A G E N D A CIBMTR WORKING COMMITTEE FOR NON-MALIGNANT MARROW DISORDERS San Diego, California Saturday, February 4, 2012, 2:45 pm - 4:45 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1 Not for publication or presentation A G E N D A CIBMTR WORKING COMMITTEE FOR NON-MALIGNANT MARROW DISORDERS San Diego, California Saturday, February 4, 2012, 2:45 pm - 4:45 pm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 a. Minutes of February, 2011 meeting (Attachment 1) 2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers a. AA03-02 Sabloff M, Chandy M, Wang Z, Logan BR, Ghavamzadeh A, Li CK, Irfan SM, Bredeson CN, Cowan MJ, Gale RP, Hale GA, Horan J, Hongeng S, Eapen M, Walters M. HLAmatched sibling bone marrow transplantation for ß-Thalassemia major. Blood 117: , 2011 b. AA07-03 Eapen M, Le Rademacher J, Antin JH, Champlin RE, Carreras J, Fay J, Passweg J, Tolar J, Horowitz MM, Marsh JCW, Deeg HJ. Effect of stem cell source on outcomes after adult unrelated donor transplantation in severe aplastic anemia. Blood 118: , 2011 c. AA08-02 Ruggeri A, Eapen M, Scaravadou A, Cairo MS, Bhatia M, Kurtzberg J, Wingard JR, Fasth A, Nigro LL, Ayas M, Purtill D, Boudjedir K, Chaves W, Walters MC, Wagner J, Gluckman E, Rocha V. Umbilical cord blood transplantation for children with thalassemia and sickle cell disease. Biol Blood Marrow Transplant 17: , 2011 d. 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. Submitted. e. AA09-01 Ayas M, Le-Rademacher J, Deeg J, Gale R, Davies S, Bajwa R, Battiwalla M, Slavin S, Camitta B, Bierings M, Harris R, Olsson R, Wirk B, George B, Bonfim C, Saber W. Outcome of allogeneic stem cell transplantation in patients with Fanconi anemia who present with myelodysplasia, clonal abnormalities and/or leukemia. Oral presentation, Annual Meeting of the American Society of Hematology San Diego, CA, December

2 Not for publication or presentation 4. Studies in progress (Attachment 3) 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) b. AA09-02 Outcomes of hematopoietic stem cell transplantation in patients with Dyskeratosis Congenita (S Gadalla) 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) d. AA11-01 Durable engraftment and correction of hematological defects in children with congenital amegakaryocytic thrombocytopenia following myeloablative umbilical cord blood transplantation (K Mahadeo) e. AA11-02 Chronic blood transfusions therapy compared to HCT in children with Sickle Cell Disease: a cost-utility analysis (R Sidonio) Manuscript Preparation Data File Preparation Data Collection Draft Protocol Received Protocol Development 5. Future/ Proposed studies a. PROP Treatment of secondary graft failure in patients with aplastic anemia and inherited bone marrow failure (D Dietz) (Attachment 4) b. PROP Outcome of second allogeneic stem cell transplantation in patients with Fanconi Anemia (M Ayas) (Attachment 5) c. PROP Outcomes of allogeneic hematopoietic cell transplantation for acquired aplastic anemia using antithymocyte globulin versus alemtuzumab based conditioning (B Wirk) (Attachment 6) d. PROP Risk stratification in patients with aplastic anemia undergoing allogeneic stem cell transplantation (G Biju) (Attachment 7) e. PROP Correlation of iron overload with clinical outcomes following allogeneic hematopoietic stem cell transplantation for thalassemia (S Chaudhury) (Attachment 8) DROPPED f. PROP Long-Term Neurologic Outcomes in Patients with Sickle Cell Disease who Undergo Hematopoietic Stem Cell Transplant (P Bodas). Requires additional data collection that may be not readily available or feasible without supplemental funds to reimburse center. OVERLAP with ongoing CIBMTR studies g. PROP Impact of pre-transplant comorbidities on stem cell transplant outcome in sickle cell disease using HSCT specific comorbidity index (A Kassim). Overlaps with RT07-01 h. PROP Chronic blood transfusion therapy compared to HSCT in children with sickle cell disease with a stroke risk: A cost-utility analysis (R Sidonio) Overlaps with AA Other business Study priority allocation 2

3 Not for publication or presentation Attachment 1 MINUTES CIBMTR WORKING COMMITTEE FOR NON-MALIGNANT MARROW DISORDERS Honolulu, Hawaii Saturday, February 19, 2011, 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 The CIBMTR Working Committee for Non-Malignant Marrow Disorders met on Saturday, February 19, 2011 at 12:17 pm. Dr Mouhab Ayas welcomed everyone. The minutes of the February 2010 meeting were approved. 2. Presentations, published or submitted papers Working Committee activity for 2010 shown below. a. AA03-02 Sabloff M, Chandy M, Wang Z, Logan BR, Ghavamzadeh A, Li C-K, Irfan SM, Bredeson CN, Cowan MJ, Gale RP, Hale GA, Horan J, Hongeng S, Eapen M and Walters MC. HLA-matched sibling bone marrow transplantation for β-thalassemia major. Blood, 2010 (doi: /blood ). b. AA07-01 Gupta V, Eapen M, Carreras J, Bajorunaite R, Aljurf M Gale RP, Hale GA, Hows JM, Ilhan O, Passweg J, Ringden O, Sabloff M, Schrezenmeier H, Pasquini R, Socié G, March J. Impact of age on the outcomes of transplantation in acquired aplastic anemia using matched sibling donors. Haematologica, 2010, 95(12): c. AA08-02 Ruggeri A, Eapen M, Scaravadou A, Cairo MS, Bhatia M, Kurtzberg J, Wingard J, Fasth A, Nigro LL, Ayas M, Purtill D, Chaves W, Walters M, Wagner J, Gluckman E, Rocha V. Unrelated donor umbilical cord blood transplantation for sickle cell disease and thalassemia. Biol Blood and Marrow Transplant, 2011 (In press) d. AA07-03 Eapen M, LeRademacher J, Carreras J, Deeg HJ, Antin JH, Champlin RE, Fay J, Passweg J, Tolar J, Marsh JCW, Horowitz MM. Effect of Stem Cell Source from Unrelated Donors on Transplant Outcomes in Severe Aplastic Anemia: a Comparison of Unrelated Bone Marrow and Peripheral Blood Progenitor Cells. Oral Presentation at the American Society of Hematology in Orlando, FL December

4 Not for publication or presentation Attachment 1 3. Studies in progress a. AA02-03 Allogeneic transplants with fludarabine-based conditioning regimens for PNH (J Marsh) Current status: this study can only be done in collaboration with the EBMT. b. AA05-01 Late graft failure after HLA identical sibling SAA BMT (R Pasquini). Current status: manuscript preparation. c. AA07-03 Effect of stem cell source from unrelated donors on transplant outcomes in severe aplastic anemia (M Eapen). Current status: manuscript preparation. The primary objective of this study is to to evaluate the effect of stem cell source on transplant outcomes for SAA. In recent years, PBPC instead of bone marrow are increasingly used and PBPC grafts now account for 25% of unrelated donor HCT for SAA. 249 patients transplanted from received either BM (n=225) or PBPC (n=71) from unrelated adult donors matched at HLA-A, -B, -C, -DRB1. Median follow up was 3 years. These data suggest that: (1) outcomes after URD HCT for SAA are now similar to outcomes observed in MRD HCT, (2) BM is the preferred graft source when considering unrelated donor HCT in patients with SAA and (3) the data also support low-dose total body irradiation in the preparative regimen for transplant conditioning. d. AA08-01 The role of the HLA DRB1 antigen DR15 in patients with severe aplastic anemia (SAA) undergoing HLA-matched BMT (M Battiwalla). Current status: manuscript preparation. e. AA09-01 Outcome of allogeneic stem cell transplantation in patients with Fanconi anemia who present with myelodysplasia, clonal abnormalities and/or leukemia (M Ayas). Current study status: data file preparation. The primary aim of this study is to determine transplant-outcomes in patients with Fanconi anemia who have myelodysplasia/any clonal abnormality/or acute myeloid leukemia. The secondary aim is to evaluate the effect of different conditioning regimens on overall survival (namely, regimens with or without radiation). Study population: MDS (n=27), leukemia (n=4) and clonal abnormality (n=136). Being a descriptive report it was suggested patients be grouped into two: 1) those with MDS/AML and 2) clonal abnormality and outcomes described for each group. Verify regimen intensity TBI dose and doses of busulfan, cylcophosphamide and melphalan. f. AA09-02 Outcomes of hematopoietic stem cell transplantation in patients with Dyskeratosis Congenita (S Gadalla). Current study status: data collection. This is a descriptive report: early ( 100 days) and long term mortality will be described. In addition, long-term complications pulmonary, hepatic and other gastrointestinal complications will be described. There are 40 cases reported to the CIBMTR and an additional 3 cases expected. We had discussed with the EBMT (n~20 more cases) regarding a joint study. Couple of committee members volunteered they/their center were approached by Dr. Korthof for their cases for inclusion in the EBMT report. M Eapen will discuss with J Marsh. g. AA10-01 Outcome of second allogeneic stem cell transplantation in patients with Fanconi Anemia (M Ayas). Current status: protocol development. The primary aim of this study is to describe the outcome of second allogeneic SCT for Fanconi anemia. 30 patients were identified in the database and received a second for graft failure. Only US cases are included as the EBMT has a similar project. 4

5 Not for publication or presentation Attachment 1 h. AA10-02 Outcomes after allogeneic stem cell transplantation for patients who developed AML/MDS after immunosuppressive therapy for severe aplastic anemia (H Joachim Deeg). Current status: data collection. There are 24 patients with AML and 82 with MDS. A supplemental data collection form has to be 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 will contact referring or transplant centers to seek their interest in filling out the questionnaire. 5. Future/ Proposed studies a. PROP Outcomes after primary treatment with matched sibling donor transplantation and immunosuppressive therapy for patients >40 years with severe aplastic anemia: A joint study from European Bone Marrow Transplant aplastic anemia working party and Center for International Blood and Marrow Transplant Research (V Gupta). The primary treatment choice of patients with SAA >40 years (BMT vs. IST) is not clear. Upper age of MSD transplantation as first line treatment for AA varies with different centres. Age has impact on response and survival of patients treated with IST. The CIBMTR transplant experience was published recently. To move forward with this proposal we will need cases from the EBMT transplant recipients and the comparison cohort, IST only. There isn t a formal commitment from the EBMT with regards to collaboration. M Eapen to discuss with J Marsh. b. PROP Durable engraftment and correction of hematological defects in children and congenital amegakaryocytic thrombocytopenia following myeloablative umbilical cord blood transplantation (KM Mahadeo) Describe outcomes after transplantation for congenital amegakaryocytic thrombocytopenia: by donor/graft, sustained hematopoietic recovery, GVHD and survival. Limit to transplants after Other business None. Proposal was approved. Meeting adjourned at 1:25 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: Registration only Research Registration 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 2428 (59) 2570 (58) 665 (54) 861 (54) Female 1649 (40) 1869 (42) 555 (45) 726 (46) Missing 4 (<1) 0 1 (<1) 1 (<1) Donor type HLA-identical siblings 3209 (79) 2744 (62) 1047 (86) 1403 (88) Twins 50 ( 1) 57 ( 1) 0 0 Other relative 233 ( 6) 203 ( 5) 103 ( 8) 84 ( 5) Unrelated 589 (14) 1435 (32) 66 ( 5) 99 ( 6) Not specified (<1) 2 (<1) Graft type Bone marrow 2756 (68) 3512 (79) 827 (68) 1269 (80) Peripheral blood 1141 (28) 766 (17) 305 (25) 226 (14) Cord blood 83 ( 2) 155 ( 3) 76 ( 6) 92 ( 6) Missing 101 ( 2) 6 (<1) 13 ( 1) 1 (<1) Year of transplant ( 3) 370 ( 8) 16 ( 1) 201 (13) ( 6) 416 ( 9) 37 ( 3) 240 (15) ( 6) 460 (10) 53 ( 4) 225 (14) ( 8) 476 (11) 73 ( 6) 147 ( 9) ( 9) 409 ( 9) 64 ( 5) 152 (10) ( 9) 399 ( 9) 91 ( 7) 178 (11) (12) 362 ( 8) 171 (14) 122 ( 8) (11) 488 (11) 161 (13) 77 ( 5) (12) 368 ( 8) 202 (17) 62 ( 4) ( 8) 544 (12) 147 (12) 153 (10) * 593 (15) 147 ( 3) 206 (17) 31 ( 2) * 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: Registration only Research Registration only Research Number of patients Number of centers Age at transplant, years 10 (<1-53) 10 (1-49) 30 (9-59) 29 (3-72) Sex Male 297 (52) 507 (52) 62 (53) 172 (54) Female 245 (43) 460 (48) 54 (47) 146 (46) Missing 29 ( 5) Donor type HLA-identical siblings 277 (49) 421 (44) 87 (75) 178 (56) Twins Other relative 79 (14) 87 ( 9) 6 ( 5) 12 ( 4) Unrelated 215 (38) 459 (47) 22 (19) 121 (38) Not specified ( 1) 7 ( 2) Graft type Bone marrow 364 (64) 675 (70) 58 (50) 190 (60) Peripheral blood 108 (19) 135 (14) 54 (47) 109 (34) Cord blood 90 (16) 152 (16) 2 ( 2) 16 ( 5) Missing 9 ( 2) 5 ( 1) 2 ( 2) 3 ( 1) Year of transplant ( 3) 67 ( 7) 1 ( 1) 13 ( 4) ( 3) 83 ( 9) 5 ( 4) 12 ( 4) ( 6) 76 ( 8) 7 ( 6) 25 ( 8) ( 8) 100 (10) 7 ( 6) 23 ( 7) ( 9) 80 ( 8) 10 ( 9) 25 ( 8) (10) 102 (11) 11 ( 9) 39 (12) (14) 110 (11) 11 ( 9) 45 (14) (10) 114 (12) 11 ( 9) 54 (17) (13) 77 ( 8) 2 ( 2) 36 (11) ( 8) 121 (13) 17 (15) 37 (12) * 80 (14) 37 ( 4) 34 (29) 9 ( 3) * 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: Registration only Research Registration only Research Number of patients Number of centers Age at transplant, years 7 (1-37) 7 (<1-44) 10 (<1-54) 10 (<1-31) Sex Male 54 (51) 68 (49) 193 (53) 162 (53) Female 52 (49) 72 (51) 170 (47) 141 (47) Missing (<1) 0 Donor type HLA-identical siblings 82 (77) 71 (51) 298 (82) 216 (71) Twins Other relative 5 ( 5) 11 ( 8) 45 (12) 13 ( 4) Unrelated 19 (18) 58 (41) 21 ( 6) 74 (24) Not specified Graft type Bone marrow 75 (71) 99 (71) 277 (76) 222 (73) Peripheral blood 22 (21) 16 (11) 47 (13) 23 ( 8) Cord blood 8 ( 8) 24 (17) 35 (10) 56 (18) Missing 1 ( 1) 1 ( 1) 5 ( 1) 2 ( 1) Year of transplant ( 1) 9 ( 6) 1 (<1) 8 ( 3) ( 3) 5 ( 4) 1 (<1) 10 ( 3) ( 7) 14 (10) 9 ( 2) 14 ( 5) ( 5) 12 ( 9) 15 ( 4) 23 ( 8) ( 7) 17 (12) 14 ( 4) 27 ( 9) ( 9) 10 ( 7) 34 ( 9) 37 (12) ( 8) 17 (12) 46 (13) 19 ( 6) (12) 19 (14) 36 (10) 27 ( 9) (17) 11 ( 8) 37 (10) 32 (11) ( 9) 18 (13) 53 (15) 77 (25) * 23 (22) 8 ( 6) 118 (32) 29 (10) * 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 AA09-01 Outcome of allogeneic stem cell transplantation in patients with Fanconi anemia who present with myelodysplasia, clonal abnormalities and/or leukemia (M Ayas). Outcomes after allogeneic hematopoietic cell transplantation (HCT) persons with Fanconi anemia with pretransplant cytogenetic abnormalities (CA), myelodysplastic syndrome (MDS) or acute leukemia (AL). 113 FA patients with CA (n=54), MDS (n=45), or AL (n=14) received allogeneic HCT. Pretransplant conditioning regimens were radiation-based in 67 patients and chemotherapy-based in 46 patients. The donor source was bone marrow/peripheral blood (matched related, n=82; unrelated, n=16), or cord blood (related, n=2; unrelated, n=13). Survival probabilities were 64%, 58%, and 55% at 1, 3, and 5 years, respectively. Age at transplant was the only variable significantly correlated with 5-year OS ( 14 years vs. > 14 years, 69 % vs. 39%, respectively; P =0.001). When analysis was restricted to recipients of related donor HCT (n=82), age again correlated with 5-year survival ( 14 years vs. > 14 years, 78% vs. 34%, respectively; P <.001); additionally, patients with CA pretransplant had better survival than those with MDS or AL (5-year OS: 67% vs. 43%, P =0.03). FA patients transplanted with CA, MDS, or AL have a reasonable survival rates. Survival rates are better in patients aged 14 years or younger. This study was an oral presentation at the American Society of Hematology in San Diego, CA December 2011 and manuscript is underway. AA09-02 Outcomes of hematopoietic stem cell transplantation in patients with Dyskeratosis Congenita (S Gadalla). This is a descriptive report: early ( 100 days) and long term mortality will be described. In addition, long-term complications pulmonary, hepatic and other gastrointestinal complications will be described. There are 40 cases reported to the CIBMTR. The protocol and data file preparation is underway. 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 has to be 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. AA11-01 Durable engraftment and correction of hematological defects in children with congenital amegakaryocytic thrombocytopenia following myeloablative umbilical cord blood transplantation (K Mahadeo). Describe outcomes after transplantation for congenital amegakaryocytic thrombocytopenia: by donor/graft, sustained hematopoietic recovery, GVHD and survival. Will limit to transplants after Due to the Committee's portfolio of active studies, proposals and the scientific interest amongst the broader committee, we will not be able to undertake any effort towards this project for the next fiscal year. 9

10 Not for publication or presentation Attachment 3 AA11-02 Chronic blood transfusions therapy compared to HCT in children with Sickle Cell Disease: a cost-utility analysis (R Sidonio). The overall goal of this project is determine the preferred strategy for a child with SCD and an abnormal TCD and to interrogate the minimum treatment thresholds that alter decision-making. First specific aim is to determine the utility of hematopoietic stem cell transplant for a child with SCD and an abnormal TCD. Second specific aim is to determine patient utility and quality of life of children with SCD that have recently undergone a hematopoietic stem cell transplant. The data file preparation is underway. 10

11 Not for publication or presentation Attachment 4 Study Proposal Study Title: Treatment of Secondary Graft Failure in Patients with Aplastic Anemia (AA) and Inherited Bone Marrow Failure (BMF) Andrew C. Dietz, MD, University of Minnesota, Minneapolis, Minnesota Jakub Tolar, MD, PhD, University of Minnesota, Minneapolis, Minnesota Specific Aims Primary Aim: 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 inherited BMF syndromes. Secondary Aim: To determine outcomes of each different treatment method used for the treatment of secondary graft failure in these populations. Scientific Justification: Aplastic anemia (AA) or bone marrow failure (BMF) is a set of heterogeneous states that involve a variety of pathophysiologic mechanisms including immune attack, DNA damage repair, telomerase regulation and ribosomal function as well as other unknown mechanisms to date. 1 Non-inherited AA, associated with T-cell mediated autoimmune destruction, occurs in approximately 2 per million in western countries resulting in about 600 cases per year in the United States. Immunosuppressive therapy yields a 60-75% remission rate with with 10-35% of those patients relapsing. Despite many different regimens attempted, there seems to be a plateau with response rate. There is additional risk of evolution to myelodysplasia or malignancy. The preferred method of cure involves matched sibling donor HSCT with 85-90% overall survival. Currently only about 20-30% of patients will have this option. Inherited BMF states often require HSCT for cure of the marrow failure component of their disease. HSCT is more effective if performed prior to major infections, alloimmunization, platelet refractoriness or transfusional iron overload. 2 One of the central problems with HSCT in these populations is graft failure with rates of 0-45% 3 for both primary and secondary graft failure, typically more than in HSCT for other indications. The risk of graft failure rises with alternative donor HSCT as well as with increased amounts of pre-transplant transfusions. Graft rejection may occur by a similar mechanism to the original stem cell destruction when immune mediated mechanisms are at play. 1 How to treat patients with graft failure is quite variable and can include reintroduction of immunosuppression, donor-lymphocyte infusion or re-transplantation depending on when the graft failure occurs. There is no current standard. In a recent CIBMTR analysis 84% of graft failure in severe aplastic anemia was secondary. One-third of the graft failure patients in this analysis underwent a second transplant. Outcomes were worse in those with a short intertransplant interval of less than 3 months or with poor performance status. There was no detectable advantage of using a different sibling donor for the 2 nd transplant when available. 4 Carefully monitoring post-hsct chimerism is indicated for these patients, with progressive mixed chimerism being a potential harbinger of graft failure. In a study of mixed chimerism, 16.3% of patients had progressive mixed chimerism seen between 2 and 30.7 months post-transplant. Of these 14 patients, 10 went on to experience graft failure, and 7 of those 10 occurred during withdrawal of post-hsct 11

12 Not for publication or presentation Attachment 4 immunosupression. The prognosis of secondary graft failure in this population was better than primary graft failure. 5 With primary graft failure the need to proceed to re-transplantation is often indicated. With secondary graft failure being more common in the CIBMTR analysis, and the absence of a current standard, there is an opportunity to learn more about historical practices and determine if a treatment algorithm can be proposed. Patient Eligibility Population: Disease states: aplastic anemia, severe aplastic anemia, Fanconi anemia, Dyskeratosis congenita, Schwachman-Diamond syndrome, Diamond-Blackfan anemia, Pure red-cell aplasia, Paroxysmal nocturnal hemoglobinuria, Severe congenital neutropenia, Thrombocytopenia with absent radii syndrome, Congenital amegakaryocytic thrombocytopenia, Pearson s syndrome, Cartilage hair hypoplasia syndrome, Reticular dysgenesis, Ligase 4 deficiency Previous Treatments: hematopoietic stem cell transplantation with primary engraftment, but subsequent secondary graft failure defined sustained decrease in absolute nuetrophil count after initial recovery All ages, all years of transplant, all graft and donor types and all transplant regimens. Data Requirements: Forms that would contain relevant information include: 2000 Recipient Baseline Data, 2005 HLA Typing, 2006 HSCT Infusion, 2028 AA pre-hsct Data, 2029 FA pre-hsct Data, 2035 CAT pre-hsct Data, Day post-hsct Data, 2128 AA post-hsct Data, 2129 FA post-hsct Data, 2135 CAT post-hsct Data, Months to 2 Years post-hsct Data, 2300 Yearly Follow-up Greater Than 2 Years, 2301 Amnesty Plan post- HSCT Data, 2400 Pre-HSCT Essential Data 2450 Post-HSCT Essential Data, 2451 Chimerism Studies The variables and endpoints requested include: Routine Demographic Information Age, Sex, Performance Status Conditioning Regimen Inclusion of TBI or not with dose, Cyclophosphamide or not with dose, Busulfan or not, Myeloablative vs. Non-myeloablative, GVHD prophylaxis (calcineurin inhibitor, MTX vs. other) Graft Characteristics Source (related, unrelated), Type (peripheral blood, bone marrow, umbilical cord blood), Degree of HLA matching, any manipulation or preparation Disease Characteristics Diagnosis, associated cytogenetics, Time from diagnosis to transplant (continuous) Transplant Associated Variables TRM, Time to ANC recovery, Time to platelet recovery, Acute GVHD, Chronic GVHD, Donor engraftment data, Risk of secondary graft failure, Time to secondary graft failure, Subsequent Treatment (DLI, 2 nd Transplant including characteristics), Survival Sample Requirements: There are no sample requirements for this study. 12

13 Not for publication or presentation Attachment 4 Study Design (Scientific Plan): With our primary aim, simple observational statistics can be applied to determine incidence and describe historical treatment options based on answers to the requested data items. With our secondary aim, if sample size allows, additional comparative statistics will be required to determine how different treatment strategies performed. Adjustment for timing of graft failure, type of transplant, type of disease, and additional factors known to effect outcomes will be required in that event. Limitations of this study will include the retrospective nature, potential for incomplete data about treatment options used at the time of secondary graft failure diagnosis, and potential lack of power to detect differences in outcomes between treatment options used. References: 1. Armand P, Antin JH. Allogeneic stem cell transplantation for aplastic anemia. Biol Blood Marrow Transplant 2007; 13(5): Pulsipher MA, Young NS, Tolar J, Risitano AM, Deeg HJ, Anderlini P et al. Optimization of therapy for severe aplastic anemia based on clinical, biologic, and treatment response parameters: conclusions of an international working group on severe aplastic anemia convened by the Blood and Marrow Transplant Clinical Trials Network, March Biol Blood Marrow Transplant 2011; 17(3): Peinemann F, Grouven U, Kröger N, Pittler M, Zschorlich B, Lange S. Unrelated donor stem cell transplantation in acquired severe aplastic anemia: a systematic review. Haematologica 2009; 94(12): Horan JT, Carreras J, Tarima S, Camitta BM, Gale RP, Hale GA et al. Risk factors affecting outcome of second HLA-matched sibling donor transplantations for graft failure in severe acquired aplastic anemia. Biol Blood Marrow Transplant 2009; 15(5): Lawler M, McCann SR, Marsh JC, Ljungman P, Hows J, Vandenberghe E et al. Serial chimerism analyses indicate that mixed haemopoietic chimerism influences the probability of graft rejection and disease recurrence following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA): indication for routine assessment of chimerism post SCT for SAA. Br J Haematol 2009; 144(6):

14 Not for publication or presentation Attachment 4 Summary: 9117 patients underwent an allogeneic stem cell transplant for aplastic anemia and inherited bone marrow failure from 1990 and engrafted, 1005 had a primary graft failure and 726 a secondary graft failure. Table below shows patient characteristics for 726 patients with a secondary graft failure. Characteristics of patients who underwent an allogeneic stem cell transplant for aplastic anemia and inherited bone marrow failure with secondary graft failure from 1990 and 2010 reported to the CIBMTR* Characteristics of patients N (%) Number of patients 726 Number of centers 186 Age at transplant Median (range) 11 (<1-65) <10 yrs 337 (46) yrs 205 (28) yrs 93 (13) yrs 47 ( 6) yrs 30 ( 4) yrs 9 ( 1) >=60 yrs 5 ( 1) Subdisease PNH 23 ( 3) Severe aplastic anemia unknown (095CORE) 22 ( 3) SAA idiopathic 302 (42) SAA secondary to hepatitis 8 ( 1) SAA secondary to toxin-other 15 ( 2) Amegakaryocytosis(not congenital) 1 (<1) Schwachmann-Diamond 1 (<1) Acquired Pure Red Cell Aplasia 2 (<1) Other acquired cytopenic syndrome, specify 9 ( 1) Inherited abnormal of erythrocyte differ, NOS 3 (<1) Fanconi anemia 82 (11) Diamond-Blackfan anemia (pure red cell aplasia) 9 ( 1) Other constitutional anemia (not THALs) 6 ( 1) Thalassemia, NOS 59 ( 8) 095 Type B+ Thalassemia major 8 ( 1) 095 Type B0 Thalassemia major 9 ( 1) 095 Type BE Thalassemia major 1 (<1) Sickle Thalassemia major 2 (<1) Sickle cell anemia 17 ( 2) Other hemoglobinopathy, specify 3 (<1) Immune Deficiencies (ID), NOS 1 (<1) 14

15 Not for publication or presentation Attachment 4 Continued. Characteristics of patients N (%) SCID ADA deficiency 1 (<1) SCID absence of T and B cells 6 ( 1) SCID absence of T, normal B cell SCID 11 ( 2) Omenn syndrome 6 ( 1) Reticular dysgenesis 1 (<1) Bare lymphocyte syndrome 10 ( 1) SCID, NOS 2 (<1) SCID other, specify 25 ( 3) Wiskott Aldrich syndrome 20 ( 3) Chronic granulomatous disease 7 ( 1) Chediak-Higashi syndrome 4 ( 1) Common variable immunodef 3 (<1) X-linked lymphoproliferative syndrome 6 ( 1) Leukocyte adhesion deficiencies 13 ( 2) Kostmann agranulocytosis 5 ( 1) Cartilage hair hypoplasia 3 (<1) CD40 ligand deficiency 4 ( 1) Combined immunodef dis (CID), NOS 3 (<1) CID other, specify 1 (<1) Other immunodeficiencies, specify 7 ( 1) Inherited platelet abn 1 (<1) Amegakaryocytosis-congen thrombocytopeni 4 ( 1) Graft type Bone marrow 570 (78) Peripheral blood 97 (13) Cord blood 59 ( 8) Year of HCT ( 7) ( 9) ( 9) (10) (12) (12) ( 9) (12) (10) (10) ( 1) Median FU of survivors, months 70 (3-239) *11 twin transplant patients excluded. 15

16 Not for publication or presentation Attachment 5 Study Proposal Study Title: Outcome of second allogeneic stem cell transplantation in patients with Fanconi Anemia Mouhab Ayas, MD, King Faisal Specialist Hospital & Research Center (KFSHRC), Riyadh, SAUDI ARABIA Specific Aims: Primary Aim: To determine the outcome of second allogeneic SCT in patients with Fanconi anemia. Secondary Aim: To evaluate the factors that may affect the ultimate outcome of such patients after the second SCT (conditioning regimens, primary vs. secondary graft failure after the first SCT, time elapsed between the 2 transplants, donor source). Secondary Aim: To evaluate toxicity and the incidence of acute and chronic GHVD in these patients. Scientific Justification: Allogeneic stem cell transplantation (SCT) is the only known curative modality for bone marrow failure in patients with Fanconi anemia (FA) 1-8 ; thus, when graft failure occurs after SCT, the prognosis is extremely grim, as the salvage options are limited. Second transplantation may be considered in these patients, but extreme care must be exercised, as FA cells are known to be exceptionally sensitive to chemotherapy and radiation therapy; therefore, further cytotoxic conditioning may be detrimental. The incidence of graft failure in FA patients undergoing allogeneic SCT varies from one study to another. Socie et al. reported a total of 4 graft failures (3 primary and 1 secondary) in 49 evaluable patients who underwent matched-related SCT (8%); the conditioning consisted of cyclophosphamide (CY) 20 mg/ kg, and thoracoabdominal irradiation (TAI) at 500 cgy, all 4 patients were retransplanted; 1 remains alive and well 1.2 years at the time of the report 3. Farzin et al. used CY 20 mg/kg, TAI at 400 cgy and ATG for conditioning of their FA patients; out of 30 patients transplanted for marrow aplasia, two patients (7%) developed graft failure (1 primary and 1 secondary) 4. Using the same regimen of CY/TAI/ATG on 22 FA patients receiving matched-related SCT, we (KFSHRC, Riyadh, Saudi Arabia), reported an incidence of graft failure of 9% (two patients) 7. Subsequently, using a nonradiation containing regimen (cyclophosphamide 60 mg/kg and ATG only), we reported a graft failure rate of 13% 8. In general, the outcome of the second SCT is poor and depends on multiple factors, and the results are even more dismal in malignant disorders Guardiola et al. reported on 82 consecutive second SCT in patients with acute leukemia, aplastic anemia, or chronic myeloid leukemia; the 100-day transplantrelated mortality (TRM) was 53%, and the 3-year overall survival (OS) was 30%. Only one of the patients transplanted for malignancies survived 9. Guardiola et al. also showed that a longer interval between the 2 transplants (80 days) was associated with a remarkably lower 100- day TRM. Therefore, second allogeneic SCT may be a viable option for many FA patients with graft failure, particularly if enough time has elapsed since the first SCT, but further cytotoxic conditioning for these patients may be harmful in light of the increased sensitivity that FA patients demonstrate to chemotherapy. The data on the toxicity patterns in FA patients following a second SCT are sketchy and scarce. Bonfim et al. used a combination of CY/fludarabine or cyclophosphamide alone on 4 FA patients undergoing a 2nd SCT: 2 had a successful outcome, 1 died, and 1 required a 3rd SCT and was reported well 33 months after the first SCT 1. Tan et al. performed a second SCT on one patient on day 33 after the first SCT using cyclophosphamide and total lymphoid irradiation, and the patient was reported well and alive; another 16

17 Not for publication or presentation Attachment 5 patient received a second SCT 10 months after the first SCT using cyclophosphamide and TBI, but he succumbed to progressive disease (MDS) 2. Bitan et al. used a combination of busulfan/fludarabine/alemtuzumab to successfully condition 1 patient for the second SCT 5. Our group at KFSHRC recently reported our experience in four FA patients who underwent second stem cell transplants using rabbit ATG only for conditioning. Three engrafted promptly and are alive and free of disease at 25, 23, and 21 months, respectively 12. As noted above, most of the reported results on this subject are on small numbers of patients with no clear consensus on the best approach in such patients. This proposal therefore intends to determine -on a larger scale- the overall and event free survival as well as the toxicity pattern in FA patients undergoing second SCT. It will also evaluate the factors affecting the outcome in these patients. Patient Eligibility Criteria: The study population will include all patients entered in the CIBMTR database as having a diagnosis of Fanconi anemia and who underwent a second allogeneic stem cell transplant after the failure of the first transplant. Data Collection: The following variables would be required: - Date of diagnosis (or age at diagnosis) - Complete blood counts just prior to transplant - Number of transfusions pre-transplant - Underlying medical conditions such as renal impairment, cardiac abnormalities - Lansky performance score pre and post HSCT - Characteristics of first SCT: Patient age or date of birth Date of the first transplant (or age at time of transplant) Preparative therapy given (use of radiation, fludarabine and ATG) GVHD prophylaxis given Donor stem cell source (MSD, MRD, MUD; bone marrow, peripheral blood stem cells, cord blood) Degree of HLA match with the donor CD34 dose, nucleated cell dose, growth factor usage Engraftment data (day ANC>500, ANC>1000, platelets 20k, platelets>50k, platelets>100k) Acute GVHD Chronic GVHD Organ toxicity grade 3 or greater (renal, liver, heart, pulmonary) Chimerism Date of graft loss Type of graft loss (primary vs secondary) - Characteristics of second SCT: Patient age or date of birth Date of the second transplant (or age at time of transplant) Preparative therapy given (use of radiation, fludarabine and ATG) GVHD prophylaxis given Donor stem cell source (MSD, MRD, MUD; bone marrow, peripheral blood stem cells, cord blood) 17

18 Not for publication or presentation Attachment 5 Degree of HLA match with the donor CD34 dose, nucleated cell dose, growth factor usage Engraftment data (day ANC>500, ANC>1000, platelets 20k, platelets>50k, platelets>100k) Acute GVHD Chronic GVHD Organ toxicity grade 3 or greater (renal, liver, heart, pulmonary) Chimerism - Date of last follow-up (or time post transplant) - Date of death (or time post transplant) - Cause of death Study Design: This proposed study is a retrospective analysis of a special group of patients with Fanconi anemia who underwent second allogeneic SCT to determine the eventual outcome of this procedure. We propose to identify the number of patients who meet the inclusion criteria and evaluate the overall survival, disease free survival, engraftment, and incidence of acute and chronic GVHD as well as the factors tha may affect any of the above. This study will be done using the data already reported to CIBMTR database. Variables to be analyzed: - Age at the second transplant - Interval between the first and second SCT - Type of graft failure after the first SCT (primary vs. secondary) - Use of radiation in the preparative therapy (in the first or second SCT) - Use of ATG - Donor stem cell source - Degree of match - Type of GVHD prophylaxis Outcomes: - Engraftment: Date of neutrophil and platelet engraftment, graft failure. - Toxicity and toxic death rate: Grade 3 and 4 organ toxicity (renal, liver, heart, pulmonary) - Acute and chronic GVHD: Date of onset of grades 2-4 GVHD and grades 3-4 GVHD and organs involved - Survivals: Overall and event free survival (date of disease progression post SCT, date of last follow up, survival status at last follow up, date of death, cause of death) and correlate survival with variables identified above. References: 1. Bonfim CM, de Medeiros CR, Bitencourt MA, et al. HLA matched related donor hematopoietic cell transplantation in 43 patients with Fanconi anemia conditioned with 60 mg/kg of cyclophosphamide. Biol Blood Marrow Transplant. 2007;13: Tan PL, Wagner JE, Auerbach AD, Defor TE, Slungaard A, Macmillan ML. Successful engraftment without radiation after fludarabine-based regimen in Fanconi anemia patients undergoing genotypically identical donor hematopoietic cell transplantation. Pediatr Blood Cancer. 2006;46: Socie G, Devergie A, Girinski T, et al. Transplantation for Fanconi s anaemia: long-term followup of fifty patients transplanted from a sibling donor after low-dose cyclophosphamide and thoraco-abdominal irradiation for conditioning.br J Haematol. 1998;103:

19 Not for publication or presentation Attachment 5 4. Farzin A, Davies SM, Smith FO, et al. Matched sibling donor haematopoietic stem cell transplantation in Fanconi anaemia: an update of the Cincinnati Children s experience. Br J Haematol. 2007;136: Bitan M, Or R, Shapira MY, et al. Fludarabine-based reduced intensity conditioning for stem cell transplantation of Fanconi anemia patients from fully matched related and unrelated donor. Biol Blood Marrow Transplant. 2006;12: Ayas M, Al-Jefri A, Al-Seraihi A, et al. Allogeneic stem cell transplantation in Fanconi anemia patients presenting with myelodysplasia and/or clonal bnormality: update on the Saudi experience. Bone Marrow Transplant. 2008; 41: Ayas M, Solh H, Mustafa MM, et al. Bone marrow transplantation from matched siblings in patients with fanconi anemia utilizing low-dose cyclophosphamide, thoracoabdominal radiation and antithymocyte globulin. Bone Marrow Transplant. 2001;27: Ayas M, Al-Jefri A, Al-Mahr M, et al. Stem cell transplantation for patients with Fanconi anemia with low-dose cyclophosphamide and antithymocyte globulins without the use of radiation therapy. Bone Marrow Transplant. 2005;35: Guardiola P, Kuentz M, Garban F, et al. Second early allogeneic stem cell transplantations for graft failure in acute leukaemia, chronic myeloid leukaemia and aplastic anaemia. French Society of Bone Marrow Transplantation. Br J Haematol. 2000;111: Grandage VL, Cornish JM, Pamphilon DH, et al. Second allogeneic bone marrow transplants from unrelated donors for graft failure following initial unrelated donor bone marrow transplantation. Bone Marrow Transplant. 1998;21: Mrsic M, Horowitz MM, Atkinson K, et al. Second HLA identical sibling transplants for leukemia recurrence. Bone Marrow Transplant. 1992;9: Ayas M, Al-Jefri A, Al-Seraihi A, Al-Mahr M, Al-Ahmari A, El-Solh H. Second Stem Cell Transplantation in Patients with Fanconi Anemia Using Antithymocyte Globulin Alone for Conditioning. Biol Blood Marrow Transplant 2008; 14:

20 Not for publication or presentation Attachment 5 Characteristics of patients that underwent a second allogeneic transplant for Fanconi anemia reported to the CIBMTR Characteristics of patients N (%) Number of patients 89 Number of centers 36 Age at transplant Median 10 (3-38) <10 yrs 40 (45) yrs 41 (46) yrs 4 ( 4) yrs 4 ( 4) Sex Male 59 (66) Female 30 (34) Karnofsky score <90% 58 (65) % 23 (26) Missing 8 ( 9) Type of donor HLA-id sibling 23 (27) Other relative 15 (17) URD well-matched 4 ( 5) URD partially matched 7 ( 8) URD mismatched 6 ( 7) URD matching unknown 1 ( 1) URD matching to be classified 33 (35) D-R sex match M-M 32 (36) M-F 16 (18) F-M 16 (18) F-F 11 (12) Missing 14 (16) D-R CMV status +/+ 23 (26) +/- 10 (11) -/+ 9 (10) -/- 11 (12) Missing 36 (40) 20

21 Not for publication or presentation Attachment 5 Continued. Characteristics of patients N (%) Graft type Bone marrow 54 (60) Peripheral blood 21 (24) Cord blood 14 (16) Year of HCT ( 1) ( 7) (12) (12) ( 6) ( 6) (10) (11) (20) (15) GVHD prophylaxis Ex vivo T-cell depletion alone 8 ( 9) Ex vivo T-cell depletion + post-tx immune supression 4 ( 4) CD34 selection alone 4 ( 4) CD34 selection + post-tx immune supression 4 ( 4) FK506 + MMF +- others 1 ( 1) FK506 + others (except MTX, MMF) 3 ( 3) FK506 alone 2 ( 2) CSA + MMF +- others (except FK506) 4 ( 4) CSA + MTX +- others (except FK506, MMF) 10 (11) CSA + others (except FK506, MTX, MMF) 12 (13) CSA alone 19 (21) Other GVHD prophylaxis 18 (21) Median FU of survivors (range), months 49 (4-110) Abbreviations: GVHD = graft versus host disease; MTX = methotrexate; CsA = cyclosporine; FK506 = tacrolimus. 21

22 Not for publication or presentation Attachment 6 Study Proposal Study Title: Outcomes of allogeneic hematopoietic cell transplantation for acquired aplastic anemia using antithymocyte globulin [ATG] versus alemtuzumab based conditioning. Baldeep Wirk, MD, College of Medicine, University of Florida, Gainesville, Florida John R. Wingard, MD, College of Medicine, University of Florida, Gainesville, Florida Specific Aims: To study the outcomes of allogeneic hematopoietic cell transplantation [HCT] for acquired aplastic anemia [AA] including treatment related mortality [TRM[, engraftment, acute and chronic graft-versushost [GVHD], progression free survival [PFS], and overall survival [OS] and infection rates for ATG versus alemtuzumab based conditioning regimens. Scientific Justification: Allogeneic HCT is curative in acquired aplastic anemia and the number of transplants have been increasing from 200 per year in the early 1990 s to over 600 per year in 2008 in Europe, for example, and this is mostly due to a greater use of unrelated donors. 1 Survival rates of HCT in acquired aplastic anemia are improving because of advancements in HLA matching, supportive care and conditioning regimens. Nonetheless the survival does not approach that of the general population. The major factors in developing late transplant related complications are the conditioning regimens used and development of chronic GVHD. Chronic GVHD impacts the quality of life but also survival. The recommended conditioning regimen for those <30 years with matched sibling donor HCT is cyclophosphamide ATG but this is still associated with chronic GVHD in 30-40%. 2 The optimal conditioning regimens for those >30 years with matched sibling donors or with unrelated donors is unknown with fludarabine, cyclophosphamide with ATG or alemtuzumab being used. 2 Irradiation based regimens in HLA identical sibling BMT for AA decreases risk of rejection but doesn t benefit survival. Fludarabine cyclophosphamide, ATG and low dose TBI [2Gy] has been used to reduce graft rejection in older patients with unrelated donors. 2 Nonetheless, chronic GVHD occurs in up to 30% of younger patients and 50% of older patients with unrelated donors. 3 Risk factors for chronic GVHD include older age and use of peripheral blood stem cells. Alemtuzumab has detectable levels in the plasma for several weeks leading to depletion of recipient autoreactive lymphocytes, donor alloreactive T cells as well as host antigen presenting dendritic cells which could result in less GVHD as has been shown in smaller studies. 4,5 This raises the potential of allowing HCT in older patients >50 years and using peripheral blood stem cells. However, these studies involve small numbers of patients with short follow up. The CIBMTR data base would provide an opportunity to clarify the influence of ATG versus alemtuzumab based conditioning regimens on outcomes in acquired AA [TRM, PFS, engraftment, OS, infection rate, acute and chronic GVHD]. Study Population: All patients with acquired aplastic anemia undergoing allogeneic HCT between , given ATG or alemtuzumab based conditioning. Outcomes: Engraftment: first of 3 consecutive days with an absolute neutrophil count of more than 500/microliter. Acute GVHD: grade I-IV according to Seattle criteria. 6 Chronic GVHD: according to criteria by Shulman et al. 7 22

23 Not for publication or presentation Attachment 6 Treatment related mortality: death due to any cause other than disease progression or relapse occurring at any time after transplant. Progression free survival: defined as time from HSCT to date of graft failure or death from any cause or last follow up. Overall survival: measured in months and defined from date of HSCT to date of death or last follow up. Variables to be Described: Patient Related: age, gender, KPS >70 vs. < or=70, HCT-comorbidity index [Sorror] 0-1 vs. 2 or more Disease Related: AA severity: very severe, severe, nonsevere AA etiology: idiopathic, drug induced, hepatitis, pregnancy, PNH Median interval from diagnosis to HCT: Prior ATG use: yes versus no Transplant Related: Donor type: matched sibling versus matched unrelated donor Stem cell source: BM, G-BM, BM+PBSC, PBSC Year of HCT PNH clone at HCT % CMV status of donor-recipient Donor-recipient gender: female donor to male recipient versus other GVHD prophylaxis: csa+mtx versus csa Chimerism: day +100, 6 months, one year Acute GVHD Chronic GVHD Infection type for atg versus alemtuzumab: bacterial vs. viral vs. fungal Causes of death: graft failure, gvhd, second malignancy, organ toxicity, relapse Variables to be Analyzed: Recipient age, severity of AA, etiology of AA [idiopathic, hepatitis, drug, pnh, pregnancy], donor type [mrd vs. mud], stem cell source [bm vs. pbsc], time from diagnosis to hct, HCT-CI score. Data Collection: All data requested will be provided by existing data collection forms and no supplemental data will be required. Follow up will be complete by the end of Study Design: Patients will be divided into two groups based on ATG versus alemtuzumab based conditioning. Overall survival and progression free survival will be calculated using the Kaplan-Meier method. The log rank test will be used for univariate comparisons to examine the association between overall survival and patient, disease and transplant related characterisitics listed in the variables to be analyzed. Multivariate analysis with Cox proportional hazards regression model for progression free survival and overall survival will be used. References: 1. Gratwohl A, Baldomero H, Schwendener A et al. The EBMT activity survey 2008; impact of team size, team density and new trends. Bone Marrow Transplant 2011;46: