Summary of Accomplishments As of 1/31/17

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1 Summary of Accomplishments As of 1/31/17 VALUE TO THE HCT COMMUNITY The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) plays a critical role in improving patient outcomes and advancing the science of hematopoietic stem cell transplantation (HCT). The Network s many achievements include: Launching 43 trials, including 5 led by National Cancer Institute (NCI) Cooperative Groups Completing accrual to 31 trials Completing follow-up to primary endpoint for 21 of the 25 BMT CTN-led studies Accruing >9,300 patients from >125 centers o Accruing >400 patients with rare diseases: sickle cell disease, severe aplastic anemia, hemophagocytic syndromes, and primary immune deficiencies Having an overall accrual rate that is approximately 125% of projections among trials currently open for enrollment Establishing a Research Sample Repository that currently includes >360,000 biospecimens Engaging in 55 ancillary and correlative studies; 35 of which used cryopreserved biospecimens from the Repository or samples shipped directly to a project laboratory Presenting 74 abstracts Publishing 73 manuscripts, including 21 of primary results BMT CTN Annual and Cumulative Accrual to All Protocols SIGNIFICANCE Approximately 22,000 HCTs are reported to the CIBMTR annually, and the number increases by about 5% per year. HCT is a rapidly evolving field, and HCT clinical trials face unique challenges, including the relatively small number of transplantations performed at any single center, the diverse indications for HCT, the complexities of the intervention, and multiple post-transplant complications. The BMT CTN was established in 2001 to address these challenges and execute multicenter HCT trials with broad national participation. The Network studies various treatment options and answers research questions relevant to both common and rare diseases. RESOURCEFUL Support from industry partners (including in-kind contributions) and other grants has increased the effective investment from NIH by an estimated $375 million EFFICIENT Median time from protocol team formation to protocol release is currently 14.7 months Median time from date of evaluable data to manuscript submission is 8.7 months PRODUCTIVE Primary manuscripts pending for only 2 trials of 24 trials reaching primary endpoint 27 publications of ancillary studies evaluating the biology of HCT and impact on patients

2 SIGNIFICANT FINDINGS AND IMPACT The research findings of the BMT CTN provide information with relevance for clinical practice. Network trials have provided important insights into several areas of HCT. Significant Findings and Impact of Published BMT CTN Studies BMT CTN Study Results Impact / Future Outlook UNDER-REPRESENTED POPULATIONS 0502 (CALGB ): Phase II study of allogeneic transplant for older patients with acute myeloid leukemia (AML) in first morphologic complete remission using a nonmyeloablative preparative regimen 0601: Unrelated donor hematopoietic cell transplantation for children with severe sickle cell disease using a reducedintensity conditioning regimen 0803 (AMC-071): High dose chemotherapy with autologous stem cell rescue for aggressive B cell lymphoma and Hodgkin lymphoma in human immunodeficiency virus (HIV)-infected patients Demonstrated the feasibility and effectiveness of allogeneic transplant using reducedintensity conditioning in this first prospective US cooperative group trial conducted in a homogeneously treated group of older AML patients in first remission Determined that a reducedintensity conditioning regimen of alemtuzumab, fludarabine, and melphalan, followed by bone marrow HCT resulted in low rates of regimen-related organ toxicity and a one year event-free survival of 76% Initially found that this regimen, although effective for engraftment of bone marrow, was associated with unacceptably high levels of graft failure after cord blood transplantation; this led to the closure of the cord blood cohort Determined that patients with HIV-associated lymphoma may successfully undergo autologous transplant with favorable outcomes This protocol was a collaborative effort between the BMT CTN and Cancer and Leukemia Group B (CALGB). CALGB accrual began in 2006, but enrollment was low; BMT CTN activated the study, and the trial rapidly met its original accrual goal. The study demonstrates that, with reducedintensity conditioning, patients older than 60 can benefit from the graft-versus-leukemia effects of allogeneic HCT with outcomes similar to younger patients. These data should increase the use of HCT in older AML patients and provide justification for BMT CTN allograft trials. This finding confirmed that using a reducedintensity regimen followed by bone marrow HCT results in acceptable rates of engraftment and survival but unacceptably high risks of chronic GVHD, underscoring the need for future trials of effective GVHD prophylaxis. Early in the study, there was the disappointing finding that cord blood resulted in unacceptably high levels of graft failure, indicating the need for other transplant strategies for sickle cell disease patients unable to find an HLA-matched donor. Two new sickle cell transplant trials will soon be launched. BMT CTN 1503 compares HLA-matched bone marrow HCT to standard of care, and BMT CTN 1507 uses haplo-identical donors. The BMT CTN conducted this study in collaboration with the AIDS Malignancy Consortium (AMC). It showed that autologous HCT is a viable therapeutic option for a patient population frequently excluded from HCT and HCT clinical trials. Based on the study findings, autologous HCT should be the standard of care for patients with relapsed / refractory HIVassociated lymphoma who meet standard eligibility criteria. The BMT CTN and AMC are also evaluating the use of allogeneic HCT for HIVinfected patients with hematological cancers and myelodysplastic syndrome in the completed BMT CTN 0903 trial.

3 Significant Findings and Impact of Published BMT CTN Studies BMT CTN Study Results Impact / Future Outlook GRAFT SOURCES 0501: Multicenter, open label, randomized trial comparing single versus double umbilical cord blood transplantation in pediatric patients with leukemia and myelodysplasia 0201: A Phase III randomized, multicenter trial comparing G-CSF mobilized peripheral blood stem cell with marrow transplantation from HLA compatible unrelated donors 0603/0604: Multicenter, Phase II trials of nonmyeloablative conditioning and transplantation of partially HLA-mismatched bone marrow / umbilical cord blood from unrelated donors in patients with hematologic malignancies Demonstrated no survival benefit and more acute GVHD for children receiving infusion of two umbilical cord blood units versus one umbilical cord blood unit after transplantation for hematologic malignancies Found no difference in survival for recipients of unrelated donor peripheral blood versus bone marrow grafts, but an increased risk of chronic GVHD requiring prolonged immune suppression with peripheral blood grafts Confirmed single-center results in a multicenter setting using reduced-intensity conditioning and haploidentical bone marrow transplantation or double cord blood transplantation in adults with hematologic malignancies, with data supporting a subsequent Phase III trial This study indicates, unexpectedly, that increasing cell dose beyond the accepted minimum by adding another cord blood unit does not improve survival or speed hematopoietic recovery after cord blood transplantation in children and increases the risk of acute GVHD. This has important implications for future strategies to improve hematopoietic recovery and decrease transplant-related mortality after cord blood HCT. Peripheral blood has largely replaced bone marrow as a graft source for unrelated donor HCT. This study suggests this may not be appropriate since it offers no survival advantage but produces higher rates of chronic GVHD. This is the largest prospective study of unrelated donor transplantation ever performed. It would not have been possible without the infrastructure provided by the BMT CTN. Acceptable outcomes of double cord and haploidentical bone marrow transplantation suggest that many more adults should be offered HCT, even when an HLA-matched adult donor is not available. Publication of these studies led to substantial increase in the use of haploidentical donors for transplantation in the US. These approaches are now being compared in a randomized Phase III trial (BMT CTN 1101). CONDITIONING REGIMENS AND INTENSITY 0301: Fludarabine-based conditioning for allogeneic marrow transplantation from human leukocyte antigen (HLA)-compatible unrelated donors in severe aplastic anemia Identified the optimal dose of cyclophosphamide for unrelated donor HCT in severe aplastic anemia is less than 150 mg/kg Optimizing transplantation regimens for rare diseases is difficult and requires a multicenter effort. This study determined that fludarabine is not sufficiently immune suppressive to replace cyclophosphamide in conditioning regimens for unrelated donor transplantation for aplastic anemia. Additionally, it found excess toxicity with a commonly used dose of cyclophosphamide when combined with fludarabine. This unexpected finding is anticipated to change practice in many centers. A follow-up study for aplastic anemia patients was launched (BMT CTN 1502) using the optimal cyclophosphamide dose found in this study. Additionally, the 1502 study will incorporate cord blood and haplo-identical donors to reach patients not able to find an unrelated donor.

4 Significant Findings and Impact of Published BMT CTN Studies BMT CTN Study Results Impact / Future Outlook 0901: Phase III allogeneic HCT comparing regimen intensity in patients with myelodysplastic syndrome or acute myeloid leukemia Found that reduced-intensity conditioning results in higher relapse rates and lower treatment-related mortality compared to myeloablative conditioning The data from this trial support myeloablative conditioning as the standard of care for patients who are able to receive it. For patients who are not candidates for myeloablative conditioning, novel regimens, which incorporate enhanced anti-leukemia activity without increasing toxicity, are needed. One such regimen of maintenance therapy post-hct for FLT3- positive AML patients is in development (BMT CTN 1506). 0303: A single-arm, multicenter Phase II trial of transplants of HLAmatched, CD34+ enriched, T cell depleted peripheral blood stem cells isolated by the CliniMACS system in the treatment of patients with AML in first or second complete remission GRAFT-VERSUS-HOST DISEASE PREVENTION AND TREATMENT Confirmed, in a multicenter setting, the feasibility and consistency of T cell depletion by CD34 selection, with results in AML that warranted development of a phase III trial versus non-t cell depleted transplantation These data were used by the Food and Drug Administration in its determination to approve the Miltenyi CD34 selection column for clinical use. It is the only CD34 selection device available in the US. A Phase III trial comparing outcomes of CD34-selected transplants using this approach with standard bone marrow transplants followed by calcineurininhibitor based GVHD prophylaxis (BMT CTN 1301 PROGRESS II) is open in the BMT CTN. 0802: Randomized, double blind, Phase III trial evaluating corticosteroids with MMF vs. corticosteroids with placebo as initial systemic treatment of acute GVHD Found no GVHD-free survival benefit with the addition of MMF. In an important ancillary study, determined that GVHD biomarker panels can be used for early identification of patients at high or low risk for treatment non-responsive-ness or death and that panels may provide opportunities for early intervention and improved survival following HCT Although the 0802 results were discouraging, the Network s ability to conduct GVHD studies in a timely manner allows definitive Phase III results to be quickly conducted and disseminated, even if negative. The BMT CTN is now focusing on a newer therapeutic agent, sirolimus, in the BMT CTN 1501 study using a biomarker risk stratification for determining eligibility. This system was developed using data and specimens collected in BMT CTN 0302 and : A trial of single autologous transplant with or without consolidation therapy versus tandem autologous transplant with lenalidomide maintenance for patients with multiple myeloma (STaMINA) DISEASE TREATMENT Determined, in this largest randomized US transplant study in multiple myeloma, there is comparable progression-free and overall survival in the three treatment arms; the addition of RVD consolidation or a second autologous HCT was not superior to a single autologous HCT followed by lenalidomide maintenance in the upfront treatment of multiple myeloma It is too early to determine the impact of these results but it is anticipated to be significant, as clinicians now have randomized study results to support reducing the treatment burden for patients. It is also surmised that any new treatments will now be compared to the standard therapy of melphalan followed by a single autologous HCT followed by lenalidomide maintenance. A long term follow-up trial to track outcomes in these patients is ongoing.

5 PRIMARY RESULTS PUBLICATIONS Laport GG et al. Reduced-intensity conditioning with fludarabine, cyclophosphamide, and high-dose rituximab for allogeneic HCT for follicular lymphoma: A Phase Two multicenter trial from the BMT CTN. Biology of Blood Marrow Transplantation Aug 1; 22(8): Epub 2016 Apr 23. Alvarnas JC et al. Autologous HCT for HIV-related lymphoma: Results of the BMT CTN 0803 / AMC 071 trial. Blood Aug 25; 128(8): Epub 2016 Jun 13. Shenoy S et al. A BMT CTN Phase II trial of unrelated donor marrow transplantation for children with severe sickle cell disease. Blood Nov 24; 128(21): Epub 2016 Sept 13. Ravandi F et al. US intergroup study of chemotherapy plus dasatinib and allogeneic HCT in Ph+ ALL. Blood Advances Dec 27; 1(3): Scott BL et al. Myeloablative vs. reduced intensity HCT for AML and MDS. Journal of Clinical Oncology. [In Press]. Devine et al. A Phase II study of allogeneic transplantation for older patients with AML in first complete remission using a reduced intensity conditioning regimen: Results from CALGB (Alliance) / BMT CTN Journal of Clinical Oncology Dec 10; 33(35): Epub 2015 Nov 2. Anderlini et al. Cyclophosphamide conditioning in patients with severe aplastic anemia given unrelated marrow transplantation: A Phase 1-2 dose de-escalation study. Lancet Haematology Sep 1; 2:e Wagner et al. One- vs two-unit cord blood transplant for leukemia. New England Journal of Medicine Oct 30; 371(18): Bolaños-Meade et al. Phase III clinical trial steroids / mycophenolate mofetil vs steroids / placebo as therapy for acute GVHD: BMT CTN Blood Nov 20; 124(22): Epub 2014 Aug 28. Cutler et al. Tacrolimus / sirolimus vs tacrolimus / methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood Aug 21; 124(8): Epub 2014 Jun 30. Jacobsen et al. Exercise and stress management training prior to HCT: BMT CTN Biology of Blood and Marrow Transplantation Oct 1; 20(10): Epub 2014 Jun 6. Yanik et al. A randomized double-blind, placebocontrolled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome following allogeneic HCT. A BMT CTN protocol. Biology of Blood and Marrow Transplantation Jun 1; 20(6): Epub 2014 Mar 11. Vose et al. Phase III Randomized study of BEAM compared with 131-iodine tositumomab / BEAM with autologous HCT for relapsed diffuse large B- cell lymphoma: Results from the BMT CTN 0401 Trial. Journal of Clinical Oncology May 1; 31(13): Epub 2013 Mar 11. Anasetti et al. PBSC versus bone marrow from unrelated donors. New England Journal of Medicine Oct 18; 367(16): McCarthy et al. Lenalidomide after HCT for multiple myeloma. New England Journal of Medicine May 10; 366(19): Krishnan et al. Autologous HCT followed by allogeneic or autologous HCT in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncology Dec; 12(13): Epub 2011 Sep 29. Brunstein et al. Alternative donor transplantation: results of parallel phase II trials using HLA-mismatched related bone marrow or unrelated umbilical cord blood grafts. Blood Jul 14; 118(2): Epub 2011 Apr 28. Devine et al. Low risk of chronic GVHD and relapse associated with T cell depleted peripheral blood stem cell transplantation for AML in first remission: results of the BMT CTN Protocol Biology of Blood and Marrow Transplantation Sep; 17(9): Epub 2011 Feb 12. Tomblyn et al. Autologous vs reduced intensity allogeneic HCT for patients with chemosensitive follicular non-hodgkin lymphoma beyond first complete response or first partial response. Biology of Blood and Marrow Transplantation Jul; 17(7): Epub 2010 Nov 10. Wingard et al. Randomized double-blind trial of fluconazole vs voriconazole for prevention of invasive fungal infection after allogeneic HCT. Blood Dec 9; 116(24): Epub 2010 Sep 8. Alousi et al. Etanercept, mycophenolate, denileukin or pentostatin plus corticosteroids for acute GVHD, a randomized phase II trial from the BMT CTN. Blood Jul 1; 114(3): Epub 2009 May 14.

6 SPONSORSHIP The BMT CTN is funded by two Institutes at the NIH: The National Heart, Lung, and Blood Institute and The National Cancer Institute. COLLABORATION The BMT CTN is a network of HCT centers that work together to achieve common goals. In addition to the Network s core centers, the BMT CTN encourages and facilitates broad participation of the HCT community through its Affiliate Center system. More than 100 Affiliate Centers enroll patients on Network trials, and about 17% of the BMT CTN s overall accrual comes from Affiliate Centers. Furthermore, the Network collaborates with a variety of partners, including: NIH Institutes: Other Contributions National Heart, Lung, and Blood Institute additional R01 support National Institute of Allergy and Infectious Diseases National Institute on Minority Health and Health Disparities NIH-Funded Networks / Consortia AIDS Malignancy Consortium Alliance for Clinical Trials in Oncology Children s Oncology Group Eastern Cooperative Oncology Group NCI National Clinical Trials Network Office of Rare Diseases Research Sickle Cell Disease Clinical Research Network SWOG Industry Partners Astellas Pharma Global Development, Inc. Celgene Corporation Gilead Sciences Inc. Millennium The Takeda Oncology Company Miltenyi Biotec GmbH BMT CTN CORE CENTERS The 20 core centers are listed to the right; consortia are noted with an asterisk. Baylor College of Medicine* o Children s National Medical Center Case Western Reserve University* o Cleveland Clinic o Oregon Health & Science University o West Virginia University City of Hope Dana Farber Cancer Institute / Brigham & Women s Hospital* o Massachusetts General Hospital o Boston Children's Hospital Duke University Fred Hutchinson Cancer Research Center H. Lee Moffitt Cancer Center Johns Hopkins University Memorial Sloan-Kettering Cancer Center Northside Hospital Ohio State University* The Data and Coordinating Center is a collabor o Roswell Park Cancer Institute o UCSF Medical Center o University of North Carolina Hospitals o Virginia Commonwealth University Pediatric Blood and Marrow Transplant Consortia o >100 pediatric programs Stanford Hospitals and Clinics University of Florida* o Emory University University of Michigan* o Mayo Clinic, Minnesota o Mount Sinai Medical Center o Vanderbilt University University of Minnesota University of Nebraska* o University of Kansas University of Pennsylvania University of Texas, MD Anderson Cancer Center Washington University Medical School The Data and Coordinating Center is a collaborative partnership of three organizations: CIBMTR 9200 W Wisconsin Ave, Ste C5500 Milwaukee, WI Ph: cibmtr.org The Emmes Corporation 401 N Washington St, Ste 700 Rockville, MD Ph: emmes.com bmtctn.net NMDP/Be The Match 500 North 5 th Street Minneapolis, MN Ph: bethematch.org