A G E N D A CIBMTR WORKING COMMITTEE FOR NON-MALIGNANT MARROW DISORDERS Salt Lake City, UT Saturday, February 16, 2013, 12:15 pm - 2:15 pm

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1 Not for publication or presentation A G E N D A CIBMTR WORKING COMMITTEE FOR NON-MALIGNANT MARROW DISORDERS Salt Lake City, UT Saturday, February 16, 2013, 12:15 pm - 2:15 pm Co-Chair: Co-Chair: Co-Chair: Statisticians: Scientific Director: Mouhab Ayas, MD, King Faisal Specialist Hospital Research Center, Saudi Arabia Telephone: ; Fax: ; mouhab@kfshrc.edu.sa H. Joachim Deeg, MD, Fred Hutchinson Cancer Research Center, Seattle, WA Telephone: ; Fax: ; jdeeg@fhcrc.org Shalini Shenoy, MD, St. Louis Children s Hospital; St. Louis, MO Telephone: ; Fax: ; shenoy@kids.wustl.edu Jeanette Carreras, MPH, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; jcarrera@mcw.edu Jennifer Le-Rademacher, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; jlerade@mcw.edu Mary Eapen MD, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; meapen@mcw.edu 1. Introduction a. Minutes of February, 2012 meeting (Attachment 1) b. Newly appointed chair: Paolo Anderlini, MD; M.D. Anderson Cancer Center; panderli@mdanderson.org 2. Accrual summary (Attachment 2) 3. Published/submitted papers and presentations a. AA08-01 Battiwalla M, Wang T, Carreras J, Deeg HJ, Ayas M, Bajwa RPS, George B, Gupta V, Pasquini R, Schrezenmeier H, Passweg J, Schultz KR, Eapen M. HLA-matched sibling transplantation for severe aplastic anemia: impact of HLA DR15 antigen status on engraftment, graft vs. host disease and overall survival. Biol Blood Marrow Transplant 18(9): , b. AA09-01 Ayas M, Saber W, Davis SM, Harris RE, Hale GA, Socie G, Le-Rademacher J, Thakar M, Deeg HJ, Al-Seraihy A, Battiwalla M, Camitta BM, Olsson R, Bajwa RS, Sales-Bonfim CM, Pasquini R, MacMillan ML, George B, Copelan EA, Wirk B, Jefri AA, Fasth AL, Guinan EC, Horn BN, Lewis VA, Slavin S, Stepensky P, Bierings M, Gale RP. Allogeneic hematopoietic cell transplantation for Fanconi anemia in patients with pre-transplant cytogenetic abnormalities, myelodysplastic syndrome, or acute leukemia. Submitted. c. SC10-04 (CIBMTR Trainee-Fellow Research Program) Michael J. Eckrich, Kwang-Woo Ahn, et. al. Effect of patient race on outcomes after allogeneic hematopoietic cell transplantation for severe aplastic anemia. Submitted. 1

2 Not for publication or presentation 4. Studies in progress (Attachment 3) a. AA09-02 Outcomes of hematopoietic stem cell transplantation in patients with Dyskeratosis Congenita (S Gadalla) b. AA10-02 Outcomes after allogeneic stem cell transplantation for patients who developed AML/MDS after immunosuppressive therapy for severe aplastic anemia (H J Deeg) c. AA12-01 Outcome of second allogeneic stem cell transplantation in patients with Fanconi anemia (M Ayas) Manuscript Preparation Data Collection Draft Protocol Received 5. Future/ Proposed studies a. PROP Correlation of levels of donor cell chimerism with hemoglobinopathy symptoms following allogeneic blood stem cell transplantation (A Abraham) (Attachment 4) b. PROP Pre-Transplant Characteristics and Post-Transplant Outcomes of Children Undergoing Hematopoietic Stem Cell Transplantation for Sickle Cell Disease (JM Marron) (Attachment 5) c. PROP Long-term outcomes (malignancies) in patients with FA: a comparison of survivors of HCT to those who received non HCT treatment (Wagner/Alters) (Attachment 6) Overlap/Dropped a. PROP Treatment of Secondary Graft Failure in Patients with Aplastic Anemia (AA) and Inherited Bone Marrow Failure (D Dietz) (AA03-01) b. PROP Hematopoietic Cell Transplantation (HCT) for treatment of Paroxysmal Nocturnal Hemoglobinuria. (PA Mehta) EBMT study. c. PROP Outcomes of allogeneic hematopoietic stem cell transplantation for thalassemia using unrelated bone marrow or peripheral blood stem cell graft. (NC Shah) Due to low number of cases (n=9). 2

3 Not for publication or presentation Attachment 1 MINUTES CIBMTR WORKING COMMITTEE FOR NON-MALIGNANT MARROW DISORDERS San Diego, California Saturday, February 4, 2012, 2:45 pm - 4:45 pm Co-Chair: Co-Chair: Co-Chair: Statisticians: Scientific Director: Mouhab Ayas, MD, King Faisal Specialist Hospital Research Center, Saudi Arabia Telephone: ; Fax: ; mouhab@kfshrc.edu.sa H. Joachim Deeg, MD, Fred Hutchinson Cancer Research Center, Seattle, WA Telephone: ; Fax: ; jdeeg@fhcrc.org Shalini Shenoy, MD, St. Louis Children s Hospital; St. Louis, MO Telephone: ; Fax: ; shenoy@kids.wustl.edu Jeanette Carreras, MPH, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; jcarrera@mcw.edu Jennifer Le-Rademacher, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; jlerade@mcw.edu Mary Eapen MD, MS, CIBMTR Statistical Center, Milwaukee, WI Telephone: ; Fax: ; meapen@mcw.edu 1. Introduction The CIBMTR Working Committee for Non-Malignant Marrow Disorders met on Saturday, February 4, 2012 at 2:45 pm. Dr Mouhab Ayas welcomed everyone. The new CIBMTR effort, the Forms Revision Process, was announced. Minutes from the 2011 Tandem meeting in Honolulu were accepted and approved by the chairs and committee members. 2. Accrual summary (Attachment 2) The accrual tables were referenced for the committee to review but not formally presented. 3. Presentations, published or submitted papers A brief update of the studies published or presented in 2011, including three publications, one accepted manuscript (AA08-01 was accepted to BBMT) and one ASH presentation, was provided. 4. Studies in progress The primary investigators, when in attendance, provided updates of the studies in progress. a. AA09-01 Outcome of allogeneic stem cell transplantation in patients with Fanconi anemia who present with myelodysplasia, clonal abnormalities and/or leukemia (M Ayas) Slides were presented by M Ayas. The manuscript has been revised and the second draft is now ready for the writing committee s review. b. AA09-02 Outcomes of hematopoietic stem cell transplantation in patients with Dyskeratosis Congenita (S Gadalla) No update was provided. c. AA10-02 Outcomes after allogeneic stem cell transplantation for patients who developed AML/MDS after immunosuppressive therapy for severe aplastic anemia (H Joachim Deeg) An update was provided by H Joachim Deeg. Data collection for the study is progressing well. 3

4 Not for publication or presentation Attachment 1 d. AA11-01 Durable engraftment and correction of hematological defects in children with congenital amegakaryocytic thrombocytopenia following myeloablative umbilical cord blood transplantation (K Mahadeo). No update was provided. Study was dropped due assessment of lower scientific priority at the time of publication. e. AA11-02 Chronic blood transfusions therapy compared to HCT in children with Sickle Cell Disease: a cost-utility analysis (R Sidonio). No update was provided. As of the WC meeting, a study protocol had not been submitted to the committee. Study was dropped due assessment of lower scientific priority at the time of publication. 6. Future/ Proposed studies Proposed studies listed on the NMMDWC voting sheet were presented. a. PROP Treatment of secondary graft failure in patients with aplastic anemia (AA) and inherited bone marrow failure (BMF) (D Dietz) This proposal was presented by D Dietz. The primary aim of this study is to describe incidence of and historical treatment options used for cases of secondary graft failure in patients who received hematopoietic stem cell transplantation (HSCT) for AA and BMF syndromes. During discussion it was recommended that Fanconi syndrome be evaluated separately and that, if possible, chimerism data be included in the evaluation. b. PROP Outcome of second allogeneic stem cell transplantation (STC) in patients with Fanconi Anemia (M Ayas) This proposal was presented by M Ayas. The primary aim of this study is to determine the outcome of second allogeneic SCT in patients with Fanconi anemia. Following the presentation, the committee discussed the difficulties of defining primary and secondary graft failure, particularly with the use of reduced intensity conditioning. c. PROP Outcomes of allogeneic hematopoietic cell transplantation (HCT) for acquired aplastic anemia (AA) using antithymocyte globulin versus alemtuzumab based conditioning (B Wirk) This proposal was presented by B Wirk. The primary aim of this study is to study the outcomes of allogeneic HCT for acquired AA including treatment related mortality, engraftment, acute and chronic graft-versus-host, progression free survival and overall survival and infection rates for ATG versus alemtuzumab based conditioning regimens. During discussion it was stated that less follow-up data would be available for patients receiving alemtuzumab-based conditioning and differences in follow-up time by conditioning regimen would need to be taken into account during data analysis. Dr Wirk brought it to the committee s attention that this proposal was inadvertently left off the voting sheet and asked the attendees to be sure to add this proposal to their voting sheet before assessing the prospective studies. d. PROP Risk stratification in patients with aplastic anemia undergoing allogeneic stem cell transplantation (G Biju) This proposal was presented by G Biju. The aim of this study is to stratify patients undergoing HLA identical sibling or family donor allogeneic stem cell transplantation for aplastic anemia into good, intermediate and high risk groups, and to compare and contrast the 1-year survival patterns in each of these groups. Discussions included the difficulty of determining the total number of transfusion a patient receives and the merits of expanding the analysis to include the development of an overall risk score. 4

5 Not for publication or presentation Attachment 1 e. PROP Correlation of iron overload with clinical outcomes following allogeneic hematopoietic stem cell transplantation for thalassemia (S Chaudhury) This proposal was presented by S Chaudhury. The primary aim of this study is to correlate transplant outcomes directly with liver iron content (mild/moderate/severe by biopsy, MRI) and contrast with the Lucarelli staging method. Following the presentation, the committee discussed the need for supplemental data to complete this study and concerns that the collection of these data would be labor intensive. 7. Other business None. Proposal was approved. Meeting adjourned at 4:45 PM. 5

6 Not for publication or presentation Attachment 2 Accrual Summary for Non-Malignant Marrow Disorders Working Committee Characteristics of recipients of allogeneic BMT for aplastic anemia and thalassemia reported to the CIBMTR between 1990 and Severe Aplastic Anemia Thalassemia Characteristics: TED only Research TED only Research Number of patients Number of centers Age at transplant, years 20 (<1-77) 19 (<1-82) 7 (<1-59) 8 (<1-38) Sex Male 2621 (59) 2656 (57) 725 (54) 877 (55) Female 1782 (40) 1964 (43) 609 (46) 727 (45) Missing 4 (<1) 0 1 (<1) 0 Donor type HLA-identical siblings 3469 (79) 2608 (56) 1147 (86) 1367 (85) Twins 51 ( 1) 61 ( 1) 0 0 Other relative 258 ( 6) 361 ( 8) 119 ( 9) 103 ( 6) Unrelated 629 (14) 1590 (34) 65 ( 5) 132 ( 8) Not specified (<1) 2 (<1) Graft type Bone marrow 2940 (67) 3667 (79) 883 (66) 1277 (80) Peripheral blood 1282 (29) 772 (17) 360 (27) 215 (13) Cord blood 85 ( 2) 178 ( 4) 81 ( 6) 112 ( 7) Missing 100 ( 2) 3 (<1) 11 ( 1) 0 Year of transplant ( 3) 377 ( 8) 16 ( 1) 201 (13) ( 5) 425 ( 9) 37 ( 3) 243 (15) ( 6) 468 (10) 53 ( 4) 226 (14) ( 7) 477 (10) 73 ( 5) 147 ( 9) ( 8) 413 ( 9) 64 ( 5) 152 ( 9) ( 9) 399 ( 9) 91 ( 7) 178 (11) (11) 365 ( 8) 171 (13) 122 ( 8) (10) 491 (11) 161 (12) 77 ( 5) (11) 366 ( 8) 202 (15) 60 ( 4) ( 7) 529 (11) 150 (11) 130 ( 8) (16) 232 ( 5) 248 (19) 46 ( 3) 2012* 227 ( 5) 78 ( 2) 69 ( 5) 22 ( 1) * Cases continue to be reported in this interval 6

7 Not for publication or presentation Attachment 2 Accrual Summary for Non-Malignant Marrow Disorders Working Committee Characteristics of recipients of allogeneic BMT for fanconi anemia and PNH tumor cancer reported to the CIBMTR between 1990 and Fanconi Anemia PNH Characteristics: TED only Research TED only Research Number of patients Number of centers Age at transplant, years 10 (<1-53) 9 (<1-49) 30 (9-64) 29 (3-71) Sex Male 323 (52) 544 (53) 73 (53) 147 (53) Female 264 (43) 480 (47) 66 (47) 130 (47) Missing 29 ( 5) Donor type HLA-identical siblings 305 (50) 405 (40) 102 (73) 145 (52) Twins Other relative 93 (15) 109 (11) 8 ( 6) 10 ( 4) Unrelated 218 (35) 510 (50) 28 (20) 114 (41) Not specified ( 1) 8 ( 3) Graft type Bone marrow 395 (64) 700 (68) 73 (53) 168 (61) Peripheral blood 121 (20) 153 (15) 61 (44) 92 (33) Cord blood 91 (15) 168 (16) 3 ( 2) 15 ( 5) Missing 9 ( 1) 3 (<1) 2 ( 1) 2 ( 1) Year of transplant ( 3) 69 ( 7) 1 ( 1) 13 ( 5) ( 3) 84 ( 8) 5 ( 4) 12 ( 4) ( 5) 77 ( 8) 7 ( 5) 25 ( 9) ( 8) 101 (10) 7 ( 5) 17 ( 6) ( 9) 81 ( 8) 10 ( 7) 24 ( 9) (10) 104 (10) 11 ( 8) 32 (12) (13) 116 (11) 11 ( 8) 36 (13) ( 9) 116 (11) 11 ( 8) 38 (14) (12) 80 ( 8) 2 ( 1) 25 ( 9) ( 7) 120 (12) 17 (12) 36 (13) (15) 53 ( 5) 40 (29) 15 ( 5) 2012* 34 ( 6) 23 ( 2) 17 (12) 4 ( 1) * Cases continue to be reported in this interval 7

8 Not for publication or presentation Attachment 2 Accrual Summary for Non-Malignant Marrow Disorders Working Committee Characteristics of recipients of allogeneic BMT for diamond-blackfan anemia and sickle cell anemia reported to the CIBMTR between 1990 and Diamond-Blackfan Anemia Sickle Cell Anemia Characteristics: TED only Research TED only Research Number of patients Number of centers Age at transplant, years 7 (1-60) 7 (<1-43) 10 (<1-57) 10 (<1-31) Sex Male 55 (50) 76 (48) 231 (53) 175 (53) Female 54 (50) 81 (52) 202 (47) 153 (47) Missing (<1) 0 Donor type HLA-identical siblings 90 (83) 69 (44) 368 (85) 214 (65) Twins Other relative 5 ( 5) 13 ( 8) 53 (12) 14 ( 4) Unrelated 14 (13) 75 (48) 13 ( 3) 100 (30) Not specified Graft type Bone marrow 77 (71) 109 (69) 347 (80) 239 (73) Peripheral blood 23 (21) 17 (11) 54 (12) 23 ( 7) Cord blood 8 ( 7) 31 (20) 33 ( 8) 66 (20) Missing 1 ( 1) Year of transplant ( 1) 9 ( 6) 1 (<1) 8 ( 2) ( 3) 5 ( 3) 1 (<1) 10 ( 3) ( 6) 13 ( 8) 9 ( 2) 14 ( 4) ( 5) 12 ( 8) 15 ( 3) 23 ( 7) ( 6) 17 (11) 14 ( 3) 27 ( 8) ( 9) 10 ( 6) 33 ( 8) 37 (11) ( 8) 18 (11) 46 (11) 19 ( 6) (12) 18 (11) 35 ( 8) 28 ( 9) (17) 11 ( 7) 37 ( 9) 32 (10) ( 9) 18 (11) 48 (11) 74 (23) (17) 16 (10) 132 (30) 41 (13) 2012* 8 ( 7) 10 ( 6) 63 (15) 15 ( 5) * Cases continue to be reported in this interval 8

9 Not for publication or presentation Attachment 3 TO: FROM: RE: Non-malignant Marrow Disorders Working Committee Members Mary Eapen, MD, MS, Scientific Director for Non-Malignant Marrow Disorders Working Committee Studies in Progress Summary AA09-02 Outcomes of hematopoietic stem cell transplantation in patients with Dyskeratosis Congenita (S Gadalla). We describe outcomes after transplantation in 34 patients transplanted between 1981 and Fourteen patients are alive at last follow-up; the 12-year probability of overall survival is 15%. Ten deaths occurred within 4 months from transplantation and were either due to graft failure or another transplantrelated complication. Of the patients with early deaths, 9 received grafts from a mismatched related or matched/mismatched unrelated donor. The remaining deaths (N=10) occurred later; 6 late deaths occurred beyond 5 years from transplantation and 4 of these attributed to pulmonary failure. A draft manuscript is underway and it is expected to be submitted before July AA10-02 Outcomes after allogeneic stem cell transplantation for patients who developed AML/MDS after immunosuppressive therapy for severe aplastic anemia (H Joachim Deeg). There are 24 patients with AML and 82 with MDS. A supplemental data collection form is being developed to obtain information on number of cycles of IST prior to onset of MDS/AML, response to IST, date of diagnosis - SAA, and whether cytogenetic abnormalities were present at diagnosis of SAA. M Eapen and HJ Deeg are contacting referring or transplant centers to seek their interest in filling out the questionnaire. AA12-01 Outcome of second allogeneic stem cell transplantation in patients with Fanconi anemia (M Ayas). The primary aim of this study is to determine the outcome of second allogeneic SCT in patients with Fanconi anemia. A draft protocol is available for review. 9

10 Not for publication or presentation Attachment 4 CIBMTR Study Proposal: Study Title: Correlation of levels of donor cell chimerism with hemoglobinopathy symptoms following allogeneic blood stem cell transplantation. Allistair Abraham, MD; Children s National Medical Center, Washington DC aabraham@childrensnational.org Shalini Shenoy, MD; Washington University School of Medicine, St. Louis, MO Shenoy@kids.wustl.edu Hypothesis: - Stable mixed donor chimerism even at low levels of 20% is adequate to control disease symptoms in patients with hemoglobinopathy and provide a cure following allogeneic stem cell transplantation. Specific Aims: The specific aim of this proposal is to correlate the kinetics and levels of donor cell engraftment with (1) hemoglobin electrophoresis results and (2) eradication of disease symptoms or need for transfusions in recipients of blood stem cell transplants for hemoglobinopathy. In order to assess this we will: Evaluate level of donor chimerism in bone marrow or peripheral blood in patients with sickle cell disease and thalassemia at 100 days, 1 year and 2 years post allogeneic transplant. Evaluate results of hemoglobin electrophoresis at 100 days, 1 year and 2 years post-transplant to correlate with aim #1. Assess necessity for regular transfusions or disease related supportive care in hemoglobinopathy patients at 1 year and 2 years post-transplant. If this information is not in the database, we will need to contact centers for more information with a brief questionnaire. All recipients who are alive at 1 year and beyond post-transplant will be eligible for this analysis. All allogeneic transplants will be included. Related and unrelated donor Marrow, peripheral blood and cord blood Those that received myeloablative, reduced intensity and non-ablative transplants Those that received cell manipulated products, DLI, etc. Second or subsequent transplants Scientific Justification: There are multiple reports in the literature showing disease-specific symptom resolution in patients with sickle cell disease and beta thalassemia who, post allogeneic hematopoietic stem cell transplantation, remain in a mixed chimeric state with respect to donor leukocytes 1-5. Disease correction has been observed with chimerism as low 10-20%. There is even reference to a patient in a recent report of mainly haploidentical transplants for sickle cell disease that 5% donor chimerism was associated with symptom resolution 6. It is unclear yet whether a long-term stable mixed chimeric state can be achieved in a haploidentical transplant setting after discontinuing immunosuppressive agents. In these cases, disease resolution is presumably due to the maintenance of a high level of donor red cell chimerism despite lower engraftment in other components 7,8. The level of donor chimerism necessary for disease eradication has never been defined. A mixed chimeric state was seen more frequently in a study of sickle cell patients undergoing myeloablative bone marrow transplant after antithymocyte globulin was added to the preparative regimen to reduce rejection 9. This mixed chimeric state is also observed more frequently with the increasing use of reduced intensity conditioning which attempts to minimize toxicity and late effects associated with myeloablation. Murine models of gene therapy for hemoglobinopathy have improved disease following low levels of engraftment 10

11 Not for publication or presentation Attachment 4 of gene modified cells 10,11. In an early report from a clinical gene therapy trial, a previously transfusion dependent thalassemia patient who maintained stable levels of approximately 11% gene modified nucleated blood cells became transfusion independent and remained so almost 3 years after treatment 12. This phenomenon of low levels of donor chimerism providing a cure may be explained by a survival of the fittest concept where normal erythropoiesis from donor cells render a cure overcoming ineffective recipient erythropoiesis when the peripheral blood red cell content crosses a certain threshold 8. It remains to be verified in a large cohort what level of donor chimerism is consistently associated with disease resolution. This issue is highlighted in one case series where a sickle cell patient with donor chimerism of 15% had a pneumonia-type illness in the face of HbS level of >50% that was likely acute chest syndrome 4. The patient as a result proceeded to second transplant with reduced intensity conditioning resulting in full donor chimerism. Previous data of mixed leukocyte chimerism suggests that donor levels of less than 75% in the first two months post-transplant is predictive of late graft failure in thalassemic patients but that after one year this rejection risk drops off significantly 1. A recent study of matched sibling donor transplant using nonmyeloablative conditioning in adults with sickle cell disease targets the goal of long-term tolerance induction in the setting of mixed chimerism by prolonged periods of immune suppression. Immune suppression has been successfully withdrawn in some patients following mixed chimerism for over a year. These recipients are reported as cured with persistent mixed chimera with sickle cell disease symptom resolution 5,13. It thus seems that tracking chimerism early, at one year, and at a subsequent time points would provide a measure of the kinetics of engraftment as it correlates with disease status. By one year and beyond, if successful, thalassemia patients would be expected to be transfusion independent and sickle cell patients would be expected to have resolution of disease symptoms unless there were additional confounding variables such as organ failure. Patient Eligibility Requirements: Allogeneic transplants for Sickle cell disease and beta thalassemia All Hemoglobinopathy transplants available in the CIBMTR registry All allogeneic transplant graft types bone marrow, peripheral blood stem cells, umbilical cord blood Includes manipulated grafts, donor lymphocyte infusions Inclusive of all conditioning types myeloablative, non-myeloablative, reduced intensity Related and Unrelated donor transplants Alive at 1-year post transplant Data Requirements: Data accession as collected from 2130 CRF and TED forms day 100, 1-year and 2-year outcomes Patient demographics and diagnosis Graft type and donor Conditioning type, immunosuppression agents and length of use Survival data Engraftment/chimerism at various time points post transplantation (100 days, 1 year, 2 years) includes whole blood, bone marrow, myeloid fraction, lymphoid fraction, CD3 fraction, red cell fraction Acute and chronic GVHD with grade and severity Organ function at reported time points Dependence on chronic red cell transfusion therapy Disease specific symptoms and disease status for sickle cell disease Hemoglobin electrophoresis at various time points including when chimerism reported 11

12 Not for publication or presentation Attachment 4 Sample Requirements: None Study Design: This is a descriptive retrospective review of sickle cell and thalassemia transplant recipient data focusing on levels of donor cell chimerism and disease status with data accessioned at 3 time points: 100 days 1 year 2 years Limitations: Disease status details may be variable if we are unable to acquire such details of data centers may have to be contacted with a simple supplemental form asking the question. Hb electrophoresis will be used as a surrogate as well. References: 1. Andreani M, Testi M, Battarra M, et al. Relationship between mixed chimerism and rejection after bone marrow transplantation in thalassaemia. Blood Transfus. 2008;6(3): Walters MC, Patience M, Leisenring W, et al. Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant. 2001;7(12): Locatelli F, Rocha V, Reed W, et al. Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood. 2003;101(6): Majumdar S, Robertson Z, Robinson A, Starnes S, Iyer R, Megason G. Outcome of hematopoietic cell transplantation in children with sickle cell disease, a single center's experience. Bone Marrow Transplant. 2010;45(5): Hsieh MM, Kang EM, Fitzhugh CD, et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med. 2009;361(24): Bolanos-Meade J, Fuchs EJ, Luznik L, et al. HLA-haploidentical bone marrow transplantation with post-transplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood; Krishnamurti L, Kharbanda S, Biernacki MA, et al. Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant. 2008;14(11): Andreani M, Testi M, Gaziev J, et al. Quantitatively different red cell/nucleated cell chimerism in patients with long-term, persistent hematopoietic mixed chimerism after bone marrow transplantation for thalassemia major or sickle cell disease. Haematologica. 2011;96(1): Bernaudin F, Socie G, Kuentz M, et al. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007;110(7): Kean LS, Manci EA, Perry J, et al. Chimerism and cure: hematologic and pathologic correction of murine sickle cell disease. Blood. 2003;102(13): Persons DA, Allay ER, Sabatino DE, Kelly P, Bodine DM, Nienhuis AW. Functional requirements for phenotypic correction of murine beta-thalassemia: implications for human gene therapy. Blood. 2001;97(10): Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature. 2010;467(7313): Hsieh MM, Fitzhugh CD, Tisdale JF. Allogeneic hematopoietic stem cell transplantation for sickle cell disease: the time is now. Blood. 2011;118(5):

13 Not for publication or presentation Attachment 4 Characteristics of patients who underwent allogeneic transplantation for thalassemia and sickle cell disease reported to the CIBMTR with 1yr chimerism data* Variable Thalassemia Sickle cell disease Number of patients with chimerism information Chimerism data at day 100 & 1 yr Chimerism data at 1 yr only (not day 100) 15 4 Chimerism data 1 yr & 2 yrs (not day 100) 10 6 Chimerism data at day 100 & 1 yr & 2 yrs Age at transplant Median (range) 7 (1-22) 9 (1-29) <10 yrs 104 (67) 62 (58) yrs 48 (31) 42 (40) yrs 3 ( 2) 2 ( 2) Conditioning regimen Myeloablative 141 (91) 71 (67) Non-myeloablative 14 ( 9) 35 (33) Donor HLA-identical sibling 140 (90) 77 (73) Unrelated 15 (10) 29 (27) Graft type Bone marrow 132 (85) 85 (80) Cord blood 23 (15) 21 (20) Year of transplant (59) 6 ( 6) (14) 19 (18) (27) 81 (76) *N=1941 were transplanted for thalassemia. N=155 (8%) have chimerism data at 1 yr N=301 were transplanted for sickle cell. N=106 (35%) have chimerism data at 1 yr 13

14 Not for publication or presentation Attachment 5 CIBMTR Study Proposal: Study Title: Pre-transplant characteristics and post-transplant outcomes of children undergoing hematopoietic stem cell transplantation for sickle cell disease. Jonathan M. Marron, MD; Dana-Farber Cancer Institute/Boston Children s Hospital, Boston, MA jonathan_marron@dfci.harvard.edu Christine N. Duncan, MD, MSc; Dana-Farber Cancer Institute/Boston Children s Hospital, Boston, MA christine_duncan@dfci.harvard.edu Specific Aims: Primary Aim: - To describe the characteristics of children with sickle cell disease who have undergone stem cell transplantation in order to ascertain commonalities and differences amongst these patients - Secondary Aims: To describe the outcomes of children with sickle cell disease who have undergone stem cell transplantation to: - Elucidate pre-transplant patient characteristics that are risk factors for post-transplant death, graft failure, and delayed/failed engraftment - Characterize pre-transplant patient characteristics that are risk factors for post-transplant organ dysfunction (i.e., lung, renal, heart, bone, liver, gonad) Scientific Justification: Sickle cell disease is a condition affecting an estimated 100,000 Americans and millions more worldwide. It causes significant morbidity and mortality, ranging from pain crises to stroke to early death. The past thirty years have brought significant advances in the treatment of patients with SCD, but only hematopoietic stem cell transplantation is curative. While HSCT carries significant risk, various advances in transplantation and post-transplant care have improved transplant outcomes considerably in recent years, with overall survival approaching 95% and event-free survival 85%. Despite this, however, fewer than 400 children are reported in the literature as having received a stem cell transplant for sickle cell disease to date, and no uniform guidelines or criteria exist for referring a child with SCD for transplant. The families of patients with SCD are often willing to accept significant risk when offered HSCT, but there is great difficulty in determining the appropriate candidate for HSCT and the ideal time for that transplant. This study will assess the pre- and post-transplant characteristics of pediatric patients who have undergone hematopoietic stem cell transplantation for sickle cell disease and analyze similarities and differences in these categories as a way to 1) examine the characteristics of those patients with SCD who have to date undergone HSCT; and 2) determine which pre-transplantation characteristics correlate with positive post-transplant outcomes. The data learned from this study will help inform the hematology and transplant community about how best to counsel children with sickle cell disease and their families regarding transplantation. It will provide further data regarding who is a good candidate for transplant and will help to further define the criteria used for the referral of patients with sickle cell disease for hematopoietic stem cell transplantation. Patient Eligibility Population: - Allogeneic HSCT for SCD at less than 18 years of age - All donor and stem cell sources 14

15 Not for publication or presentation Attachment 5 Data Requirements: The following data are required for this study: Recipient Demographic Data: - Date of birth - Gender - Ethnicity - Race - Country of primary residence - Presence or absence of clinically significant coexisting diseases or organ impairment prior to HSCT - Health insurance status - Combined household gross annual income Sickle Cell Data: - Date of original sickle cell disease diagnosis - Sickle cell disease genotype - Sickle chronic lung disease stage - Total number of acute chest crises within 2 years prior to HSCT - Total number of acute chest crises within the recipient s lifetime - Need for exchange transfusion for ACS (yes or no) - Presence or absence of osteonecrosis [if present, which joint(s)] - Number of episodes of priapism in the last 2 years prior to HSCT - Presence or absence of sickle nephropathy - Total number of strokes in the recipient s lifetime - Number of vaso-occlusive pain crises requiring hospitalization within 2 years prior to HSCT - Presence or absence of treatment with hydroxyurea therapy - Date of initiation (if applicable) of hydroxyurea therapy - Presence or absence of gonadal dysfunction prior to HSCT - Presence or absence of abnormal brain MRI/MRA prior to HSCT - Presence or absence of abnormal EKG prior to HSCT - Presence or absence of abnormal echocardiogram prior to HSCT - Pre-HSCT Lansky/Karnofsky Score Transplant Data: - Primary reason documented for HSCT - Date of HSCT - HSCT type - Cell source - Degree of HLA match - Type of preparative regimen utilized Outcome Data: - Survival status - Cause of death - Number of days since HSCT - Need for repeat/subsequent HSCT - Date of neutrophil recovery - Date of platelet recovery - Chimerism data 15

16 Not for publication or presentation Attachment 5 - Presence or absence of acute graft vs. host disease - Maximum grade of acute GVHD - Maximum stage of organ-specific GVHD (skin, lower intestinal tract, upper intestinal tract, liver, lung, other) - Presence or absence of chronic GVHD - Overall severity of chronic GVHD - Organ involvement of chronic GVHD - Performance status (Lansky/Karnofsky Score) at the time of most recent reported follow-up - Presence or absence of post-hsct organ dysfunction at the time of most recent reported followup - Pulmonary dysfunction - Liver dysfunction - Osteonecrosis - Cardiac dysfunction - Gonadal dysfunction - Renal dysfunction - Stroke or seizure Sample Requirements: No biologic samples will be required for this study Study Design: The primary objective of this study is to describe the pre-transplant characteristics of children who have undergone allogeneic HSCT for sickle cell disease. We will use data that has been previously collected as part of the existing CIBMTR database. There is no requirement for supplemental data collection. Using descriptive statistics, we will characterize similarities and differences seen in these patients prior to transplant. Our secondary objectives are to determine which pre-transplant characteristics are associated with the post-transplant outcomes of death, graft failure, delayed/failed engraftment, and post-transplant organ dysfunction. This will also utilize only data previously collected via the CIBMTR database. We will use descriptive statistics to report the frequency of these poor outcomes and utilize sub-group analyses to elucidate which pre-transplant characteristics are risk factors for these poor post-transplant outcomes. References: 1. Bernaudin F, et al. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood 2007; 110(7): Hsieh MM, Fitzhugh CD, Tisdale JF. Allogeneic hematopoietic stem cell transplantation for sickle cell disease: the time is now. Blood 2011; 118(5): Kodish E, et al. Bone marrow transplantation for sickle cell disease: A study of parents decisions. NEJM 1991; 325(19): Shenoy S. Has stem cell transplantation come of age in the treatment of sickle cell disease? Bone Marrow Transplantation 2007; 40: Sickle Cell Disease Data and Statistics. Centers for Disease Control and Prevention. Available at < Last updated: September 16, Walters MC, et al. Bone marrow transplantation for sickle cell disease. NEJM 1996; 335(6):

17 Not for publication or presentation Attachment 5 Characteristics of <18 years old patients who underwent unrelated allogeneic transplantation for sickle cell disease reported to the CIBMTR (US only) Variable N (%) Number of patients 60 Median age at transplant, years 10 (1-17) Conditioning regimen Graft type Myeloablative 17 (28) Non-myeloablative 43 (72) Bone marrow 28 (46) Cord blood 32 (54) Year of transplant (23) (77) 17

18 Not for publication or presentation Attachment 6 CIBMTR Study Proposal Study Title: Malignancies in patients with Fanconi anemia Investigators: Dr. John Wagner, University of Minnesota and Dr. Blanche Alters, National Cancer Institute Objective: Compare malignancy risks in patients with Fanconi anemia after allogeneic transplantation to risks in non-transplanted patients Background: The risk of a malignancy in non-transplanted patients with Fanconi anemia is estimated to be 10,000 to 15,000 fold higher than in the normal population. The higher risk of malignancy is related to chromosomal instability and defective repair processes. Studies have shown that by the age of 40 years more than half the patients with Fanconi anemia develop a myelodysplastic syndrome or leukemia. The incidence of solid tumor particularly head and neck tumors and squamous cell carcinoma are also higher than in the normal population. Reports after allogeneic hematopoietic cell transplantation suggest FA patients do not develop myelodysplastic syndrome or leukemia because transplantation provides these patients with normal lymphoid hematopoietic cells. Transplantation does not correct the congenital defects in other tissues and these patients remain at risk for developing solid cancers. Whether the risk of solid cancer is higher in transplanted compared to non-transplanted patients has not been studied. In a very early report (prior to 1994) from the Hospital Saint Louis and the Fred Hutchinson Cancer Research Center, there were 5 solid cancers in 79 patients with Fanconi anemia. These patients were years old when they developed cancer and within the age range should they not have received a transplant. What is not known whether the risk is higher after transplantation compared to the nontransplanted patients. In this study we seek to determine whether the risk of solid cancer is higher after allogeneic transplantation compared to non-transplanted patients with Fanconi anemia. Study Population: Data for the transplanted cohort will be provided by the CIBMTR and data for the non-transplanted cohort, from the National Cancer Institute. Selection criteria for CIBMTR cases Allogeneic transplant recipients with the diagnosis of Fanconi anemia and transplanted between All donor and graft types / conditioning regimen / GVHD prophylaxis are eligible Outcome of interest: Estimate the probability of solid cancers in both treatment groups Describe the type of solid cancer and the outcome (i.e., alive/dead after cancer) Identify risk factors that lead to solid cancers in post-transplant patients 18

19 Not for publication or presentation Attachment 6 Characteristics of patients who underwent allogeneic transplantation for Fanconi anemia registered to the CIBMTR from * Variable N (%) Number of patients 762 Median age at transplant, years 10 (1-53) Donor type HLA-identical siblings 311 (41) Other relative 71 ( 9) Unrelated 380 (50) Graft type Bone marrow 523 (68) Peripheral blood 97 (13) Cord blood 142 (19) Year of transplant (35) (65) Number of cancer 35 ( 5) Cancer type Lymphoma (EBV negative) 2 Chondroblastic osteosarcoma 1 Gastric antral carcinoid (non-metastic) 1 Squamous cell carcinoma 3 Oropharyngeal 2 Bowels disease, carcinoma basiciliar 1 Skin 2 Leukemia 1 AML 1 AML + MDS 1 AML + Skin 1 Not specified 19 Age at cancer <10 years 4 (15) years 13 (46) years 9 (32) years 2 ( 7) Missing 7 Survival status for cancer (n=35) Alive 16 (46) Dead 19 (54) *55 centers (285 patients) were excluded due to low follow-up (<70%). N=4 out of 55 patients from 2 centers reported a malignancy. 19