. The abstract will be presented at the 2011 EBMT meeting. One comment was that age at transplant could be a confounder for number of years at risk. Comparing the risk of the study cohort to that of non-transplant patients was suggested for future

6


work.

b. LE09-03: National survey of transplant physician practice patterns regarding fertility preservation (N Majhail/A Loren): (Attachment 7)

Analysis

Navneet presented this study on behalf of Dr. Alison Loren. This study stemmed from the initiative of the LEWC fertility sub-committee. The study described practice patterns regarding fertility issues among physicians caring for transplant patients in the United States. The study was presented at the poster session I at the Tandem Meetings on February 17. Multivariate analyses are underway to evaluate the factors associated with referral patterns. It was suggested that the sub-committee could contact the NDMP patient advocacy office and develop patient educational materials based on the results.

c. LE10-01: Avascular necrosis of bone in children and adolescents after hematopoietic cell transplantation (X Li): (Attachment 8)

Protocol Development

Navneet presented this study on behalf of Dr. Li. This is a case-control study evaluating the risk factors of developing AVN for children and adolescents after HCT. The study protocol has been circulated in the working committee and comments were received. PI has finalized the protocol based on the comments received. The next step for this study is to prepare the data file and carry out the analysis.

d. LE10-02: Chronic health conditions in hematopoietic stem cell transplant recipients with SAA (D Buchbinder/D Nugent): (attachment 9)

Protocol Development

Dr. David Buchbinder presented this study. This study is to describe the chronic health conditions in the allogeneic HCT recipients with severe aplastic anemia surviving more than two years after transplant. The study proposal has been revised based on comments received from the LEWC meeting last year and CIBMTR stats meeting. It was noted that main issue of the study is under reporting. The study will focus on chronic health conditions that were specifically asked on the form. Conditions reported on ‘other specify’ field will not be included. A case-control study design was suggested.

7. Approved studies not using active statistical resources (e.g. in data accrual/form development)

a. LE05-01: Bronchiolitis obliterans after HCT (S Mineishi): (Attachment 10)

Form Development

b. LE06-01: Single nucleotide polymorphism analysis in patients who developed AML or MDS after auto SCT for lymphoma (T Fenske):

Tissue Analysis

This study is currently under tissue analysis. DNA was successfully extracted from the sample tissues. A group of control patients were identified at the University of Washington and DNA sample will be extracted. Clinical and demographic information on the control patients will be collected. Case patient demographic information is available from the CIBMTR database.

7


c. LE07-01: Second cancer after RIC transplants (O Ringden):

(Attachment 11) Data Accrual

Dr. Olle Ringden presented this study. This study is to evaluate the incidence of second cancer after reduced intensity conditioning HCT. Dr. Ringden presented the patient accrual in the latest data retrieval. Audience asked if more information can be obtained from other databases such as SEER. Dr. Doug Rizzo noted that linking patient records can be challenging without reliable identifier (e.g. social security number).

8. Update on LEWC projects that were initiated in response to survey of members in 2007

In 2007, the Late Effects Working Committee members were surveyed to assess areas for focus of future studies. Late liver complications, post-transplant fertility and quality of life were the three areas that the members were most interested in. Dr Rizzo was already addressing the QOL issues through a pilot study at selected centers. The committee started two working groups to address topics of liver complications and fertility. The working groups consisted of volunteers from the committee membership. Drs. Linda Burns and Alison Loren led the efforts of the liver toxicity group and the fertility group, respectively.

a. Late liver complications (attachment 12)

Dr. Linda Burns updated the committee on the liver complication form development. Linda briefly reviewed the new form. The new form will be piloted this year.

b. Fertility issues after transplant Navneet updated the committee on behalf of Alison. Two studies have come out from the fertility sub-committee. Study LE07-04: pregnancy after HCT has been published in BBMT. LE09-03: Physician survey on fertility issues is now under analysis as discussed before. The next step is to re-convene the sub-committee to review the fertility issues and fertility options after HCT.

c. QOL pilot project Dr. Rizzo updated the committee on quality of life project. The data collection mechanism is in place. Currently seven centers are on the pilot program of this project. Patients from these centers will be contacted directly to answer quality of life questionnaires and followed up longitudinal. Doug welcomed medical directors from adult center in this committee to contact him if interested in participating in the pilot program.

d. Pulmonary function forms (attachment 10) 9. Tandem Presentations

a. LE09-03: National Survey of transplant physician practice patterns regarding fertility preservation (N Majhail/A Loren). Poster presentation, Session I, Thursday, February 17, 6:45pm-7:45pm

Mohamed noted study LE09-03 was presented at the poster session I of the Tandem meeting.

10. Other Business a. Guideline update on screening and preventive practices for long-term survivors.

In 2006, Dr. Doug Rizzo et al published recommended guidelines of screening and preventive practices for long term survivors of HCT. Based on the committee’s recommendation last year, the writing group has been re-engaged to review the guidelines and to update them. Dr Rizzo and Navneet are leading the effort of reviewing the guidelines and anticipate a revised

8


manuscript later this year.

The meeting adjourned at 2:10 PM. The following are the proposal voting results

Proposal # PI Vote results (N=26)1210-22 M Gabriel/P Shaw High priority 65%

Low priority 35%1210-33 C Duncan/M Sorror High priority 77%

Low priority 23% The committee has decided to accept both proposals and assigned high priority to both studies.

9


Accrual Summary for Late Effects Working Committee

Follow-up of patients after allogeneic transplant reported to CIBMTR between 1990 and 2011 Variable

Registration N (%)a

Median (range) b

Research N (%)a

Median (range) b

All patients 157540 75696 3 year survivors 44031 24738 5 year survivors 29350 17574 10 year survivors 9889 6700Follow-up of survivors, months 50 (<1-260) 64 (<1-260) Leukemia 102681 48784 3 year survivors 28157 15304 5 year survivors 19071 10969 10 year survivors 6664 4414 Lymphoma 13008 5452 3 year survivors 3148 1503 5 year survivors 1951 983 10 year survivors 545 299 Other Malignancy 20127 9533 3 year survivors 4567 2422 5 year survivors 2771 1575 10 year survivors 811 511 Aplastic Anemia 9176 4765 3 year survivors 3585 2316 5 year survivors 2489 1729 10 year survivors 928 716 Immunodeficiency 3551 2077 3 year survivors 1268 868 5 year survivors 808 599 10 year survivors 269 210 Other diseases 8997 5085 3 year survivors 3306 2325 5 year survivors 2260 1719 10 year survivors 672 550

aFor categorical variables bFor continuous variables

10


Follow-up of patients after autologous transplant reported to CIBMTR between 1990 and 2010 Variable

Registration N (%)a

Median (range) b

Research N (%)a

Median (range) b

All patients 155170 34392 3 year survivors 35119 11903 5 year survivors 18118 6989 10 year survivors 3032 1455Follow-up of survivors, months 30 (<1-254) 53 (<1-220) Leukemia 10785 3037 3 year survivors 2756 1134 5 year survivors 1625 755 10 year survivors 379 235 Lymphoma 60834 10998 3 year survivors 13841 4133 5 year survivors 7706 2695 10 year survivors 1612 691 Breast Cancer 19948 6720 3 year survivors 6541 2606 5 year survivors 3498 1527 10 year survivors 453 253 Multiple Myeloma/Plasma Cell Disorder 45538 8651 3 year survivors 7660 2322 5 year survivors 2835 936 10 year survivors 175 71 Other Diseases 18065 4986 3 year survivors 4321 1708 5 year survivors 2454 1076 10 year survivors 413 205

aFor categorical variables bFor continuous variables

11


Study Proposal 1111-10 Study Title: Evaluate the risk of squamous cell CA in patients receiving voriconazole as fungal prophylaxis following allogeneic stem cell transplantation. Jeanne Palmer, MD, Medical College of Wisconsin, Milwaukee, WI Specific Aims: To determine whether patients with SCCA of the following hematopoietic stem cell transplantation (HCST) have increased exposure to voriconazole as compared to patients without SCCA following HCST. Scientific Justification: Squamous cell carcinoma of the skin is a common complication of allogeneic stem cell transplant. This is observed a median of 5-7 years following transplant. Risk factors include young age, male gender, total body irradiation, and chronic GVHD. Voriconazole is a tri-azole antifungal that is used in treatment and prevention of fungal infections. It is well documented in the literature that voriconazole can cause phototoxicity[1]. Recently, there have been reports in the literature about aggressive squamous cell carcinoma of the skin following long term use of Voriconazole[2,3]. Specifically, in one study, use of voriconazole as compared to other fungal prophylaxis in lung transplant recipients demonstrated an increased risk of squamous cell carcinoma of the skin[4] . Another study was done using lung transplant patients which used multivariate analysis to analyze the potentially causative factors associated with squamous cell carcinoma of the skin in which voriconazole and sun exposure were independently associated with squamous cell carcinoma of the skin[2]. It is unknown whether voriconazole increases the risk of squamous cell carcinoma in HSCT patients. Understanding the risk voriconazole poses on patients who have undergone a HSCT is important to determine the best choice of anti-fungal prophylaxis. Patient Eligibility Requirements:

Patients who have undergone HSCT and have developed squamous cell carcinoma. Matched controls with similar age, conditioning regimen, gender, donor (MUD, MRD), ethnicity,

acute GVHD grade 2-4 and chronic GVHD status, CMV status, history of invasive fungal infection, and distance from the equator

Data Requirements: Age Conditioning regimen Gender Donor relationship and HLA match Ethnicity Development of aGVHD grades 2-4 cGVHD CMV status History of invasive fungal infection Distance from equator (zip code) Pretransplant disease Supplemental information

Will need to obtain information regarding voriconazole usage, specifically duration of time they were on voriconazole. If the study is approved, grant funding will be identified to support this investigation.

Will analyze whether those who developed SCCA of the skin were more likely to have been exposed to voriconazole, and whether length of time exposed to voriconazole impacted outcome.

12


Data Analysis: This analysis would shed light on whether exposure to voriconazole leads to an increased risk in

development of SCCA of the skin. Comparisons would be done in the group with SCCA of the skin, and without to see what factors were associated with an increased risk. Multivariate analysis can help determine whether voriconazole is an independent risk factor for development of SCCA of the skin following allogeneic stem cell transplantation.

References:

1. Cowen EW, Nguyen JC, Miller DD, et al. Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J.Am.Acad.Dermatol. 2010;62:31-37.

2. Vadnerkar A, Nguyen MH, Mitsani D, et al. Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients. The Journal of Heart and Lung Transplantation. 2010;29:1240-1244.

3. Epaulard O, Saint-Raymond C, Villier C, et al. Multiple aggressive squamous cell carcinomas associated with prolonged voriconazole therapy in four immunocompromised patients. Clinical Microbiology and Infection. 2010;16:1362-1364.

4. Feist A, Osborne S, Thistlethwaite P, Madani M, Yung G. Voriconazole Use Increases the Incidence of Skin Cancer in Lung Transplant Recipients. Am.J.Respir.Crit.Care Med. 2009;179:A4589.

13


Characteristics of patients who developed squamous cell carcinoma post-transplant, transplanted between 2002 and 2009 in the United States

Voriconazole No Yes Not reporteda

Variable Median (range)

N (%)Median (range)

N (%)Median (range)

N (%)Number of patients 88 93 124Number of centers 38 42 47Age at transplant, years, median (range) 60 (8-72) 56 (11-70) 52 (6-72)Age at transplant, years 0-9 1 (1) 0 3 (2) 10-19 0 2 (2) 2 (2) 20-29 3 (3) 4 (4) 4 (3) 30-39 5 (6) 2 (2) 14 (11) 40-49 9 (10) 16 (17) 29 (23) 50-59 24 (27) 34 (37) 38 (31) 60-69 41 (47) 35 (38) 33 (27) >=70 5 (6) 0 1 (1)Sex Male 69 (78) 70 (75) 96 (77) Female 19 (22) 23 (25) 28 (23)Recipient race Caucasian 86 (98) 87 (94) 118 (95) African-American 0 0 2 (2) Asian/Pacific Islander 0 1 (1) 1 (1) Hispanic 1 (1) 4 (4) 1 (1) Other/unknown 1 (1) 1 (1) 2 (2)Disease ALL/HD/NHL 26 (30) 17 (18) 32 (26) AML/MDS 41 (47) 55 (59) 53 (43) CML 3 (3) 3 (3) 18 (15) SAA/Immunodeficiency 2 (2) 3 (3) 2 (2) Others 16 (18) 15 (16) 19 (15)Transplant year 2002-2003 9 (10) 4 (4) 48 (39) 2004-2005 15 (17) 14 (15) 65 (52) 2006-2007 37 (42) 46 (49) 10 (8) 2008-2009 27 (31) 29 (31) 1 (1)Conditioning regimen Myeloablative 25 (30) 35 (41) 55 (49) Non-myeloablative 59 (70) 50 (59) 58 (51) Missing 4 8 11Condition regimen TBI+CY+-Other 15 (17) 14 (15) 26 (21) BU+CY+-Other 3 (3) 0 1 (1) TBI+-Other 19 (22) 11 (12) 27 (22) BU+-Other 31 (35) 41 (44) 42 (34) CY+-Other 8 (9) 4 (4) 5 (4) Other 12 (14) 23 (25) 23 (19)

14


Continued.

Voriconazole No Yes Not reporteda


N (%)Median (range)

N (%)Median (range)

N (%)Graft type BM 7 (8) 17 (18) 35 (28) PB+-BM 79 (90) 69 (74) 87 (70) CB 2 (2) 7 (8) 2 (2)Donor type HLA-matched siblings 24 (27) 21 (23) 7 (6) Other relatives 0 1 (1) 0 Unrelated donor 64 (73) 71 (76) 117 (94)GvHD Prophylaxis T-cell depletion 2 (2) 4 (4) 4 (3) FK506+MTX 40 (45) 45 (48) 44 (35) FK506 19 (22) 19 (20) 23 (19) MTX+CsA 9 (10) 11 (12) 28 (23) CsA 17 (19) 13 (14) 23 (19) Other/unknown 1 (1) 1 (1) 2 (2)Onset of aGvHD No 28 (32) 27 (29) 34 (27) Yes 60 (68) 66 (71) 90 (73)Onset of cGvHD No 12 (14) 17 (18) 16 (13) Yes 75 (86) 76 (82) 108 (87) Missing 1 0 0Site of squamous cell carcinoma Skin 19 (22) 23 (25) 25 (20) Other 5 (6) 1 (1) 7 (6) Unknown – to be checked 64 (73) 69 (74) 92 (74)Follow-up of survivors, months, median (range)

49 (12-98) 47 (12-90) 73 (16-103)

a Voriconazole usage information was not collected on legacy (before year 2007) NMDP patients.

15


Study Proposal 1111-20 Study Title: Sequential occurrence of new malignancies in donor-recipient pairs after allogeneic HCT: Incidence, characteristics and biologic significance for malignant evolution. Gorgun Akpek, MD, MHS, University of Maryland, Baltimore, MD Specific Aims: The primary objective of the study is to identify and characterize new malignancies that are diagnosed sequential y in donors and their recipients following allogeneic HCT.

Scientific Justification: Many studies have identified variety of new or secondary malignancies derived from donor cells in allogeneic HCT recipients occurring from 3 to 20 years after the transplant1-3. However, the information about the new malignancies developing in both donors and their recipients after the transplant is lacking. I have been following a patient who developed CLL at 6 years after his donor was diagnosed with CLL. At the time of transplant, the donor had no clinical or cytogenetic evidence of CLL and patient had underlying AML for which he was transplanted. There is this interval between the clinical diagnosis of donor’s CLL and the time when the patient’s developing the same disease, which suggests that the time interval for CLL to be phenotypically recognized from its origination is about 6 years. Additional cases of secondary CLL need to be identified in order to support this initial observation. The same logic can be applied to other malignancies as well. A previous CIBMTR proposal by N Frey, DS08-01 is aimed to identify cytogenetic abnormalities in donor derived hematopoietic cells after unrelated donor stem cell transplantation. The study is currently in data collection phase. Goals of that study include: characterizing donor derived cytogenetic abnormalities that develop in the recipient after transplant, describing the outcomes, explaining leukomogenesis, and evaluating the process of informing the donor. In the current proposal, all new malignancies besides donor-derived leukemia will be retrieved and the aim of the study is to identify the new malignancy clinically diagnosed in donor-recipient pairs, which can contribute to our understanding of malignant evolution. Patient Eligibility Population: The study population will include all patients, adult and pediatric, who received allogeneic HCT transplant for the treatment of underlying hematologic conditions including malignancies, between 1990 and 2009. Data Requirements: Outcome Data:

The primary endpoint will be to determine the incidence of donor-derived new malignancies that were diagnosed sequentially in donors and long-term allogeneic HCT survivors in different time points.

The secondary endpoints are: To compare the incidence and types of secondary malignancies based on conditioning

intensity (myeloablative, reduced intensity, and non-myeloablative). To use the information about shared malignancies in donor-recipient pairs and generate

the hypothesis that each type of malignancy requires approximate time intervals to be recognized clinically.

16


Variables: Patient related: Age Gender: female vs. male History of other malignancy prior to the primary hematologic diagnosis for which allo-HCT

was performed Donor related: Age Gender: female vs. male History of malignancy prior to stem cell donation

Transplant related: Year of transplant (5-year interval periods between 1990 and 2009) Graft type: BM vs. PBSC vs. cord Donor type: Related or unrelated HLA match status: well matched vs. partially matched Conditioning: Myeloablative vs. reduced intensity vs. non-myeloablative 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

Sample Requirements:* No need.

Study Design: In this study, the time intervals between the diagnoses of the new malignancies shared by the donor-recipient pairs will be estimated. The average duration for the same type of malignancy occurring first in the donor then in the recipient, will be postulated as the time that is necessary to develop a particular type of human neoplasm. The study proposed here will analyze CIBMTR data to identify secondary malignancies in allo-HCT long-term survivors and also to identify donors who developed the same type of malignancy. CIBMTR Selective Post-Transplant Essential Data form and NMDP donor form will be used for capturing new malignancies developing in patients and donors, respectively. Simple linear regression analysis will be done to identify variables that are associated with the occurrence of secondary malignancies. References:

1. Ades L, Guardiola P, Socie G. Second malignancies after allogeneic hematopoietic stem cell transplantation: new insight and current problems. Blood Rev 2002 Jun;16(2):135-46.

2. Lowe T, Bhatia S, Somlo G. Second malignancies after allogeneic hematopoietic cell transplantation. Biology Blood Marrow Transplantation 2007 Oct;13(10):1121-34.

3. Majhail NS. Old and new cancers after hematopoietic-cell transplantation. Hematology Am Soc Hematol Educ Program 2008;142-9.

17


Characteristics of patient who underwent unrelated donor transplant between 1990 and 2009 in the United States and reported secondary malignancies to CIBMTR

Variable

Median (range)N (%)

Number of patients 1564Number of centers 138Age at transplant, years, median (range) 43 (<1-79)Age at transplant, years 0-9 210 (13) 10-19 152 (10) 20-29 148 (9) 30-39 201 (13) 40-49 289 (18) 50-59 323 (21) >=60 241 (14)Sex Male 969 (62) Female 595 (38)Disease AML 388 (25) ALL 212 (14) CML 286 (18) NHL 124 (8) HD 7 (<1) MDS/MPS 247 (16) Other Leukemia 139 (9) MM/PCD 2 (<1) Solid Cancer 2 (<1) Aplastic Anemia 85 (5) Other Non-Malignant Diseases 72 (5)Transplant year 1990-1994 194 (12) 1995-1999 313 (20) 2000-2004 454 (29) 2005-2009 603 (39)Conditioning regimen Myeloablative 994 (66) Non-myeloablative 505 (34) Missing 65Graft type BM 843 (54) PB+-BM 600 (38) CB 121 (8)GvHD Prophylaxis T-cell depletion 244 (16) FK506+MTX 411 (26) FK506 204 (13) MTX+CsA 465 (30) CsA 206 (13) Other/unknown 34 (2)

18


Continued.

Note: Total number of unrelated donor transplant patients in United States and reported to CIBMTR in this period=23846

Variable

Median (range)N (%)

New malignancy Lymphoma or lymphoproliferative disease 364 (23) Hodgkin disease 3 (<1) Other cancer – to be cleaned 1026 (66)Follow-up of patients, years <1 334 (21) 1-3 276 (18) 3-5 257 (16) 5-10 419 (27) >=10 278 (18) Follow-up of survivors, months, median (range) 75 (10-244)

19

NMDP Form 0760 / 0761 / 0762 revision 4 (page 1 of 6) October 2010

Copyright © 2010 National Marrow Donor Program. All rights reserved.Internal use: Document number F00172 revision 4 Replaces: F00172 revision 3 May 2009

1. Date of actual contact with the donor:

Conditions Present on Day of Contact

Using the following Modified Toxicity Criteria, review each body symptom with the donor. For each symptom associated with a

system, select the statement that most closely reflects the donor's current condition.

In the Modified Toxicity Criteria below, the term “activities of daily living” (ADL) refers to tasks performed by individuals in a typical day

that allow independent living. Basic activities of daily living include feeding, dressing, hygiene, and physical mobility.

For any toxicities or sites of pain reported as grade 3 or higher, see the Donor Forms Instruction Manual for direction on

whether a Stem Cell Donor Adverse Event form is required.

Flu-Like Symptoms

2. Fever in absence of infections

1 o none (grade 0)

2 o 38.0 – 39.0° C / 100.0 – 102.2° F (grade 1)

3 o greater than 39.0 – 40.0° C / 102.2 – 104.0° F (grade 2)

4 o greater than 40.0° C / 104.0° F for less than 24 hours (grade 3)

5 o greater than 40.0° C / 104.0° F for more than 24 hours (grade 4)

Constitutional Symptoms

3. Fatigue (lethargy, malaise, asthenia)

1 o none (grade 0)

2 o mild fatigue over baseline (grade 1)

3 o moderate or causing difficulty performing some ADL (grade 2)

4 o severe fatigue interfering with ADL (grade 3)

5 o disabling (grade 4)

Dermatologic

4. Rashes on skin

1 o none (grade 0)

2 o macular or papular eruption or erythema that is asymptomatic (discrete areas of raised or flat, discolored and/or reddened

skin patches, with no other symptoms) (grade 1)

3 o macular or papular eruption or erythema with pruritus or other associated symptoms (same as above in conjunction with

symptoms such as itching and pain) (grade 2)

4 o severe, generalized erythroderma or macular, papular, or vesicular eruption

(same as above with the possible addition of fluid-filled blisters; also, the

condition is not widely spaced, but instead covers the majority of the body)

(grade 3)

5 o generalized exfoliative dermatitis or ulcerating dermatitis (skin inflammation

leading to peeling and/or ulceration) (grade 4)

If not using the NMDP FormsNet™

application, a copy of this completed

form may be mailed to:

National Marrow Donor Program

Suite 100

3001 Broadway Street NE

Minneapolis, MN 55413

Retain the original at the Donor Center.

Date of

Collection:o n/a; filgrastim

injection only

Product Type: o Marrow o PBSC o no product collected

2 0Month Day Year

Post-Donation – One Month,

Six Months, and One Year

Donor Assessment

– –

Recipient NMDP ID:

Donor NMDP ID:

DC Code: TC Code:

– –

o One month (Form 760)

o Six months (Form 761)

o One year (Form 762)

Follow-up visit for which

this form is being

completed:

2 0Month Day Year

Registry Use Only

Sequence

Number:

Date

Received:

20

zwang

Typewritten Text

zwang

Typewritten Text

Attachment 4B

zwang

Typewritten Text

zwang

Typewritten Text



Donor NMDP ID:Follow-up Visit: o One month o Six months o One year – –

5. Injection site reaction (filgrastim, IV, or marrow collection)

1 o none (grade 0)

2 o pain; itching; erythema (grade 1)

3 o pain and swelling with inflammation or phlebitis (grade 2)

4 o ulceration or necrosis that is severe; operative intervention indicated (grade 3)

Gastrointestinal

6. Nausea

1 o none (grade 0)

2 o loss of appetite without alteration in eating habits (grade 1)

3 o oral intake decreased without significant weight loss, dehydration or malnutrition (grade 2)

4 o inadequate oral caloric or fluid intake (grade 3)

5 o life-threatening consequences (grade 4)

7. Vomiting

1 o none (grade 0)

2 o 1 episode in 24 hours (grade 1)

3 o 2–5 episodes in 24 hours (grade 2)

4 o 6 or more episodes in 24 hours (grade 3)


8. Loss of appetite (anorexia)

1 o none (grade 0)

2 o loss of appetite without alteration in eating habits (grade 1)

3 o altered intake without significant weight loss or malnutrition (grade 2)

4 o significant weight loss or malnutrition (grade 3)

5 o life-threatening (grade 4)

Neurological

9. Inability to sleep (insomnia)

1 o normal (grade 0)

2 o occasional difficulty sleeping, not interfering with function (grade 1)

3 o difficulty sleeping, interfering with function but not interfering with ADL (grade 2)

4 o frequent difficulty sleeping, interfering with ADL (grade 3)


10. Dizziness, vertigo, or lightheadedness

1 o none (grade 0)

2 o with head movements only; not interfering with function (grade 1)

3 o interfering with function, but not interfering with ADL (grade 2)

4 o interfering with ADL (grade 3)


11. Fainting (syncope)

1 o none (grade 0)

2 o present (grade 3)


21

zwang

Typewritten Text

Attachment 4B

Sites of Pain

12. Back 0 o none (grade 0) 1 o mild (grade 1) 2 o moderate (grade 2) 3 o severe (grade 3) 4 o disabling (grade 4)

13. Bones (including

sternum and ribs)0 o none (grade 0) 1 o mild (grade 1) 2 o moderate (grade 2) 3 o severe (grade 3) 4 o disabling (grade 4)

14. Headache 0 o none (grade 0) 1 o mild (grade 1) 2 o moderate (grade 2) 3 o severe (grade 3) 4 o disabling (grade 4)

15. Hip 0 o none (grade 0) 1 o mild (grade 1) 2 o moderate (grade 2) 3 o severe (grade 3) 4 o disabling (grade 4)

16. IV site 0 o none (grade 0) 1 o mild (grade 1) 2 o moderate (grade 2) 3 o severe (grade 3) 4 o disabling (grade 4)

17. Joints

(excluding hip)0 o none (grade 0) 1 o mild (grade 1) 2 o moderate (grade 2) 3 o severe (grade 3) 4 o disabling (grade 4)

18. Limbs (arms, legs,

hands, feet)0 o none (grade 0) 1 o mild (grade 1) 2 o moderate (grade 2) 3 o severe (grade 3) 4 o disabling (grade 4)

19. Muscles 0 o none (grade 0) 1 o mild (grade 1) 2 o moderate (grade 2) 3 o severe (grade 3) 4 o disabling (grade 4)

20. Neck 0 o none (grade 0) 1 o mild (grade 1) 2 o moderate (grade 2) 3 o severe (grade 3) 4 o disabling (grade 4)

21. Throat 0 o none (grade 0) 1 o mild (grade 1) 2 o moderate (grade 2) 3 o severe (grade 3) 4 o disabling (grade 4)

22. Other pain site: 0 o none (grade 0) 1 o mild (grade 1) 2 o moderate (grade 2) 3 o severe (grade 3) 4 o disabling (grade 4)

23. Specify pain site:

24. (Complete at One Month follow-up visit only) Was the donor evaluated for splenomegaly (an enlarged spleen) or splenic rupture?

1 o yes

2 o no

3 o not applicable

Disease Status at One Year Post-Donation

26. Did the donor develop any cancer(s) since date of the last report?

1 o yes

2 o no

For each of the sites listed below, indicate the severity of pain present using the following scale:

0 = none (grade 0)

1 = mild pain not interfering with function (grade 1)

2 = moderate pain interfering with function but not ADL (grade 2)

3 = severe pain severely interfering with ADL (grade 3)

4 = disabling (grade 4)

Complete questions 26–97 for the one year post-donation assessment only. If this report is for the one month or six

months post-donation assessment, continue with question 98.

Completion of a Stem Cell Donor Adverse Event Form is not required for any of the conditions listed in questions 26–95.

Specify the cancer diagnosis:Specify date of diagnosis:

27. Acute lymphocytic leukemia (ALL) 1 o no 2 o yes 28.

29. Acute myelogenous leukemia (AML) 1 o no 2 o yes 30.

31. Chronic lymphocytic leukemia (CLL) 1 o no 2 o yes 32.

33. Chronic myelogenous leukemia (CML) 1 o no 2 o yes 34.

35. Other leukemia 1 o no 2 o yes 36. Specify other leukemia:

37.




25. Specify the results of splenic evaluation:

2 0Month Year

2 02 02 0

2 0

22

zwang

Typewritten Text

Attachment 4B




Specify the cancer diagnosis:Specify date of diagnosis:

38. Hodgkin lymphoma 1 o no 2 o yes 39.

40. Non-Hodgkin lymphoma 1 o no 2 o yes 41.

42. Myelodysplastic syndrome (MDS) 1 o no 2 o yes 43.

44. Myeloproliferative disorder (MPD) 1 o no 2 o yes 45.

46. Bladder cancer 1 o no 2 o yes 47.

48. Brain cancer 1 o no 2 o yes 49.

50. Breast cancer 1 o no 2 o yes 51.

52. Colorectal cancer 1 o no 2 o yes 53.

54. Kidney (renal cell) cancer 1 o no 2 o yes 55.

56. Lung cancer 1 o no 2 o yes 57.

58. Melanoma in situ 1 o no 2 o yes 59.

60. Melanoma, invasive 1 o no 2 o yes 61.

62. Non-melanoma skin cancer (e.g., basal

cell, squamous) 1 o no 2 o yes 63.

64. Oral cavity / pharynx 1 o no 2 o yes 65.

66. Ovarian cancer 1 o no 2 o yes 67.

68. Pancreatic cancer 1 o no 2 o yes 69.

70. Prostate cancer 1 o no 2 o yes 71.

72. Testicular cancer 1 o no 2 o yes 73.

74. Thyroid cancer 1 o no 2 o yes 75.

76. Uterine cancer 1 o no 2 o yes 77.

78. Other cancer 1 o no 2 o yes 79. Specify other cancer:

80.

2 0Month Year

2 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 0

2 0

23

zwang

Typewritten Text

Attachment 4B




Specify if the donor developed any of the following diseases since the date of the last report:

81. Systemic lupus erythematosus (SLE, lupus)

1 o yes

2 o no

83. Rheumatoid arthritis (RA)

1 o yes

2 o no

85. Vasculitis, inflammation or autoimmune disease of blood vessels

1 o yes

2 o no

87. Thrombosis (including DVT and thrombophlebitis)

1 o yes

2 o no

89. Multiple sclerosis (MS)

1 o yes

2 o no

91. Idiopathic thrombocytopenic purpura (ITP), autoimmune disease of platelets

1 o yes

2 o no

93. Other autoimmune disorder

1 o yes

2 o no

96. Did the donor answer “yes” to any of the conditions listed in questions 26–95?

1 o yes

2 o no

90. Specify date of diagnosis:


94. Specify other autoimmune disorder:






2 0Month Year

2 0Month Year

2 0Month Year

2 0Month Year

2 0Month Year

2 0Month Year

2 0Month Year

97. Is the donor willing to be contacted by an NMDP Quality Assurance Nurse for additional

information?

1 o yes

2 o no

24

zwang

Typewritten Text

Attachment 4B




98. Additional notes on donor assessment: (optional)

99. Signed: Person completing form

Please print first and last name:

Date:

Preferred method of contact: Phone number or e-mail address

25

zwang

Typewritten Text

Attachment 4B


Study Proposal 1111-31 Study Title: Outcome of hematopoietic stem-cell transplantations following solid organ transplantations. Tal Schechter-Finkelstein, MD, The Hospital for Sick Children, University of Toronto, Toronto, Canada David A. Jacobsohn, MD, ScM, Children’s National Medical Center, George Washington University, Washington, DC Hans Klingemann, MD, PhD, Tufts Medical Center Specific Aims:

To assess the outcome of hematopoietic stem-cell transplantation (HSCT) following solid organ transplantation.

To determine the incidence of infectious complication following the above transplantations To evaluate the cumulative incidence of lymphoproliferative disease for HSCT following solid

organ transplantation. Scientific Justification: As the use of solid organ transplantation has become standard of care therapy in the setting of end stage organ failure, new indications for allogeneic hematopoietic stem cell transplantation (HSCT) have emerged and with them the need to fully understand the risks and benefits of allogeneic HSCT following solid organ transplantation. There is minimal data on sequential HSCT following solid organ transplantation in the literature and most information comes from case reports of successful transplantation. 1-6 However, those publications likely reflect a positive reporting bias, as no reports of a cohort have been published to date. These reports demonstrate feasibility but likely do not reflect true outcomes. Indications for HSCT after solid organ transplantation that have been reported include mainly severe aplastic anemia (SAA) following liver transplantation.2-6 Other indications include malignancies and Post-transplant lymphoproliferative disease (PTLD).7 In a recent cohort from a tertiary hospital of outcomes of pediatric recipients of allogeneic HSCT following previous solid-organ transplantation between 2000-2010, Four children were identified. Two patients underwent heart transplantation followed by cord-blood allogeneic HSCT for T-cell lymphoma/PTLD and 2 patients underwent liver transplantation followed by living-donor allogeneic HSCT SAA. Despite engraftment, all patients died from 37d to 1-year after HSCT. Causes of death included infections (n=2), multi-organ failure (n=1) and solid organ graft rejection (n=1). The outcome of the patients in this series demonstrates the increased risk of severe opportunistic infections in these chronically immunosuppressed patients as well as the risk of solid organ rejection at the time of immune system recovery. Multiple complications were observed including Epstein-barr virus (EBV) reactivation followed by EBV positive PTLD (n=1) and 5 episodes of severe infections.7 Though feasibilty has been shown with this cohort, the authors concluded that allogeneic HSCT in immunosuppressed patients follwing solid organ transplantation remains a very high risk procedure that resulted in severe morbidity and mortality. The need for complete cohort evaluation of such transplants is essential for clinicians to be able to understand appropriate indications, complications and outcomes.

Patient Eligibility Population:

Inclusion criteria: Recipients of solid organ transplantation followed by hematopoietic stem cell transplantation

26


Data Requirements: This initial retrospective review of the CIBMTR database will not require collection of supplemental data or combining data with data from another group. The specific variables to be analyzed from the existing CIBMTR data collection forms will include: CIBMTR Form ID

Form Name Data Requested

Form 2000 Recipient Baseline Data

Age Gender Ethnicity Height Weight

Primary disease: Indication for organ transplantation:

Type of organ transplanted Donor if known- cadaveric/living donor Time between solid and stem-cell transplants

Indication for HSCT (malignant vs. non-malignant). Malignancy-CR1, CR2, CR3 Year of transplant Degree of HLA match between the donor and

recipient Number of cord units used Donor and recipient CMV status.

Specific transplant regimens (radiation Therapy, use of thymoglobulin)

GVHD prophylaxis regimen and doses Acute GVHD data:

Day 0-day 100: Grading and staging and organs involved.

Time after HSCT to develop GVHD Response to therapy.

Baseline outcome data: Time of neutrophil engraftment infectious complication Patients outcome: Treatment related mortality/

relapse lymphoproliferative disease following HSCT

Form 210 0 100 Days Post- HSCT Data

Diagnosis of: Acute/chronic GVHD and staging Outcome /secondary graft-failure

Form 2200 Six Months to Two Years Post-HSCT Data

Diagnosis of: Chronic GVHD (limited or extensive) and organ

involved Form 2300 Yearly Follow-up

For Greater Than Two Years Post-HSCT Data

Diagnosis of: Chronic GVHD (limited or extensive) Patients outcome and causes of treatment-related

mortality

27


Sample Requirements: This study will not require any biologic samples from the NMDP research sample repository.

Study Design: This study will be a retrospective review of data already collected through the CIBMTR database. Specifically, each aim and proposed analysis is outlined below:

To assess the outcome of HSCT following solid organ transplantation. Survival analysis will be done based on type of solid organ involved. Time between transplants will be tested as predictors of survival by Kaplan-Meier analysis using the log-rank test.

To determine the incidence of infectious complication following the above transplantations. The percentage of infectious complication in each group of solid organ transplanted will be reported.

To evaluate the cumulative incidence of lymphoproliferative disease for HSCT following solid organ transplantation.

This proposed study is limited by the fact that it is a retrospective analysis of the CIBMTR database. Case finding may be limited by a clinician’s report for previous solid organ transplants as well as type of donor and time between solid organ transplant and HSCT. However, only data from registry can provide knowledge regarding the extent, feasibility and outcome of such transplantations. Despite the limitations of a retrospective study, this initial project will provide important and novel information about the survival of HSCT following solid organ transplantation. References:

1. Mangat JS, Rao K, Kingston J, Veys P et al. Early pediatric antracycline cardiotoxicity: Managed be serial heart and bone marrow transplantation J Heart Lung Transplant 2007; 26: 658-660.

2. Kawahara K, Storb R, Sanders J et al. Successful allogeneic bone marrow transplantation in a 6.5-year-old male for severe aplastic anemia complicating orthotopic liver transplantation for fulminant non-A-non-B hepatitis. Blood 1991; 78: 1140�-1143

3. Hagglund H, Winiarski J, Ringden O et al. Successful allogeneic bone marrow transplantation in a 2.5-year-old boy with ongoing cytomegalovirus viremia and severe aplastic anemia after orthotopic liver transplantation for non-A, non-B, non-C hepatitis. Transplant 1997; 64: 1207�1208

4. Trede NS, Warwick AB, Rosoff PM et al. Tacrolimus (FK506) in allogeneic bone marrow transplantation for severe aplastic anemia following orthotopic liver transplantation. Bone Marrow Transplant 1997; 20: 257�-260

5. Perkins JL, Neglia JP, Ramsay NKC et al. Successful bone marrow transplantation for severe aplastic anemia following orthotopic liver transplantation: long-term follow-up and outcome. Bone Marrow Transplant, 2001,28:523-526

6. Yoshimi A, Nnny Y, Ueda K et al. successful hematopoietic stem cell transplantation from an HLA-identical sibling in a patient with aplastic anemia and HLA-haploidentical living-related liver transplantation for fulminant hepatitis. Biol Blood Marrow Transplant 2009;15:389-390.

7. Schechter T, Gassas A, Weitzman S et al. Outcome of hematopoietic stem-cell transplantations following solid organ transplantations. Bone Marrow Transplant 2011; 46:1321-1325

28


Characteristics of patients with prior solid organ transplants who received a subsequent HCT for hematological malignancies reported to the CIBMTR

Variable N (%)

Median (Range)Number of patients 17Age, Median (range), years 32 (5-64)Age, years 0-9 1 ( 6) 10-19 2 (12) 20-29 4 (24) 30-39 4 (24) 40-49 4 (24) 60-69 2 (12)Male 12 (71)Region US 10 (59) Canada 1 ( 6) Europe 6 (35)Prior solid organ transplant Liver transplant 2 (12) Kidney transplant 15 (88)HCT indication AML 7 (41) ALL 3 (18) CML 2 (12) NHL 4 (24) HL 1 ( 6)Year of transplant 1995-1999 6 (35) 2000-2004 6 (35) 2005-2009 5 (29)Interval from diagnosis of hematological malignancy to HCT, months 9 (1-40)Graft type Bone marrow 5 (29) Peripheral Blood 10 (59) Umbilical Cord blood 2 (12)Donor Autologous 1 ( 6) HLA-identical siblings 5 (29) Unrelated donor 11 (65)Regimen conditioning Cyclophosphamide+TBI±other 6 (35) Busulfan+Cyclophosphamide±other 6 (35) Other 5 (29)Vital status at last contact Alive 2 (12)a

Dead 15 (88)b

a Length of follow-up (range): 24-128 months. b Interval from HCT to death (range): 0.5-8 months.

29


Study Proposal 1111-44 Study Title: Late Effects of Children Undergoing Allogeneic HSCT at a Young Age. Lynda Vrooman, MD,MSc, Dana Farber Cancer Institute, Children’s Hospital, Boston, MA Christy Duncan, MD, MSc, Dana Farber Cancer Institute, Children’s Hospital, Boston, MA Specific Aims: Primary Aims: To report the frequency of late effects in patients who underwent allogeneic stem cell transplant for

hematologic malignancy (ALL, AML, CML, JMML) at very young age (less than 3 years of age). To report the frequency of organ impairment in patients who underwent allogeneic stem cell

transplant for hematologic malignancy at very young age. To report the frequency of chronic GVHD and new malignancy in patients who underwent

allogeneic stem cell transplant for hematologic malignancy at very young age. Secondary Aims:

To determine risk factors for the development of any organ toxicity and particular organ toxicities, including growth disturbance, congestive heart failure, myocardial infarction, stroke/seizure, osteonecrosis, and hypothyroidism in survivors of allogeneic stem cell transplant for hematologic malignancy at very young age.

To report the overall and disease free survival of patients who underwent allogeneic stem cell transplant for hematologic malignancy at very young age.

Scientific Justification: Hematopoietic stem cell transplant (HSCT) is an important treatment modality in infants and very young children with high-risk and relapsed leukemias. Infancy is a period marked by increases in constitutional growth, the continued development of organ systems including the nervous and pulmonary systems, and the achievement of a rapid succession of developmental milestones. Normal growth and development can be negatively impacted by various disease states, including malignancy. Management of malignancy in this extreme of the pediatric age-range poses particular challenges, and infants have been found to have an increased risk of acute toxicities from certain chemotherapy treatments.1,2 Just as there is concern for a high risk of acute toxicities, there is also concern regarding the long-term sequelae for those treated in infancy. Small cohorts of children transplanted at very young age have been reported to have issues with hypothyroidism, growth hormone deficiency, short stature, osteopenia, abnormal teeth development, as well as dyslipidemias and concern for an increased risk of cardiovascular complications and metabolic syndrome.3,4 5 6 When faced with caring for survivors of hematologic malignancy who have undergone hematopoietic stem cell transplantation at a very young age, there is little reported that focuses in detail on this potentially vulnerable group. Indeed, infants and very young children undergoing HSCT for hematologic malignancies may be at particularly high risk for certain long-term morbidities. This study will assess the frequency of late effects in patients who have undergone allogeneic stem cell transplant at very young age (less than 3 years of age), report the overall survival of this population, and investigate potential risk factors for the development of late effects, including the development of particular organ toxicities, such as growth disturbance, congestive heart failure, myocardial infarction, stroke/seizure, osteonecrosis, and hypothyroidism.

Patient Eligibility Population:

Patient who have survived disease-free for one year or greater following allogeneic stem cell transplant for ALL, AML, CML, and JMML.

30


Patients who underwent allogeneic stem cell transplantation at less than 3 years of age. Transplanted with related or unrelated donor. All stem cell sources. All conditioning regimens. Follow-up data available regarding survival, disease status, graft-versus-host disease, and other

organ impairment.

Data Requirements: The following data are required for this proposal. No supplemental data will be required.

Date of birth Sex Race Nationality Underlying diagnosis Age at initial diagnosis Disease status at time of transplant Performance status prior to transplant Date of HSCT Donor type and stem cell source Conditioning regimen Use of total body irradiation Current survival and disease status Date of current status Cause of death (when applicable) GVHD status New malignancy, and date of new malignancy Functional status at longest follow-up

Has the recipient ever developed the organ impairment or disorder, beginning one year post HSCT?

Any clinically significant organ impairment or disorder since one year post HSCT (yes/no) Avascular necrosis Bronchiolitis obliterans Cataracts Congestive heart failure Cryptogenic organizing pneumonia (COP) Diabetes / hyperglycemia Gonadal dysfunction / infertility requiring hormone replacement Growth hormone deficiency /growth disturbance Hemorraghic cystitis / hematuria requiring medical intervention Hypothyroidism Interstitial pneumonitis/ARDS Myocardial infarction Non-infectious liver toxicity Pancreatitis Post-transplant microangiopathythrombotic thrombocytopenic purpura, hemolyticuremic

syndrome Pulmonary hemorrhage Renal failure

31


Stroke / seizure Other

Sample Requirements:* This study does not require the use of biologic samples.

Study Design: The primary objectives of this study are to report the frequency of late effects in patients who underwent allogeneic stem cell transplant for hematologic malignancy (ALL, AML, CML, JMML) at very young age (less than 3 years of age) and who survived one year s/p HSCT without relapse. We will report the frequency of organ impairment (any organ impairment and each organ impairment) with descriptive statistics. The Kaplan-Meier method will be used to estimate the probability of survival. Multivariate Cox regression analysis will be used to evaluate for potential risk factors for the development of any organ toxicity and for particular organ toxicities, including growth disturbance, congestive heart failure, myocardial infarction, stroke/seizure, osteonecrosis, and hypothyroidism. References:

1. Arndt C, Hawkins D, Anderson JR, et al: Age is a risk factor for chemotherapy-induced hepatopathy with vincristine, dactinomycin, and cyclophosphamide. J Clin Oncol 22:1894-901, 2004

2. Morgan E, Baum E, Breslow N, et al: Chemotherapy-related toxicity in infants treated according to the Second National Wilms' Tumor Study. J Clin Oncol 6:51-5, 1988

3. Sanders JE, Im HJ, Hoffmeister PA, et al: Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia. Blood 105:3749-56, 2005

4. Pieters R: Infant acute lymphoblastic leukemia: Lessons learned and future directions. Curr Hematol Malig Rep 4:167-74, 2009

5. Perkins JL, Kunin-Batson AS, Youngren NM, et al: Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr Blood Cancer 49:958-63, 2007

6. Tomizawa D, Koh K, Sato T, et al: Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia 21:2258-63, 2007

32


Characteristics of patients (age<3) with AML, ALL, CML, CMML receiving allogeneic HCT and reported to CIBMTR between 1995 and 2009


N (%)Number of patients 972Number of centers 148Age, years <1 225 (23) 1 387 (40) 2 360 (37)Sex Male 521 (54) Female 451 (46)Region of teams US 683 (70) Canada 42 (4) Europe 108 (11) Asia 29 (3) Australia/New Zealand 53 (5) Mideast/Africa 38 (4) Central/South America 19 (2)Disease AML 534 (55) ALL 400 (41) CML 25 (3) CMML 13 (1)Transplant year 1995-1997 234 (24) 1998-2000 191 (20) 2001-2003 172 (18) 2004-2006 176 (18) 2007-2009 199 (20)Conditioning regimen Myeloablative 892 (95) Non-myeloablative 43 (5) Missing 37Condition regimen TBI+CY+-Other 379 (39) BU+CY+-Other 7 (1) TBI+-Other 41 (4) BU+-Other 500 (51) CY+-Other 11 (1) Other 34 (3)Graft type BM 524 (54) PB+-BM 85 (9) CB 363 (37)

33


Continued.


N (%)Donor type HLA-matched siblings 225 (23) Other relatives 66 (7) Unrelated donor 681 (70)GvHD Prophylaxis T-cell depletion 96 (10) FK506+MTX 67 (7) FK506 49 (5) MTX+CsA 367 (38) CsA 345 (35) Other/unknown 48 (5)Onset of aGvHD 626 (65)Onset of cGvHD 205 (21)Pulmonary functions IPn 136 (14) Bronchiolitis obliterans 10 (1)

Pulmonary hemorrhage 33 (5)Other non-infectious pulmonary abnormalities 91 (13)

Other organ impairment 488 (53)Renal failure severe enough to warrent dialysis 49 (6)TTP/HUS 26 (3)Depression 2 (<1)Hemorrhage cystitis 16 (2)Seizures 57 (7)Avascular necrosis 2 (<1)Cataracts 62 (7)Gonadal dysfuntion 10 (1)Hypothyroidism 69 (8)Myocardial infarction 1 (<1)Veno-occlusive disease 105 (17)Other impairmenta 301 (35)

Secondary malignancies Clonal cytogenetic abnormality 1 (<1)Acute myeloid leukemia 1 (<1)Other leukemia 1 (<1)Lymphoma or lymphoproliferative disease 10 (1)Other cancerb 16 (2)

Follow-up of survivors, months, median (range) 63 (3-197)Follow-up of patients, years <1 407 (42) 1-3 197 (20) 3-5 97 (10) 5-10 179 (18) >=10 92 (9)

a Other impairment will be cleaned at the data file preparation stage b Other cancer will be cleaned at the data file preparation stage.

34


Study Proposal 1111-47 Study Title: Solid organ transplantation after hematopoietic cell transplantation. Meera Gupta, MD, University of Pennsylvania, Philadelphia, PA Peter L. Abt, MD, University of Pennsylvania, Philadelphia, PA Matthew Levine, MD, PhD, University of Pennsylvania, Philadelphia, PA Specific Aims: Among hematopoietic cell transplant (HCT) recipients who survive more than 6 months reported in the CIBMTR database, and in a collaborative effort with the United Network of Organ Sharing (UNOS), the study will (1) determine the incidence, prevalence and risk of end-stage organ failure requiring solid organ (kidney, liver, heart, lung, pancreas) transplantation. The study will (2) identify potential risk factors and predictors of organ failure in the hematopoietic cell transplant population. The study will also (3) report on outcomes of solid organ transplantation in HCT recipients and compare survival with solid organ transplant recipients alone. The purpose is to identify modifiable risk factors with the ultimate goal of developing guidelines for optimal management of organ failure for patients who have received or will be receiving hematopoietic cell transplant. Scientific Justification: Solid organ transplantation is challenging in patients who have undergone hematopoietic cell transplantation (HCT). End-stage organ disease and transplantation in this population is associated with significant morbidity and often require significant preparation, higher levels of care and specialty teams. The scientific and clinical communities recognize that HCT is considered a fairly new procedure. First successful in 1968, it has been used to treat patients with leukemia, lymphomas, multiple myeloma, immune deficiency syndromes, breast and ovarian cancers, and aplastic anemia. Hematopoietic cell transplantation alone carries with it significant mortality, morbidity, and challenges in management.1 Despite these challenges, approximately 25,000 allogeneic hematopoietic cell transplants are performed worldwide every year. The National Marrow Donor Program reports that one-year survival among unrelated allogeneic bone marrow transplant recipients continues to increase, 57.9% during the 2004-2008 study period.1 Improved survival rates following allogeneic HCT will likely result in an increase in prevalence of this population and even more recognized prevalence of end stage organ failure. This will undoubtedly increase the need for solid organ transplantation and ultimately determine whether HCT predisposes to later organ failure. A single-center based research study of patients after allogeneic HCT suggests that solid organ failure as a common direct complication after allogeneic bone marrow transplant secondary to prior chemotherapy, irradiation, sepsis, and exposure to nephrotoxic agents.2,4,5 Socie’, et. al., reported that bone marrow-solid organ transplant recipients who survive 2 years from HCT are likely to be cured. However, the mortality among these patients remains significantly higher long term when compared to the general population. 3 Causes of death after hematopoietic stem cell transplant have also been reported and include: multi-organ failure, solid-organ graft rejection, viral reactivation, PTLD and sepsis.11 Acute renal injury after autologous (21%), non-myeloablative(40%) and myeloablative SCT (69%) has been shown to lead to significant increase in mortality 6-12months after transplant, 7%, 34%, and 58% respectively.6 Liver failure secondary to HCT has also been recognized. Mortality caused by hepatic failure in this population ranges from 4% to 15% in different series of adult patients and morbidity is greater than 80%. El-Sayed, et. al., reports a 22.3% incidence of liver failure from graft-versus-host disease and 9.7% from veno-occlusive disease, both of which were associated with high prevalence of Hepatitis B and Hepatitis C reactivations. Those with chronic liver disease have not been followed long-term.7,8 Single-center small sample size analyses have been reported on the morbidity and mortality due

35


to liver disease in patients after allogeneic bone marrow transplant. However, this study also recognized that longer follow-up was necessary in patients who survive more than 2 years. These results also recognize that solid organ transplantation has yet to be considered an outcome measure.9,10 While solid organ transplant after HCT has been reported, these studies have been single-center reports, with the related challenges in interpretation questionable applicability to other centers. Therefore, several clinical questions remain to be answered. First, there have been no large scale long-term studies of HCT recipients identifying the incidence of organ failure requiring solid organ transplantation and outcomes from those transplants. Data available are sparse and single-center at best. In 1998, a case report literature review of 21 patients after HCT who underwent solid organ transplantation determined that successful outcomes depend on the indication for transplant and histocompatibility.12

Addressing the need for large-scale research on this topic, this study will embark on a collaborative effort between the CIBMTR and UNOS to identify the incidence and prevalence of organ failure requiring organ transplantation (renal, hepatic, pancreatic, pulmonary, cardiac) among hematopoietic cell transplant recipients. We will also investigate the outcomes of those transplants relative to recipients who have not received HCT. In doing so, we will recognize the long term effects of HCT on patients and use this knowledge to develop strategies to preserve solid organ function. Patient Eligibility Population:

Inclusion criteria: Recipient of hematopoietic cell transplant Age <99 years at transplant Survival ≥ 6 months after HCT Initial HCT Registration in CIBMTR 1985-2010

Exclusion Criteria: Age not <99 years at transplant Survival<6 months after HCT Not registered in CIBMTR 1985-2010

Data Requirements:

Data Collection: The CIBMTR database, in collaboration with the UNOS database, will enable us to analyze hematopoietic cell transplant recipients with end-stage organ disease requiring solid organ transplantation according to the following variables:

Total number and percentage of patients with allogeneic HCT Patient Social Security Number Patient Date of Birth Patient Gender Patient Race Age at primary diagnosis Primary disease Secondary diseases Disease stage before transplant Time from diagnosis to transplantation (months) Date of transplant Age at transplant

36


Donor graft type (bone marrow, cord, etc.) Donor types (matched sibling, identical twin, mismatched related, unrelated) Prior treatments (chemotherapy, radiation therapy, immunotherapy, etc.) Specific transplant/immunosuppression regimens Prophylaxis against graft versus host disease (GVHD) Acute GVHD (grade II, III or IV) within 12 months after HCT Chronic GVHD (none, resolved by 12months, or active at 12 months after transplant) Diagnosis of cancer within 6 months after HCT Rejection events Infection/Sepsis events

Data from the CIBMTR database will then be merged with the United Network for Organ Sharing (UNOS). Attempts may be made to merge with the Scientific Registry of Transplant Recipients (SRTR). See Study Design Section. Possible Variables associated with End-Stage Solid Organ Disease to be Analyzed:

Patient Related: age, race, gender, Kamofsky/Lansky performance score pre-transplant Disease Related: specific disease, cancer status, infections, rejections Therapeutic Regimens: steroids, methotrexate (ablative medications), calcineurin inhibitors, length and dose of medications Hematopoietic cell sources: BM vs. PBSC vs. cord blood Type of transplant: Matched sibling/family vs. Matched family vs. Matched Unrelated GVHD related: presence of GVHD at 0-12 months post HCT

Supplemental data will not be collected through the CIBMTR. Outcome data will be obtained through the UNOS Registry. Selection criteria from the UNOS database will include the standard STAR file with above variables as well as the following:

Patients with history of HCT: all patients waitlisted and after solid organ transplantation Primary disease causing end-stage organ disease Date of solid organ listing Organ type Time interval from listing to organ transplantation Need for dialysis One-year and three-year survival Multiple organ listing and transplant Donor variables: summary statistics including social security number, date of birth, age, race,

preoperative organ evaluation, cause of death, ischemia time (warm and cold)

Sample Requirements: The study design will not require biologic samples (DNA, serum, cell lines or viable peripheral blood mononuclear cells) from the NMDP Research Sample Repository. Please refer to section VI for further details on non-sample data requirements. Study Design (Scientific Plan): We will perform a retrospective cohort study of patients aged < 99 years who were recipients of hematopoietic cell transplant from 1985-2010 and survived at least > 6 months after HCT. We will then merge the data collected on these subjects in the CIBMTR with data on solid organ transplantation in the follow-up period (through 2010) in the UNOS registry using each patient’s social security number, date of birth, and transplant dates as identifiers. This will be accomplished by the primary investigators of the study and data managers at CIBMTR and UNOS. We will then be able to determine the prevalence of

37


organ failure requiring need for transplant. We will determine the time interval from bone marrow transplant to solid organ transplant listing and the listing diagnosis, which will also allow us to report the cumulative incidence of organ failure requiring solid organ transplant. Finally, of those patients who are listed for solid organ transplant, we will determine the number of those who underwent transplant, report on outcomes such as graft and patient survival, and compare those who were not transplanted. We will also compare outcomes to those of recipients of solid organ transplants who have not had antecedent HCT. All variables anticipated to be associated with end-stage organ disease will be collected and analyzed using univariate and multivariate modeling. Feasibility and best statistical approach will be determined with the guidance of the statistical staff. Appropriate IRB forms and various patient protection measures in place from the study sites will be submitted upon study approval by the CIBMTR review committee. Limitations of this methodology include that the CIBMTR does not include all hematopoietic cell transplant recipients, missing social security numbers for unrelated and autologous HCT, potential missing data in both CIBMTR and UNOS, and patient loss to follow up with registered centers. Limitations listed can be dealt with alternative ways of identifying patients lacking social security numbers with other patient identifiers, and by collaborating with the Scientific Registry of Transplant Recipients. Like UNOS, the SRTR also supports the ongoing evaluation of the scientific and clinical status of solid organ transplantation, including kidney, heart, liver, lung, intestine, and pancreas. Data in the registry are collected by the Organ Procurement and Transplantation Network (OPTN) from hospitals and organ procurement organizations (OPOs) across the country. The SRTR contains current and past information about the full continuum of transplant activity, from organ donation and waiting list candidates to transplant recipients and survival statistics. References:

1. Biology of Blood and Marrow Transplantation to mark the NMDP's 20th anniversary. See Saving Lives through Blood and Marrow Transplantation: 20 years of the NMDP.

2. Thomas SE, Hutchinson RJ, Debroy M, Magee JC. Successful renal transplantation following prior bone marrow transplantation in pediatric patients. Pediatr Transplant. 2004 Oct;8(5):507-12.

3. Gerard Socie, MD, PhD, et al. Long-term survival and late deaths after allogeneic bone marrow transplantation. New England Journal of Medicine. July 1999;341:14-21.

4. Lopes JA, Goncalves S, Jorge S, Raimundo M, Resende L, Lacerda JF et al. Contemporary analysis of the influence of acute kidney injury after reduced intensity conditioning hematopoietic cell transplantation on long-term survival. Bone Marrow Transplant 2008; 42: 619.

5. Parikh CR, Yarlagadda SG, Storer B, Sorror M, Storb R, Sandmaier B. Impact of acute kidney injury on long-term mortality after nonmyeloablative hematopoietic cell transplantation. Biol Blood Marrow Transplant 2008; 14: 309-315.

6. Schrier RW, Parikh CR. Comparison of renal injury in myeloablative autologous, myeloablative allogeneic and non-myeloablative allogeneic hematopoietic cell transplantation. Nephrol Dial Transplant 2005; 20: 678-683.

7. El-Sayed, M, El-Haddad, A, Fahmy, OA, Salama, II, Mahmoud, HK. Liver disease is a major cause of mortality following allogeneic bone-marrow transplantation. European Journal of Gastroenterology & Hepatology 2004, 16; 1347-1354.

8. McDonald GB, Shulman HM, Spencer GD: Liver disease after human marrow transplant. Semin Liver Dis 7:210, 1987.

9. Locasciulli, A, Testa, M, Valsecchi, MG et. Al. Morbidity and mortality due to liver disease in children undergoing allogeneic bone marrow transplantation: a 10-year prospective study. Blood, Vol 90, No 9 (November 1) 1997: pp3799-3805.

10. Tomas, JF, et. al. Long-term liver dysfunction after allogeneic bone marrow transplantation: clinical features and course in 61 patients. Bone Marrow Transplantation (2000) 26, 649-655.

38


11. Schechter T, et. al. Hematopoietic stem-cell transplantation following solid-organ transplantation in children. Bone Marrow Transplantation (2011) 46, 1321-1325.

12. Dev. B, Sykes M, Spitzer, TR. Outcomes of recipients of both bone marrow and solid organ transplants. A review. Medicine (Baltimore). 1998 Sep:77(5): 355-69.

39


Study Proposal 1111-59 Study Title: Avascular Necrosis of Bone in Adults after Hematopoietic Cell Transplantation Linda J. Burns, MD, University of Minnesota, Minneapolis, MN Brian McClune, DO, University of Minnesota, Minneapolis, MN Navneet Majhail, MD, MS, National Marrow Donor Program, Minneapolis, MN Specific Aims:

Determine the incidence of avascular necrosis (AVN) in adults following hematopoietic cell transplantation (HCT).

Identify risk factors associated with AVN in this population. Evaluate the role of the intensity of conditioning in the development of AVN. Evaluate the role of immunosuppressive agents, particularly corticosteroids, calcineurin

inhibitors, and mycophenolate mofetil, in the development of AVN.

Scientific Justification: AVN, also known as osteonecrosis, results from a lack of blood supply to bones with resultant death of bone tissue. An incidence of 4% to 19% in survivors of HCT has been reported (1-8). Physical therapy and pain control are the primary early treatment modalities, with joint replacement surgery ultimately required to improve joint function. Proposed risk factors include female sex, older age, allogeneic donor source, acute and chronic graft-versus-host disease (aGVHD and cGHVD), corticosteroid therapy, total body irradiation (TBI), calcineurin inhibitors and mycophenolate mofetil use (1, 2, 5, 7, 9- 12). The CIBMTR has not preciously analyzed the incidence and risk factors in the adult population, and this would be a nice companion to the ongoing analysis in the pediatric population. It will be interesting to see if there are similarities and/or differences in the two populations. Patient Eligibility Population: Patients 18 years and greater undergoing autologous and allogeneic transplantation from all donor sources; all diseases will be included, with the exception of myeloma.

Variables:

Patient and disease related: Age Gender Disease (acute leukemia, chronic leukemia, lymphoma, nonmalignant disorder). Karnosfky score Comorbidity score Number of prior chemotherapies (<3 or 3 or more)

Transplant related: Prior autologous HCT Donor type (sib vs MUD vs UCB) Conditioning (MA vs RIC/NMA; TBI vs no TBI) Use and types of immunosuppressive therapy Acute and chronic GVHD and therapy

Data Requirements: The yearly post-HCT data form includes a section on Other Organ Impairment/Disorder, question 175 on the development of avascular necrosis and the date of diagnosis.

40


Sample Requirements:* None.

Study Design: This is a retrospective analysis, and has the same limitations that were identified during the discussion at the CIBMTR Working Committee for Late Effects in 2010 – that being that AVN cases may be under-reported in the database, dosage information of immunosuppressive agents and their duration of therapy is not collected reliably, and that the time of onset of AVN was not collected until 2007. With these limitations, a descriptive analysis only may be required. References:

1. Enright H, Haake R, Weisdorf D. Avascular necrosis of bone: a common serious complication of allogeneic bone marrow transplantation. Am J Med 341:14-21, 1990

2. Schulte CM, Beelen DW. Avascular osteonecrosis after allogeneic hematopoietic stem-cell transplantation: a diagnosis and gender matter. Transplantation 78:1055-1063, 2004.

3. Weismann A, Periera P, Bohm P, Faul C, Kanz L, Einsele H. Avascular necrosis of bone following allogeneic stem cell transplantation: MR screening and therapeutic options. Bone Marrow Transplant 22:565-569, 1998.

4. Schulte CM, Beelen DW. Low pretransplant bone-marrow density and rapid bone loss do not increase risk for avascular osteonecrosis after allogeneic hematopoietic stem cell transplantation. Transplantation 79:1748-1755, 2005.

5. Socie G, Cahn JY, Carmelo J, et al. Avascular necrosis of bone after allogeneic bone marrow transplantation: analysis of risk factors for 4388 patients by the Societe Francaise de Greffe de Moelle (SFGM). Br J Haematol 97:865-870, 1997.

6. Fink JC, Leisenring WM, Sullivan KM, Sherrard DJ, Weiss NS. Avascular necrosis following bone marrow transplantation: a case controlled study. Bone 22:67-71, 1998.

7. Campbell S, Sun CL, Kurian S, et al. Predictors of avascular necrosis of bone in long-term survivors of hematopoietic cell transplantation. Cancer 115:4127-4135, 2009.

8. Fryer JP, Granger DK, Leventhal JR, Gillingham K, Najarian JS, Matqas AJ. Steroid-related complications in the cyclosporine era. Clin Transplant 8:224-229, 1994.

9. Tauchmanova L, DeRosa G, Serio B, et al. Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation: a single center experience and review. Cancer 97:2453-2461, 2003.

10. Socie G, Selimi F, Sedel L, et al. Avascular necrosis of bone after allogeneic bone marrow transplantation: clinical findings, incidence and risk factors. Br J Haematol 86:624-628, 1994.

11. Torii YMD, Hasegawa YMD, Kubo TMD, et al. Osteonecrosis of the femoral head after allogeneic bone marrow transplantation. Clin Orthop Relat Res 382:124-132, 2001.

12. McAvoy S, Baker KS, Mulroonery D, et al. Corticosteroid dose as a risk factor for avascular necrosis of the bone after hematopoietic cell transplantation. Biol Blood Marrow Transplant 16:1231-1236, 2010.

41


Table: Characteristics of patients (age>18 years old) receiving an allogeneic transplant, reported to the CIBMTR between 1990 and 2009, by status of post-transplant AVN.

Post-tx AVN No Yes

Variable

Median (range) N (%)

Median (range)N (%)

Number of patients 19177 805Number of centers 379 167Age at transplant, years, median (range) 40 (18-79) 34 (18-72)Age at transplant, years 18-29 4824 (25) 312 (38) 30-39 4660 (24) 200 (25) 40-49 4789 (25) 159 (20) 50-59 3448 (18) 102 (13) 60-69 1360 (7) 30 (4) >=70 96 (1) 2 (<1)Sex Male 10951 (57) 491 (61) Female 8224 (43) 314 (39)Region of teams US 10475 (55) 532 (66) Canada 863 (5) 45 (6) Europe 4597 (24) 134 (17) Asia 895 (5) 33 (4) Australia/New Zealand 900 (5) 25 (3) Mideast/Africa 652 (3) 24 (3) Central/South America 795 (4) 12 (1)Disease ALL/HD/NHL 4630 (24) 217 (27) AML/MDS 8667 (45) 356 (44) CML 4618 (24) 141 (18) SAA/Immunodeficiencies 1010 (5) 74 (9) Inborn disorder of metabolism 14 (<1) 2 (<1) Others 238 (1) 15 (2)Transplant year 1990-1994 5581 (29) 172 (21) 1995-1999 3823 (20) 138 (17) 2000-2004 4307 (22) 230 (29) 2005-2009 5466 (29) 265 (33)Total body irradiation No 9775 (52) 350 (44) Yes 9190 (48) 447 (56) Missing 154 5

42


Post-tx AVN No Yes

Variable


Median (range)N (%)

Condition regimen TBI+CY+-Other 7364 (38) 378 (47) BU+CY+-Other 248 (1) 7 (1) TBI+-Other 1578 (8) 62 (8) BU+-Other 7686 (40) 258 (32) CY+-Other 1073 (6) 56 (7) Other 1228 (6) 44 (5)Graft type BM 10715 (56) 435 (54) PB+-BM 7853 (41) 339 (42) CB 609 (3) 31 (4)Donor type HLA-matched siblings 11259 (59) 358 (44) Identical twins 128 (1) 3 (<1) Other relatives 560 (3) 14 (2) Unrelated donor 7230 (38) 430 (53)GvHD Prophylaxis T-cell depletion 1202 (6) 26 (3) FK506+MTX 3478 (18) 193 (24) FK506 1639 (9) 71 (9) MTX+CsA 9152 (48) 367 (46) CsA 3094 (16) 130 (16) Other/unknown 612 (3) 18 (2)Onset of aGvHD No 7160 (37) 217 (27) Yes 11951 (63) 588 (73) Missing 66 0Onset of cGvHD No 10401 (54) 188 (23) Yes 8692 (46) 617 (77) Missing 84 0Follow-up of survivors, months, median (range) 72 (1-259) 72 (3-245)

43


Study Proposal 0811-01 Study Title: Prevalence and associated risk factors for diabetes mellitus and hyperglycemia in children following hematopoietic stem-cell transplantation. Josephine Ho, BSc, MD, MSc, University of Calgary, Alberta Children’s Hospital, Calgary, CANADA Gregory Guilcher, MD, University of Calgary, Alberta Children’s Hospital, Calgary, CANADA Tal Schechter-Finkelstein, MD, University of Toronto, The Hospital for Sick Children, Ontario, CANADA Specific Aims:

To assess the prevalence of diabetes mellitus/hyperglycemia in children post-hematopoietic stem-cell transplantation (HSCT) (at 100 days, 6 months, 1 year, and yearly follow-up).

To determine if there are baseline risk factors that are associated with the development of diabetes mellitus/hyperglycemia in children post-HSCT (baseline risk factors to be assessed: age, gender, ethnicity, smoking, body mass index, household gross income, baseline endocrine diseases, indication for HSCT)

To evaluate if the development of diabetes mellitus/hyperglycemia in children post-HSCT is associated with: the development of other endocrine dysfunction that can affect metabolism (gonadal dysfunction, growth hormone deficiency, or hypothyroidism), donor source, or the development of graft versus host disease (GVHD) (acute and chronic).

Scientific Justification: Children who have undergone HSCT are at a higher risk for metabolic syndrome (1, 2) and specific metabolic abnormalities such as diabetes and hypertension (3). Impaired glucose tolerance and lipid abnormalities have also been found in children following HSCT (4). These metabolic abnormalities increase the risk for the development of future cardiovascular disease and mortality (5). Risk factors for abnormal glucose metabolism are important to identify as hyperglycemia is a component of the metabolic syndrome. Hyperglycemia itself can also lead to long term complications including retinopathy, neuropathy and nephropathy and increased cardiovascular disease risk (6). Taskinen et al compared 23 pediatric allogeneic HSCT survivors to non-transplanted leukemia survivors and healthy controls (4). HSCT survivors had a significantly higher incidence of hyperinsulinemia (52% vs 31% vs 0% respectively) (4). Combined hyperinsulinemia and hypertriglyceridemia was found in 39% of HSCT survivors compared to 8% of leukemia survivors and 0% of healthy controls (4). Diabetes mellitus has been reported in 38 out of 748 (5%) long term survivors of pediatric HSCT in an older retrospective review done between 1969 and 1999 (7). In this study, risk factors associated with developing type 2 diabetes were leukemia as the underlying disease, ethnicity, family history of diabetes and asparaginase toxicity (7). The authors concluded that children who are post-HSCT are more likely to develop diabetes than the general population (7). Multiple factors related to HSCT can contribute to the development of abnormal glucose metabolism and hyperglycemia (1, 2, 8) including: drugs causing insulin resistance or pancreas dysfunction (eg. glucocorticoids, calcineurin inhibitors), cranial radiation leading to hypothalamic dysfunction and appetite dysregulation, decreased physical activity level due to cardiac dysfunction from anthracyclines or mediastinal radiation and lung damage, impaired metabolism from hypothyroidism, growth hormone deficiency and gonadal dysfunction leading to decreased strength and physical activity. The objective of this study is to assess the prevalence, baseline risk factors and associations with other endocrine dysfunction of diabetes mellitus/hyperglycemia in children post-HSCT. Early recognition of children at risk for abnormal glucose metabolism and aggressive targeting of modifiable risk factors may reduce future cardiovascular morbidity and mortality in children post-HSCT.

44


Patient Eligibility Population: Inclusion criteria:

Age at time of HSCT (autologous or allogeneic) 0-18 years

Exclusion criteria: Existing diagnosis of diabetes mellitus/hyperglycemia at baseline

Data Requirements: This initial retrospective review of the CIBMTR database will not require collection of supplemental data or combining data with data from another group. The specific variables to be analyzed from the existing CIBMTR data collection forms will include: CIBMTR Form ID

Form Name Data Requested

Form 2000 Recipient Baseline Data Age Gender Ethnicity Smoking Height Weight Household gross income Primary disease:

Disease stage Year of transplant Graft and donor source

Specific transplant regimens (radiation therapy, corticosteroids, etc.) Baseline endocrine diseases: -adrenal insufficiency -diabetes mellitus -osteoporosis -thyroid disease Baseline cardiovascular disease: -hypertension

Form 2100 100 Days Post- HSCT Data Diagnosis of: -Diabetes mellitus/hyperglycemia Other endocrine diagnosis: -Gonadal dysfunction -Growth hormone deficiency -Hypothyroidism Acute GVHD and staging

Form 2200 Six Months to Two Years Post-HSCT Data

Diagnosis of: -Diabetes mellitus/hyperglycemia Other endocrine diagnosis: -Gonadal dysfunction -Growth hormone deficiency -Hypothyroidism Chronic GVHD (limited or extensive)

45


Form 2300 Yearly Follow-up For Greater Than Two Years Post-HSCT Data

Diagnosis of: -Diabetes mellitus/hyperglycemia Other endocrine diagnosis: -Gonadal dysfunction -Growth hormone deficiency -Hypothyroidism Chronic GVHD (limited or extensive)

Sample Requirements: This study will not require any biologic samples from the NMDP research sample repository.

Study Design: This study will be a retrospective review of data already collected through the CIBMTR database. Specifically, each aim and proposed analysis is outlined below:

To assess the prevalence of diabetes mellitus/hyperglycemia in children post-HSCT. Prevalence will be reported as a percentage of children who develop diabetes mellitus/hyperglycemia at 100 days, 6 months, 1 year, and yearly follow-up.

To determine if there are baseline risk factors that are associated with the development of diabetes mellitus/hyperglycemia in children post-HSCT. Baseline risk factors to be assessed will include: age, gender, ethnicity, smoking, body mass index, household gross income, baseline endocrine diseases, indication for HSCT. These risk factors will be analyzed using odds ratios and confidence intervals. The Mantel-Haenzel test for homogeneity will be used to look for evidence of effect modification or confounding.

To evaluate if the development of diabetes mellitus/hyperglycemia in children post-HSCT is associated with the development of other endocrine dysfunction that can affect metabolism, donor source or GVHD. The odds of developing diabetes mellitus/hyperglycemia in children who develop gonadal dysfunction, growth hormone deficiency, hypothyroidism, or GVHD will be assessed using odds ratios and confidence intervals. The odds of developing diabetes mellitus/hyperglycemia depending on donor source will be assessed using odds ratios and confidence intervals.

This proposed study is limited by the fact that it is a retrospective analysis of the CIBMTR database. Case finding may be limited by a clinician’s variable diagnosis of diabetes mellitus or hyperglycemia. For example, a child with transiently elevated blood glucose may not have been given a diagnosis of hyperglycemia in some centers. In addition, it is possible that a child may have developed type 1 diabetes mellitus unrelated to the HSCT. Assessment of potential associated risk factors for the development of diabetes mellitus/hyperglycemia will be limited by the data collection forms in use (for example, family history of type 2 diabetes mellitus, obesity or metabolic syndrome is not documented). Despite the limitations of a retrospective study, this initial project will provide important information to help in the understanding of the development dysglycemia in children post-HSCT. Future studies could focus on additional surveys to assess potential risk factors (family history, child’s physical activity level, associations of depression and self-esteem scales with body mass index) as well as current clinical practices regarding counseling and interventions (frequency of nutritional assessments by registered dietician, frequency of physical activity recommendations, frequency of smoking and alcohol counseling, assessments of waist circumference, monitoring of body mass index and blood pressure). Screening of at risk populations for insulin resistance (fasting insulin and fasting glucose measurements) prior to developing frank diabetes mellitus could also be assessed. Ultimately, early identification of children at risk for glucose metabolism abnormalities post-HSCT may help to prevent future cardiovascular morbidity and mortality.

46


References: 1. Majhail NS, Flowers ME, Ness KK, Jagasia M, Carpenter PA, Arora M, et al. High prevalence of

metabolic syndrome after allogeneic hematopoietic cell transplantation. Bone marrow transplantation. 2009;43(1):49-54.

2. Talvensaari KK, Lanning M, Tapanainen P, Knip M. Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome. The Journal of clinical endocrinology and metabolism. 1996 Aug;81(8):3051-5.

3. Baker KS, Ness KK, Steinberger J, Carter A, Francisco L, Burns LJ, et al. Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood. 2007 Feb 15;109(4):1765-72.

4. Taskinen M, Saarinen-Pihkala UM, Hovi L, Lipsanen-Nyman M. Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood. Lancet. 2000 Sep 16;356(9234):993-7.

5. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. Jama. 2002, 4;288(21):2709-16.

6. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. The New England journal of medicine. 1993 Sep 30;329(14):977-86.

7. Hoffmeister PA, Storer BE, Sanders JE. Diabetes mellitus in long-term survivors of pediatric hematopoietic cell transplantation. J Pediatr Hematol Oncol. 2004 Feb;26(2):81-90.

8. Han JW, Kwon SY, Won SC, Shin YJ, Ko JH, Lyu CJ. Comprehensive clinical follow-up of late effects in childhood cancer survivors shows the need for early and well-timed intervention. Ann Oncol. 2009 Jul;20(7):1170-7.

47


Pre- and post-transplant conditions collected on CIBMTR forms

CIBMTR Legacy forms (Before 2007)

FormsNet 2 forms (After 2007)

Pre-transplant comorbidities Adrenal insufficiency Not collected Collected Diabetes mellitus Collected Collected Thyroid disease Collected Collected Hypertension Collected Collected

Post-transplant conditions Gonadal dysfunction Collected Collected Growth disturbance Collected Collected Hypothyroidism Collected Collected Diabetes mellitus Not collected Collected

48


Characteristic of patients (age < 18) who received HCTs reported to the CIBMTR between 2000 and 2010

Transplant type Allo Auto


N (%)Median (range)

N (%)Number of patients 10134 1011Number of centers 233 110Age at transplant, years 1-9 6265 (62) 725 (72) 10-18 3869 (38) 286 (28)Sex Male 6025 (59) 584 (58) Female 4109 (41) 427 (42)Karnofsky score prior to transplant >=90 7549 (81) 724 (78) <90 1792 (19) 205 (22) Missing 793 82Region of teams US 6202 (61) 771 (76) Canada 430 (4) 108 (11) Europe 941 (9) 2 (<1) Asia 460 (5) 4 (<1) Australia/New Zealand 439 (4) 5 (<1) Mideast/Africa 1145 (11) 15 (1) Central/South America 517 (5) 106 (10)Disease AML 1905 (19) 25 (2) ALL 2455 (24) 2 (<1) CML 389 (4) 1 (<1) NHL 188 (2) 28 (3) HD 12 (<1) 68 (7) MDS/MPS 610 (6) 0 Other Leukemia 210 (2) 1 (<1) Solid Cancer 33 (<1) 874 (86) Aplastic Anemia 955 (9) 2 (<1) Other Non-Malig Diseases 3377 (33) 10 (1)Year of transplant 2000 957 (9) 119 (12) 2001 972 (10) 105 (10) 2002 937 (9) 68 (7) 2003 973 (10) 43 (4) 2004 1014 (10) 78 (8) 2005 1046 (10) 145 (14) 2006 968 (10) 101 (10) 2007 826 (8) 74 (7) 2008 1001 (10) 186 (18) 2009 926 (9) 86 (9) 2010 514 (5) 6 (1)

49


Continued.



N (%)Median (range)

N (%)Pre-transplant conditions Adrenal insufficiency 27 (<1) 1 (<1) Diabetes mellitus 68 (1) 3 (<1) Thyroid disease 43 (<1) 13 (1) Hypertension 182 (2) 17 (2)Conditioning regimen Myeloablative 7263 (81) 628 (83) Non-myeloablative 1718 (19) 129 (17) Missing 1153 254Condition regimen TBI+CY+-Other 3642 (36) 8 (1) BU+CY+-Other 60 (1) 0 TBI+-Other 458 (5) 6 (1) BU+-Other 4139 (41) 124 (12) CY+-Other 843 (8) 338 (33) Other 992 (10) 535 (53)Graft type BM 5109 (51) 53 (5) PB+-BM 1824 (18) 936 (94) CB 3100 (31) 6 (1) Missing 101 16Donor type Auto 0 1011 HLA-matched siblings 2997 (30) 0 Identical twins 27 (<1) 0 Other relatives 536 (5) 0 Unrelated donor 6494 (65) 0 Missing 80 0GvHD Prophylaxis Auto transplant 0 1011 T-cell depletion 628 (6) 0 FK506+MTX 1072 (11) 0 FK506 686 (7) 0 MTX+CsA 3887 (38) 0 CsA 3253 (32) 0 Other/unknown 608 (6) 0Post-tranplant conditions Gonadal dysfunction 379 (4) 17 (2) Growth disturbance 484 (5) 39 (4) Hypothyroidism 340 (3) 43 (4) Diabetes mellitus 237 (2) 1 (<1) Follow-up of survivors, months, median (range) 43 (<1-141) 35 (<1-126)

50


Characteristic of patients (age < 18) who received HCTs reported to the CIBMTR between 2007 and 2010


Variable



Number of patients 3267 352Number of centers 138 70Age at transplant, years 1-9 2105 (64) 260 (74) 10-18 1162 (36) 92 (26)Sex Male 1936 (59) 207 (59) Female 1331 (41) 145 (41)Karnofsky score prior to transplant >=90 2341 (81) 234 (77) <90 536 (19) 68 (23) Missing 390 50Region of teams US 2392 (73) 300 (85) Canada 119 (4) 32 (9) Europe 131 (4) 0 Asia 86 (3) 0 Australia/New Zealand 177 (5) 5 (1) Mideast/Africa 265 (8) 10 (3) Central/South America 97 (3) 5 (1)Disease AML 642 (20) 7 (2) ALL 728 (22) 0 CML 66 (2) 0 NHL 50 (2) 9 (3) HD 4 (<1) 25 (7) MDS/MPS 242 (7) 0 Other Leukemia 66 (2) 0 Solid Cancer 6 (<1) 306 (87) Aplastic Anemia 300 (9) 1 (<1) Other Non-Malig Diseases 1163 (36) 4 (1)Year of transplant 2007 826 (25) 74 (21) 2008 1001 (31) 186 (53) 2009 926 (28) 86 (24) 2010 514 (16) 6 (2)Pre-transplant conditions Adrenal insufficiency 27 (1) 1 (<1) Diabetes mellitus 20 (1) 1 (<1) Thyroid disease 19 (1) 4 (1) Hypertension 71 (2) 8 (2)

51


Continued. Transplant type Allo Auto

Variable



Conditioning regimen Myeloablative 2110 (75) 192 (78) Non-myeloablative 703 (25) 53 (22) Missing 454 107Condition regimen TBI+CY+-Other 1014 (31) 1 (<1) BU+CY+-Other 35 (1) 0 TBI+-Other 129 (4) 0 BU+-Other 1289 (39) 26 (7) CY+-Other 213 (7) 98 (28) Other 587 (18) 227 (64)Graft type BM 1237 (39) 20 (6) PB+-BM 418 (13) 312 (92) CB 1523 (48) 6 (2) Missing 89 14Donor type Auto 0 352 HLA-matched siblings 724 (23) 0 Identical twins 2 (<1) 0 Other relatives 131 (4) 0 Unrelated donor 2352 (73) 0 Missing 58 0GvHD Prophylaxis Auto transplant 0 352 T-cell depletion 84 (3) 0 FK506+MTX 397 (12) 0 FK506 385 (12) 0 MTX+CsA 774 (24) 0 CsA 1277 (39) 0 Other/unknown 350 (11) 0Post-tranplant conditions Gonadal dysfunction 68 (2) 6 (2) Growth disturbance 69 (2) 4 (1) Hypothyroidism 76 (2) 14 (4) Diabetes mellitus 185 (6) 0 Follow-up of survivors, months, median (range) 24 (<1-53) 26 (<1-55)

52


Abstract for LE09-01

Second Malignancies After Autologous Hematopoietic Cell Transplantation In Children

Purpose: Autologous hematopoietic cell transplantation (AHCT) is curative for selected cancers in children. Childhood AHCT survivors can be at risk for late complications, including secondary malignant neoplasms (SMNs). Incidence and risk factors for SMNs following AHCT in children are not well known. Patients and Methods: We assembled a cohort of 1,487 pediatric AHCT recipients transplanted between 1987 and 2003 to investigate the incidence and risk factors for SMNs. The median age at AHCT was 8 years, and median follow-up of survivors was 8 years from AHCT. Primary diagnoses included neuroblastoma (39%), lymphoma (26%), sarcoma (18%), CNS tumors (14%), and Wilms tumor (2%). Results: SMNs were reported in 35 patients (AML/MDS=13, solid cancers=20, subtype missing=2). The overall cumulative incidence of SMNs at 10 years from AHCT was 2.60%. The corresponding cumulative incidence of secondary AML/MDS was 1.06% and for secondary solid tumors was 1.30%. We found no association between SMNs risk and age, gender, diagnosis, disease status, time since diagnosis, or use of total body irradiation or etoposide as part of conditioning. Overall survival at 5 years from the time of diagnosis of SMNs was 33% (95% CI, 16-52%). When compared to age- and gender-matched general population, AHCT recipients had 25 times higher risks of developing SMNs (95% CI, 17.0-35.0). Risks of SMNs increased with longer follow-up from AHCT. Conclusion: Although the overall incidence of SMNs among pediatric AHCT recipients is low, they are at considerably increased risk for SMNs compared to the general population and need life-long surveillance for secondary cancers.

53


Abstract for LE10-02

Late Effects in Hematopoietic Cell Transplant Recipients with Severe Aplastic Anemia: A Report

from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR)

Objective: With improvements in hematopoietic cell transplantation (HCT) for severe aplastic anemia (SAA), there is a growing population of SAA survivors of HCT. However, there is a paucity of information regarding late effects in SAA HCT survivors. We analyzed the burden of malignant and non-malignant late effects in HCT survivors with acquired SAA. Methods: A descriptive analysis of 1,718 patients post-HCT for acquired SAA between 1995-2006 reported to the CIBMTR was conducted. Cumulative incidences (CI) of selected late effects are reported for among "condition-free" (i.e. survivors without a previous diagnosis of the specified late effect) HCT survivors with SAA. Results: One-year overall survival for the recipients of related donor HCT was 83% (80-85) and 62% (58-66) for the recipients of unrelated donor HCT. Of the HCT recipients, 1176 (68.5%) patients with a median age at HCT of 20 years (<1-65) utilized a related donor and 542 (31.5%) patients with a median age at HCT of 20 years (<1-67) utilized an unrelated donor. The median interval from diagnosis to transplant was 3 months (<1-348) for related donor HCT and 14 months (1-318) for unrelated donor HCT. Radiation (of any type) was utilized in 6% and 78% of related and unrelated donor HCT cases; respectively. Cy-TBI (68%) was a commonly utilized conditioning regimen for unrelated donor HCT. The median follow-up is 70 months (1-160) and 67 months (3-182) for related and unrelated donor HCT; respectively. The 2-year CI of chronic GVHD was 20% (18-22) and 37% (32-41) in related and unrelated donor HCT; respectively. Table 1 demonstrates that among 1-year condition-free survivors, the CI of late effects is greater among unrelated donor HCT survivors and continues to increase. Conclusion: These findings suggest that HCT survivors with SAA are a robust and healthy group in general. However, subgroups of patients undergoing HCT for SAA are at-risk for late effects and must be educated about and should be monitored for late effects. Subgroups of survivors may be at-risk group for a greater burden of specific late effects. Ongoing analyses in our cohort will explore selected risk-factors for late effects after HCT for SAA.

54


Table 1. Interval specific cumulative incidence of select late effects among 1-year condition free survivors following related and unrelated donor HCT for acquired SAA between 1995 and 2006 reported to the CIBMTR

Health conditions post-transplant N at risk

HLA-matched Siblings

% (95% CI) N at risk Unrelated donors

% (95% CI) Stroke/seizures Over next 2 years 707 1.7 (0.9-2.7) 283 1.3 (0.3-2.8) Over next 5 years 416 1.8 (1-2.9) 118 2.8 (1.2-5.1) Gonadal dysfunction Over next 2 years 709 2.6 (1.6-3.8) 273 6.2 (3.8-9.1) Over next 5 years 419 3 (2-4.3) 108 10.5 (7.3-14.3) Renal failure Over next 2 years 715 1.1 (0.5-1.9) 287 1.9 (0.7-3.6) Over next 5 years 425 1.4 (0.7-2.3) 127 2.4 (0.9-4.5) Avascular necrosis Over next 2 years 724 1.4 (0.7-2.3) 276 3.2 (1.5-5.4) Over next 5 years 426 1.8 (1-2.8) 117 6.3 (3.6-9.7) Cataracts Over next 2 years 734 0.6 (0.2-1.2) 284 2.2 (0.9-4.1) Over next 5 years 433 1.1 (0.5-1.9) 118 5.1 (2.9-8) Growth disturbance Over next 2 years 735 0.2 (0-0.7) 286 1.9 (0.7-3.6) Over next 5 years 433 0.5 (0.1-1.2) 113 7.2 (4.4-10.7) Hypothyroidism Over next 2 years 731 0.7 (0.3-1.4) 286 0.6 (0.1-1.8) Over next 5 years 432 1.2 (0.5-2.1) 119 5.5 (2.8-9) Secondary solid cancer Over next 2 years 820 0.6 (0.2-1.1) 276 0.7 (0.1-1.9) Over next 5 years 528 0.7 (0.2-1.3) 121 1.4 (0.4-3)

55

Interstitial Pneumonitis / Idiopathic Pneumonia Syndrome

1. Did the recipient develop interstitial pneumonitis / idiopathic pneumonia syndrome (IPn / IPS) since the date of the last report?

(IPn / IPS is characterized by hypoxia, chest radiography with diffuse interstitial infiltrates not caused by fluid overload.)

1 o yes

2 o no

2. Date of diagnosis of IPn / IPS:

3. Were any diagnostic tests performed for IPn / IPS (other than radiographic studies)?

1 o yes

2 o no

To be completed in conjunction with a Form 2200 – Six Months to Two Years Post-HSCT Data, or Form 2300 – Yearly

Follow-Up for Greater Than Two Years Post-HSCT Data. Information reported here should reflect the date of last contact

as reported in the post-HSCT data collection form, or immediately prior to death.

Continue with Bronchiolitis Obliterans section at question 41

Was the procedure

Specify all diagnostic tests performed for IPn / IPS: considered diagnostic or positive?

4. 1 o yes 2 o no Bronchioalveolar lavage 5. 1 o yes 2 o no

6. 1 o yes 2 o no Transbronchial biopsy 7. 1 o yes 2 o no

8. 1 o yes 2 o no Open / thorascopic (VATS) lung biopsy 9. 1 o yes 2 o no

10. 1 o yes 2 o no Autopsy 11. 1 o yes 2 o no

12. 1 o yes 2 o no Other diagnostic test 14. 1 o yes 2 o no

13. Specify other diagnostic test:

15. Was any positive microbiologic culture obtained from the above diagnostic testing?

1 o yes

2 o no

16. Was an infectious etiology identified from the pathology report (e.g., hyphal elements, abscess,

viral inclusions)?

1 o yes

2 o no

Report all bacterial, viral or fungal infections in the infection section

of the form 2100 or 2200.



CIBMTR Form 2515 revision 2 (page 1 of 9) January 2011

Copyright © 2011 National Marrow Donor Program and

The Medical College of Wisconsin, Inc. All rights reserved.Internal use: Document number F00xxx revision 1 Replaces: n/a

Late Effects – Pulmonary

Complications

Mail this form to your designated campus

(Milwaukee or Minneapolis). Retain the

original at the transplant center.

Registry Use Only

Sequence

Number:

Date

Received:

Today’s Date:

Date of HSCT for which this form is

being completed: &

CIBMTR Center Number:

HSCT type: o autologous o allogeneic, o allogeneic, o syngeneic

unrelated related (identical twin)

2 0Month Day Year

CIBMTR Recipient ID:

Month Day Year

Month Day Year

Product type: o marrow o PBSC o cord blood o other product,

o multiple cord specify: blood units infused

Visit: o 6 months o 1 year o 2 years o > 2 years, specify:

56

zwang

Typewritten Text

Attachment 12

zwang

Typewritten Text

27. Were any CT or high-resolution CT scans performed?

1 o yes

2 o no

38. Is a pathology / autopsy report or other documentation of IPn / IPS attached?

1 o yes

2 o noAttach a copy of the report with all identifiers removed, except for the birth date and ID

numbers. Reference question 38 of the report.

17. Is a pathology report available?

1 o yes

2 o no




CIBMTR Recipient ID:CIBMTR Center Number:

Specify all of the following changes seen on the pathology report:

18. 1 o yes 2 o no Bronchiolitis obliterans

19. 1 o yes 2 o no COP / BOOP

20. 1 o yes 2 o no Diffuse alveolar damage with hyaline membranes

21. 1 o yes 2 o no Diffuse alveolar hemorrhage

22. 1 o yes 2 o no Nondiagnostic (e.g., “normal,” no pathologic

alterations, no diagnostic alterations)

23. 1 o yes 2 o no Suggestive of infection (e.g., hyphael elements,

abscess, viral inclusions, multinucleated giant cell,

intra- or extracellular microbes)

24. 1 o yes 2 o no Technically unsatisfactory (e.g., inadequate

specimen)

25. 1 o yes 2 o no Other changes present (e.g., pulmonary alveolar

proteinosis (PAP), pulmonary venooclusive disease

(PVOD), granulomas, etc.)

26. Specify other changes present:

Report all bacterial, viral or fungal infections in

the infection section of the form 2100 or 2200.

28. Date of CT scan:

Specify all findings present in the chest CT radiology report:

29. 1 o yes 2 o no 3 o unknown Airspace consolidation / patchy or diffuse infiltrates

30. 1 o yes 2 o no 3 o unknown Bronchial wall thickening

31. 1 o yes 2 o no 3 o unknown Bronchiectasis / bronchial dilation

32. 1 o yes 2 o no 3 o unknown Centrilobular opacities

33. 1 o yes 2 o no 3 o unknown Diffuse interstitial bilateral infiltrates

34. 1 o yes 2 o no 3 o unknown Expiratory lung trapping / hypoattentuation of lung parenchyma

35. 1 o yes 2 o no 3 o unknown Ground glass opacities / attenuation

36. 1 o yes 2 o no 3 o unknown Nodular opacities / nodules

37. Is a CT or high-resolution CT scan report attached?

1 o yes

2 o no

If more than one scan was performed, copy this section and complete for each scan. Check

here o if additional pages are attached.

Attach a copy of the report with all identifiers removed, except for the

birth date and ID numbers. Reference question 37 of the report.

Month Day Year

57

zwang

Typewritten Text

zwang

Typewritten Text

Attachment 12

39. Did the recipient experience two or more episodes of IPn / IPS since the date of the last report?

1 o yes

2 o no

Bronchiolitis Obliterans

41. Did the recipient have a diagnosis of bronchiolitis obliterans syndrome since the date of the last report? (Bronchiolitis obliterans

is generally defined as an obstructive lung injury associated with a decline in the FEV1 or FEV1/FVC from pre-transplant values.)

1 o yes

2 o no

42. Date of diagnosis of bronchiolitis obliterans:

43. Were any diagnostic tests performed for bronchiolitis obliterans?

1 o yes

2 o no

Continue with Pulmonary Hemorrhage section at question 88

Was the procedure

Specify all diagnostic tests performed for bronchiolitis obliterans: considered diagnostic or positive?








1 o yes

2 o no


viral inclusions)?

1 o yes

2 o no


1 o yes

2 o no









Month Day Year

40. Are additional copies attached?

1 o yes

2 o no

Copy this section (questions 2–38) and complete for each episode.












specimen)







58

zwang

Typewritten Text

Attachment 12

67. Were any pulmonary function tests (PFTs) performed as part of the diagnostic workup?

1 o yes

2 o no


1 o yes

2 o no

86. Is a pathology / autopsy report or other documentation of bronchiolitis obliterans attached?

1 o yes


















1 o yes

2 o no





Month Day Year

68. Date of PFT:

Specify all PFT findings:

69. FEV1: liters o not tested o unknown

70. FVC: liters o not tested o unknown

71. FEF 25–75: liters o not tested o unknown

72. Residual volume: liters o not tested o unknown

73. DLCO: o not tested

74. DLCO adjusted for anemia: o not tested

If more than one PFT was performed, copy this section and complete for each test. Check


Month Day Year

•

•

•

•

•

•

Specify units:

1 o ml CO/min/mm Hg

2 o mmol CO/min/kPa

1 o ml CO/min/mm Hg

2 o mmol CO/min/kPa

59

zwang

Typewritten Text

Attachment 12

87. Did the recipient experience two or more episodes of bronchiolitis obliterans since the date of the last report?

1 o yes

2 o no

Pulmonary Hemorrhage

89. Did the recipient have a diagnosis of pulmonary hemorrhage since the date of the last report?

1 o yes

2 o no

90. Date of diagnosis of pulmonary hemorrhage:

91. Were any diagnostic tests performed for pulmonary hemorrhage?

1 o yes

2 o no

Continue with Cryptogenic Organizing Pneumonia section at question 137

Was the procedure

Specify all diagnostic tests performed for pulmonary hemorrhage: considered diagnostic or positive?








1 o yes

2 o no


viral inclusions)?

1 o yes

2 o no


1 o yes

2 o no









Month Day Year


1 o yes

2 o no













specimen)







60

zwang

Typewritten Text

Attachment 12

zwang

Typewritten Text






1 o yes

2 o no


1 o yes

2 o no

134. Is a pathology / autopsy report or other documentation of pulmonary hemorrhage attached?

1 o yes














1 o yes

2 o no





Month Day Year

116. Date of PFT:










Month Day Year

•

•

•

•

•

•

Specify units:

1 o ml CO/min/mm Hg

2 o mmol CO/min/kPa

1 o ml CO/min/mm Hg

2 o mmol CO/min/kPa

61

zwang

Typewritten Text

Attachment 12

135. Did the recipient experience two or more episodes of pulmonary hemorrhage since the date of the last report?

1 o yes

2 o no

Cryptogenic Organizing Pneumonia / Bronchiolitis Obliterans with Organizing Pneumonia

137. Did the recipient have a diagnosis of cryptogenic organizing pneumonia (COP) / bronchiolitis obliterans with organizing

pneumonia (BOOP) since the date of the last report? (An acute or sub-acute non-infectious respiratory dysfunction, associated

with multifocal airspace disease and restrictive or obstructive changes on PFT testing.)

1 o yes

2 o no

138. Date of diagnosis of COP / BOOP:

139. Were any diagnostic tests performed for COP / BOOP?

1 o yes

2 o no

Continue with question 185

Was the procedure

Specify all diagnostic tests performed for COP / BOOP: considered diagnostic or positive?








1 o yes

2 o no


viral inclusions)?

1 o yes

2 o no


1 o yes

2 o no










1 o yes

2 o no


Month Day Year












specimen)







62

zwang

Typewritten Text

Attachment 12


1 o yes

2 o no


1 o yes

2 o no

182. Is a pathology / autopsy report or other documentation of COP / BOOP attached?

1 o yes


















1 o yes

2 o no





Month Day Year

164. Date of PFT:










Month Day Year

•

•

•

•

•

•

Specify units:

1 o ml CO/min/mm Hg

2 o mmol CO/min/kPa

1 o ml CO/min/mm Hg

2 o mmol CO/min/kPa

63

zwang

Typewritten Text

zwang

Typewritten Text

Attachment 12

183. Did the recipient experience two or more episodes of COP / BOOP since the date of the last report?

1 o yes

2 o no

185. Did the recipient develop any other non-infectious pulmonary toxicity since the date of the last report?

1 o yes

2 o no

187. Did the recipient receive mechanical ventilation since the date of the last report?

1 o yes

2 o no


Please print name:

Phone: ( )

Fax: ( )

E-mail address:





186. Specify other toxicity:

Specify mechanical ventilation received:

188. 1 o yes 2 o no Biphasic positive airway pressure (BiPAP)

189. 1 o yes 2 o no Continuous positive airway pressure (CPAP)

190. 1 o yes 2 o no Intubation with mechanical ventilator


1 o yes

2 o no


64

zwang

Typewritten Text

Attachment 12

Iron Overload

1. Has the recipient been diagnosed with iron overload since the date of last report? (Iron overload is characterized by deposition

of excessive iron in organs, e.g., heart and liver; it is typically diagnosed by high serum ferritin level and/or evidence of iron

deposition on biopsy or imaging of liver or heart.)

1 o yes

2 o no

Diagnosis of Iron Overload:

3. Was serum ferritin measured at diagnosis? Specify unit of measurement:

1 o yes 1 o ng/mL

2 o no 2 o µg/L

4. Was blood transferrin saturation measured at diagnosis?

1 o yes %

2 o no

5. Was a liver biopsy performed at diagnosis?

1 o yes

2 o no

To be completed in conjunction with a Form 2200 – Six Months to Two Years Post-HSCT Data, or Form 2300 – Yearly

Follow-Up for Greater Than Two Years Post-HSCT Data. Information reported here should reflect the date of last contact as

reported in the post-HSCT data collection form, or immediately prior to death.

Continue with Cirrhosis section at question 62

6. Is a copy of the liver biopsy report attached?

1 o yes

2 o no

7. Was liver / hepatic iron concentration measured?

1 o yes

2 o no8. Specify liver / hepatic iron concentration:

9. Specify method of measurement:

1 o dry weight

2 o wet weight

CIBMTR Form 2516 late effects–hepatic revision 1 (page 1 of 5) January 2011



Late Effects – Hepatic

Complications

Mail this form to your designated campus

(Milwaukee or Minneapolis). Retain the

original at the transplant center.

Registry Use Only

Sequence

Number:

Date

Received: Visit: o 6 months o 1 year o 2 years o > 2 years, specify:

Today’s Date:

Date of HSCT for which this form is

being completed: &

CIBMTR Center Number:

HSCT type: o autologous o allogeneic, o allogeneic, o syngeneic

unrelated related (identical twin)

2 0Month Day Year

CIBMTR Recipient ID:

Month Day Year

2. Date of diagnosis of iron overload: 2 0Month Day Year

•1 o ng/mL

2 o µg/L

Product type: o marrow o PBSC o cord blood o other product,

o multiple cord specify: blood units infused

65

zwang

Typewritten Text

Attachment 13

zwang

Typewritten Text





10. Did the liver biopsy show any degree of portal fibrosis present?

1 o yes

2 o no

11. Was a liver imaging scan performed at diagnosis?

1 o yes

2 o no

18. Was cardiac imaging (e.g., MRI scan) or other study done to evaluate cardiac iron overload (iron deposition in the heart) at

diagnosis?

1 o yes

2 o no

3 o unknown

31. Does the recipient have a known hemochromatosis (HFE) gene mutation (heterozygous [carrier] or homozygous)?

1 o yes

2 o no

3 o unknown

12. Is a copy of the liver imaging scan report attached?

1 o yes

2 o no

13. Specify the liver imaging scan method used:

1 o superconducting quantum interference device (SQUID)

2 o magnetic resonance imaging (MRI)

3 o other

method

15. Was liver / hepatic iron concentration measured?

1 o yes

2 o no16. Specify liver / hepatic iron concentration:


1 o dry weight

2 o wet weight

•1 o ng/mL

2 o µg/L

14. Specify other liver imaging method:

19. Is a copy of the cardiac imaging scan report attached?

1 o yes

2 o no

Specify all cardiac studies performed at diagnosis: Did this show cardiac iron overload?

20. 1 o yes 2 o no MRI scan of heart 21. 1 o yes 2 o no 3 o not done

22. 1 o yes 2 o no Echocardiogram 23. 1 o yes 2 o no 3 o not done

24. 1 o yes 2 o no Nuclear cardiac scan (e.g., MUGA scan) 25. 1 o yes 2 o no 3 o not done

26. 1 o yes 2 o no Other form of cardiac imaging 27. Specify other imaging method:

28. 1 o yes 2 o no 3 o not done

29. Was a cardiac biopsy performed to evaluate iron overload?

1 o yes

2 o no

3 o unknown

30. Is a copy of the cardiac biopsy report attached?

1 o yes

2 o no

66

zwang

Typewritten Text

Attachment 13

End Organ Damage Due to Iron Overload:

Specify the most recent laboratory values recorded since the date of the last report:

32. Serum AST (SGOT): o not tested

33. Upper limit of normal

for your institution:

34. Serum ALT (SGPT): o not tested



36. Did the recipient have any cardiac involvement since the date of the last report?

1 o yes

2 o no

Treatment(s) Given for Iron Overload:

42. Were any treatment(s) given for iron overload since the date of the last report?

1 o yes

2 o no

55. Has serum ferritin testing been repeated since diagnosis of iron overload (or since the last submission of this report form)?

1 o yes

2 o no

Specify all treatment(s) given for iron overload: Specify date treatment began:

43. 1 o yes 2 o no Deferasirox 44.

45. 1 o yes 2 o no Deferiprone 46.

47. 1 o yes 2 o no Deferoxamine 48.

49. 1 o yes 2 o no Phlebotomy 50.

51. 1 o yes 2 o no Treatment details not available

52. 1 o yes 2 o no Other treatment(s) 53. Specify other treatment(s):

54.





2 0Month Day Year

2 02 02 0

2 0

56. Date of serum ferritin test:

57. Specify serum ferritin level:

Copy questions 55–57 to report all instances of ferritin testing performed since diagnosis

(or since the last submission of this report form).

1 o ng/mL

2 o µg/L

2 0Month Day Year

Specify units:

1 o U/L2 o µkat/L

1 o U/L2 o µkat/L

1 o U/L2 o µkat/L

•

•1 o U/L2 o µkat/L•

•

Specify cardiac involvement due to iron overload:

37. 1 o yes 2 o no Heart failure

38. 1 o yes 2 o no Arrythmia

39. 1 o yes 2 o no Abnormal ejection fraction

40. 1 o yes 2 o no Other cardiac involvement 41. Specify other cardiac involvement:

67

zwang

Typewritten Text

zwang

Typewritten Text

Attachment 13





58. Is the recipeint currently enrolled on a clinical trial evaluating iron overload post-transplant?

1 o yes

2 o no

59. Has liver biopsy, liver MRI scan, or SQUID been repeated since the date of the last report?

1 o yes

2 o no

Cirrhosis

63. Has the recipient been diagnosed with liver cirrhosis since the date of the last report?

1 o yes

2 o no

65. Was a liver biopsy performed since the date of the last report?

1 o yes

2 o no

Specify the following liver function values at the time of diagnosis of cirrhosis (within 3 months before or after the date of diagnosis of

cirrhosis):

67. Serum AST (SGOT): o not tested



69. Serum ALT (SGPT): o not tested



71. Serum albumin: o not tested

72. International normalized ratio (INR): o not tested

Solid Organ Transplantation

73. Was a solid organ (liver, kidney, heart, lung, or other solid organ) transplant performed since the date of the HSCT?

1 o yes

2 o no

Continue with Solid Organ Transplantation section at question 73

Continue with Gall Bladder Disorders section at question 83

•

•

1 o g/L2 o g/dL

74. Date of solid organ transplant: 2 0Month Day Year

64. Date of diagnosis of cirrhosis: 2 0Month Day Year

66. Is a copy of the liver biopsy report attached?

1 o yes

2 o no

2 0Month Day Year

60. Date of most recent liver biopsy or scan:

61. Specify most recent liver / hepatic iron concentration:


1 o dry weight

2 o wet weight

•1 o ng/mL

2 o µg/L

Specify units:

1 o U/L2 o µkat/L

1 o U/L2 o µkat/L

1 o U/L2 o µkat/L

•

•

1 o U/L2 o µkat/L•

•

68

zwang

Typewritten Text

Attachment 13





Specify the solid organ(s) transplanted since the date of the HSCT:

75. 1 o yes 2 o no Heart

76. 1 o yes 2 o no Kidney

77. 1 o yes 2 o no Liver

78. 1 o yes 2 o no Lung

79. 1 o yes 2 o no Other organ

81. Specify the indication for the solid organ transplant:

82. Specify the donor for the solid organ transplant:

1 o same donor as HSCT donor

2 o living related donor

3 o living unrelated donor

4 o cadaveric donor

Gall Bladder Disorders

83. Was a cholecystectomy (surgical removal of gall bladder) performed since the date of the last report?

1 o yes

2 o no

Specify the indication(s) for cholecystectomy since the date of the last report:

85. 1 o yes 2 o no Cholecystitis (acute inflammation of the gall bladder)

86. 1 o yes 2 o no Gall bladder or bile duct stones

87. 1 o yes 2 o no Pancreatitis

88. 1 o yes 2 o no Other indication


Please print name:

Phone: ( )

Fax: ( )

E-mail address:

Continue with the signature lines at question 90.

84. Date of cholecystectomy: 2 0Month Day Year

89. Specify other indication for cholecystectomy:

80. Specify other solid organ transplanted:

69

zwang

Typewritten Text

Attachment 13

a g e n d a cibmtr working committee for late effects ... · prop 0811-10 prevalence and associated...

Documents