N ATIONAL M ARROW D ONOR P ROGRAM ® Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM Advances in AML/MDS: The Role of Multicenter Clinical Trials Dennis L. Confer, MD Chief Medical Officer, NMDP

N ATIONAL M ARROW D ONOR P ROGRAM ® Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM About These Slides Our thanks to the presenters who gave permission to include their original data Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

N ATIONAL M ARROW D ONOR P ROGRAM ® Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM 3 Annual Numbers of Blood and Marrow Transplantations, Worldwide - Number of Transplants

N ATIONAL M ARROW D ONOR P ROGRAM ® Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM 4 Current Annual Activity Estimates – Worldwide – Autologous transplants ~40,000 annually Allogeneic transplants ~25,000 annually –More than half of allogeneic transplants use unrelated donor products –More than 14 million adult donors are registered worldwide –The world’s inventory of unrelated donor (i.e., public) umbilical cord blood units exceeds 400,000

N ATIONAL M ARROW D ONOR P ROGRAM ® Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM 5 National Marrow Donor Program Adult Donors & Cord Blood Units – Oct, 2009 Adult Donors 8,013,658 CBUs 114,500

N ATIONAL M ARROW D ONOR P ROGRAM ® Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM 6 NMDP Transplants Facilitated by Fiscal Year 1987–2009 Cord blood Peripheral blood stem cells Bone marrow

N ATIONAL M ARROW D ONOR P ROGRAM ® Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM 7 NMDP Minority Transplants by FY 2007–2009 Cord blood Adult donors 20% 28% 34% 3% 23% 14%

N ATIONAL M ARROW D ONOR P ROGRAM ® Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM 8 NMDP Transplant Recipients by Diagnosis – Selected Malignancies

N ATIONAL M ARROW D ONOR P ROGRAM ® Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM 9 NMDP Transplant Recipients by Age – By Fiscal Year

N ATIONAL M ARROW D ONOR P ROGRAM ® Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM 10 NMDP Transplant Recipients by Age – By Fiscal Year

Slide 11 Rationale www. bmtctn.net

Slide 12  Established: Sept. 2001; renewed Oct  16 Core Center cooperative agreements  1 DCC cooperative agreement: CIBMTR with subcontracts to NMDP & EMMES  Goal of the Program:  Provide the infrastructure needed to allow promising HCT therapies to be developed/evaluated in high quality multicenter studies

Slide SWOGCOG ECOGCALGB BMT CTN Steering Comm BMT CTN Foundation Collectively Administer DCC CIBMTREMMES NMDP 2007 State of Science Symposium #2 Sets scientific agenda for  12 Working Committees N of pts =4401,0581,6152,0902,500[3,000][3,600][4,200] Governance and leadership Established 16 Core Centers Manual of Policies/procedures Electronic data capture system Per patient reimbursement model Websites for members & public 1.Expanding donor/graft source 5. Decrease infections 2.Reduce regimen related toxicity 6. Late effects/QOL 3.GVHD prevention/therapy 7. Rare diseases 4.Decrease relapse Early and ongoing collaboration with cooperative groups to synergize and avoid duplication (intensified since 2005) 11 high priority trials – 6 in development: 1. Maint vs consol vs 2 nd Tx for MM 2. Calcineurin-inhibitor-free Rx for CGVHD 3. Reduced intensity tx for CLL 4. Chemo vs HCT for Ph+ ALL 5. Reduced vs standard intensity conditioning 6. Peritransplant QOL 2000 State of Science Symposium #1 - Set scientific agenda for  7 focus areas for HCT trials N of trials = [22] [27] [32]

Slide 14 =PBMTC Centers =Affiliate Centers =Core Centers Mmh06_16.ppt BMT CTN Centers, 2009 >70 centers have enrolled >3,000 patients since 2003

Slide 15 Blood and Marrow Transplant Clinical Trials Network – BMT CTN  10 Trials completed accrual  Unrelated donor PBSC v. Bone Marrow – 551 donor-recipient pairs  T-cell depletion for AML – 47 recipients  8 Trials are enrolling  Prevention of acute GvHD  Single v. double umbilical cord blood  Haploidentical NST  Umbilical cord blood NST  8 Trials are in development

Slide 16

Slide 17 Endpoints in PBSC v. Marrow Trial  Recipients  2-year survival  3-year survival, engraftment, graft failure, GvHD, relapse, infections  Immune reconstitution  Quality of life  Donors  Donation-related experiences  Long-term follow-up  Quality of life

Slide 18 Accrual to PBSC v. Marrow – 60 Months

Slide 19 Blood and Marrow Transplant Clinical Trials Network – BMT CTN  10 Trials completed accrual  Unrelated donor PBSC v. Bone Marrow – 551 donor-recipient pairs  T-cell depletion for AML – 47 recipients  8 Trials are enrolling  Single v. double umbilical cord blood  Prevention of acute GvHD  Haploidentical NST  Umbilical cord blood NST  8 Trials are in development

Slide 20 Accrual to 0603 – Haploidentical NST

Slide 21 Accrual to 0604 – Cord Blood NST

Slide 22 BMT CTN Yearly and Cumulative Accrual to All Protocols, mid-June 2009

Slide 23 8 Protocols Anticipated to Open in 0702 – Myeloma – At IRBs 0801 – Chronic GVHD – At IRBs 0802 – Acute GVHD – At IRBs 0803 – HIV+ Lymphoma – Submitted to PRC 0804 – Peripheral T-Cell NHL: CALGB 0805 – Ph+ ALL: SWOG 0805 0901 – NST vs myeloablative – In development 0902 – Stress Reduction – Submitted to PRC

Slide 24 US Transplants on Cooperative Group Trials: Impact of the BMT CTN Number of Transplants 80% of BMT CTN transplants – allotransplants >5% of US transplants – both auto and allo >900 unrelated transplants (almost 10%) Cooperative Groups BMT CTN Total

Ann Arbor, Michigan June 7-8, 2007

BMT CTN 0901: A Multi-center Phase III Study Comparing Myeloablative to Nonmyeloablative Transplantation in Patients with Myelodysplastic Syndrome or Acute Myelogenous Leukemia BMT CTN Steering Committee Meeting October 2009

Slide 27 Reduced versus Conventional Intensity Conditioning in Patients Age with AML in CR Hypothesis Reduction in transplant-related mortality will be less than any increase in relapse rates associated with reduced intensity conditioning. DFS will increase.

Proposed Trial Design for 0901 Advanced MDS/ AML< 5% blasts 2 year Survival Patients randomized RIC regimens 1 Flu/BU* Flu/Mel MA Regimens Bu*/Flu Bu*/Cy Cy/TBI GVHD Prophylaxis T-cell replete per Institutional guidelines * IV or PO Bu 1 Bu <8mg/kg Mel <150mg/m 2

Slide 29 Proposed Phase III AML Clinical Trial Proposal: Unrelated donor transplant versus chemotherapy for high risk AML Can transplant from unrelated donors improve AML patient survival when compared to non-transplant therapies?

Slide 30 Concept of a Study Design 1.Include: AML, yrs, high-risk cytogenetics 2.Genetic assignment between allogeneic transplant (related & unrelated) and no transplant 3.Must survive minimum time frame 4.Total AML enrolled: N = Unrelated Donor: N ~ No Donor: N ~ Endpoint: Survival at 3 years. 8.Power: 80% to detect a 15% difference.

Slide 31 Selection of High-Risk AML Patients Based on Cytogenetics AML (100%) N=2000 Good Risk (20%) n=400 Int. Risk (50%) N=1000 Poor Risk (30%) N=600 Survive 6 months (80%) N=480 Sibling Donor (30%) N=144 Unrelated Donor (45%) N=216 No Donor (25%) N=120

Slide 32 Logistics and Feasibility  Requires Intergroup collaboration  Requires timely cytogenetics testing, HLA typing and donor search  DNA-based high-resolution HLA typing at diagnosis  Facilitated search of NMDP registry – NMDP’s process improvement initiative

N ATIONAL M ARROW D ONOR P ROGRAM ® Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM 33 NMDP Transplants Facilitated and Projected to 2015 Cord blood Peripheral blood stem cells Bone marrow

34 The Needs and the Barriers  There are at least 10,000 U.S. candidates annually for unrelated donor transplantation  NMDP has set a goal of 10,000 transplants in 2015 (perhaps 8,000 of these would be in the U.S.)  Barriers to meeting this goal, include referral timing, graft availability, financial issues, space and personnel shortages, etc.  One of the most significant barriers, however, is having the processes and systems that can support this level of activity

35 The Phoenix Initiative  An effort to transform the way we operate and manage the donor and patient processes  Provide more and better information  Provide quicker and better access to the worldwide pool of donors and cord blood units  Provide more predictability, reduce the pain of Unavailable donors Untimely results Surprises and last minute “revelations”  Meet the transplant center’s timeline

36 Changes to the Process  Put all the donors and all the CBUs in a single view Merge the NMDP, Cooperative Registry and BMDW lists  Provide information on DC, CBB or coop registry identity and performance  Implement a “donor readiness” score  Pre-contact adult donors who are on the search  Facilitate communication between TCs and DC/CBB  Reduce paper, increase e-communications, and increase viewability of online search-related documents

37 Summary and Conclusions  Many critical questions in transplantation can only be addressed in multicenter clinical trials  BMT CTN in collaboration with the cancer cooperative groups provides a structure for answering complex questions  The availability of alternative donors – unrelated adult, umbilical cord blood units and mismatched family members – extends transplant options to most potential candidates  To optimize the use of alternative donors and meet the growing demand, new approaches for search and donor management are needed

Go Online for More Information on Allogeneic Transplantation! Virtual Presentations on advances in risk stratification, role of ASCT in AML, options for high-risk AML and MDS patients, and ongoing and planned clinical trials for transplantation. Visit the NMDP site by clicking the logo for more information on this important resource clinicaloptions.com/oncology