1988 199 1992 1994 1996 1998 2 22 24 26 28 21 212 214 216 218 Adult Donors Cord Blood Units The National Donor Program Graft Sources for Hematopoietic Cell Transplantation Dennis L. Confer, MD Chief Medical Officer, NMDP/Be The Match Associate Scientific Director, CIBMTR 1968 First successful related donor transplants 1973 First successful unrelated donor transplant 1979 Laura Graves URD transplant for ALL 1986 NBMDR established 1987 Two transplants completed Today: World s largest registry >14 million donors >23, CBUs >73, Transplants completed The Success of NMDP is coupled to 29 years of uninterrupted Federal support 4/18/216 2 Simon Bostic, URD Transplant Recipient The National Donor Program 1968 First successful related donor transplants 1973 First successful unrelated donor transplant 1979 Laura Graves URD transplant for ALL 1986 NBMDR established 1987 Two transplants completed Today: World s largest registry >14 million donors >23, CBUs >73, Transplants completed The Success of NMDP is coupled to 29 years of uninterrupted Federal support 4/18/216 3 4/18/216 4 The National Donor Program Non-profit 51(c)3 corporation headquartered in Minneapolis, Minnesota 9 employees $4 million annual budget Contracted to operate the legislatively authorized CW Bill Young Cell Transplantation Program Four separate contracts BMCC, CBCC, SPA/OPA and SCTOD bloodcell.transplant.hrsa.gov branding www.bethematch.org www.bethematchclinical.org National Donor Program Adult Donors & Cord Blood Units April 1, 216 15,, 14,, 13,, 12,, 11,, 1,, 9,, 8,, 7,, 6,, 5,, 4,, 3,, 2,, 1,, Adult Donors 14,199,518 CBUs 231,977 24 22 2 18 16 14 12 1 8 6 4 2 4/18/216 5 4/18/216 6 1
19 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 28 29 21 211 Survival Survival Survival 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 28 29 21 211 212 213 214 215 Number of Transplants 65 6 55 5 45 4 35 3 25 2 15 1 5 NMDP Transplants Facilitated by Fiscal Year 1987 215 >73, Total Cord blood Peripheral blood stem cells Bone marrow Transplants by Recipient Age 7 4/18/216 Year of Transplant 4/18/216 Survival After Unrelated Donor Transplantation Age <5 years, myeloablative conditioning, acute leukemia in remission or MDS 1 9 8 7 6 5 4 3 2 1 Adjusted 1-year Overall Survival Odds of 1-year survival increased by 8% per year (95% CI, 7-9%) on average between 199 and 211 Year of Transplant 1..9.8.7.6.5.4.3.2.1. Influence of HLA 8/8 Match 7/8 Match 6/8 Match 1. 1. Early Disease Stage Intermediate Disease Stage Advanced Disease Stage.9.9.8.8.7.7 12 24 36 48 6.6.5.4.3.2.1. 12 24 36 48 6 S. Lee, et al. Blood 27 Showed impact of single allele mismatch at A, B, C and DRB1.6.5.4.3.2.1. 12 24 36 48 6 Months after transplant Months after transplant Months after transplant Other HLA/Donor Characteristics Associated with Outcome Low-expression HLA alleles (DQ, DP, DRB3,4,5) Permissive versus non-permissive DP mismatches Multiple mismatches Donor age - age >5 about equivalent to a single locus mismatch Non-HLA genomics KIR Phenotype One-year Survival by Year of Transplant, Donor and Age, 1 8 6 4 2 HLA-matched siblings, Age < 5 Unrelated donors, Age < 5 11 Acute Leukemia, CML or MDS early disease status. 12 2
Incidence, % Incidence, % 1987 1988 1989 199 1991 1992 1993 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 27 28 29 21 211 212 213 214 215 Number of Transplants 65 6 55 5 45 4 35 NMDP Transplants Facilitated by Fiscal Year 1987 214 >73, Total Cord blood Peripheral blood stem cells Bone marrow BMT CTN Protocol 21 Results of a Phase III Randomized Multicenter Trial of HLA compatible Unrelated Donor Transplantation: G-CSF Mobilized Peripheral Blood Stem Cells () Versus Bone 3 25 2 15 1 5 13 4/18/216 Year of Transplant Study Characteristics Design: Randomized, multicenter trial. Primary endpoint: Two-year survival by intent-to-treat. Randomization: vs. marrow, 1:1. Stratification: Transplant center and disease risk. Accrual: 55 donor-recipient pairs. Power: 8% to detect a 12.5% difference, alpha.5. Enrollment: March 31 st, 24 to September 9 th, 29. Analysis: as of November 15 th, 211. Median follow-up: 36 months BMT CTN 21 1 9 8 7 6 5 4 3 2 1 Analysis after Transplantation Overall Survival Disease-free Survival 2-year point P value =.335 2-year point P value =.382 6 12 18 24 3 36 6 12 18 24 3 36 Months Preplanned subset analyses did not find study arm interaction with: -Disease Risk -Donor HLA matching -Patient Age BMT CTN 21 1 9 8 7 6 5 4 3 2 1 Analysis after Transplantation Non-relapse Mortality Relapse 1 9 8 7 6 5 4 3 2 1 P value =.986 P value =.735 6 12 18 24 3 36 6 12 18 24 3 36 Months BMT CTN 21 1 9 8 7 6 5 4 3 2 1 Engraftment after Transplantation Neutrophils Platelets > 2k 1 1 9 9 8 8 7 7 6 6 5 5 days 7 days 5 4 4 3 3 2 2 1 P <.1 P <.1 1 7 14 21 28 35 42 49 56 3 6 9 12 15 18 Days BMT CTN 21 3
Incidence, % Incidence, % Acute Graft-versus-Host Disease (GVHD) Grades 2-4 Grades 3-4 1 9 8 7 6 5 4 3 2 1 p-value=.768 p-value=.346 1 9 8 7 6 5 4 3 2 1 3 6 9 12 15 18 3 6 9 12 15 18 Days BMT CTN 21 1 9 8 7 6 5 4 3 2 Overall Chronic GVHD P value Chronic Extensive Off therapy at 2 yrs 32% 57% 48% 37% P<.1 P=.26 1 9 8 7 6 5 4 3 2 1 P value =.14 1 12 24 Months BMT CTN 21 Summary Survival is not different after marrow or transplants from unrelated donors. Other outcomes are similar, with the exception of better engraftment and more chronic extensive GVHD with. Is the shift to greater use justified? Patients Without an Adult Donor May be Helped by Banked Umbilical Cord Blood Advantages: Immediately available (important for patients with rapidly progressive diseases) No risk to donor Allows more HLA-mismatch with lower risk of GVHD Disadvantages: Low cell numbers - inadequate cell dose for many adults, requiring two units (expensive) Slow hematopoietic recovery and higher risk of graft failure BMT CTN 21 Cord Blood Transplantation Multiple studies from individual centers, Eurocord, the NYBC, EBMT and CIBMTR document that Umbilical Cord Blood cells Can establish durable hematopoiesis Have potent graft-versus-tumor effects Can lead to successful transplant outcomes in a variety of malignant and non-malignant diseases in adults and children Outcomes of UCB transplants have clearly improved over time 2 Year Survival After Cord Blood Transplants for ALL, AML and MDS 1 9 8 7 6 5 4 3 2 1 1996-99 2-5 26-11 Children (<16) Adults 23 24 4
Incidence, % Leukemia-free Survival in Children depends on HLA Match and Cell Dose: Better, the Same or Slightly Worse than Matched Bone (Eapen, Lancet, 27) 1 Leukemia-free Survival In Adults Transplantation in Remission: Slightly worse than Matched or Peripheral Blood 1 Eapen et al; Lancet Oncol 21 8 CB matched (n=35), 6% 6 CB 1-Ag MM high (n=157), 41% 4 2 BM matched (n=369), 4% CB 1-Ag MM low (n=44), 36% BM MM (n=123), 3% CB 2-Ag MM (n=267), 33% 1 2 3 4 5 Years 8 8/8 PBPC, 5% 6 8/8 BM, 52% 4 7/8 PBPC 39% 7/8 BM, 41% 2 4-6/6 UCB, 44% Months 6 12 18 24 25 Lesser (intermediate resolution A, B; high resolution DRB1) vs. Allele-level HLA-match Loci mismatched using usual typing Loci mismatched using high resolution typing for A, B, C, DRB1 5 4 3 2 1 2 11% 31% 49% 1% 1 1% 8% 22% 44% 25% 4% 18% 24% 54% 27 Effect of Allele-level Matching at A, B, C, DRB1 on Transplant-related Mortality after Cord Blood Transplantation 1 8 6 4 2 Likely to change the paradigm for cord selection 4/8 (37%) 5/8 (34%) 6/8 (26%) Eapen et al; Lancet Oncol 211 P <.1 3/8 (41%) 7/8 (26%) 8/8 (9%) 1 Note very 2 low TRM with 3 Years 8/8 match Cell Dose Major limitation to Cord Blood Transplantation is the small number of cells in each unit Slow hematopoietic recovery Slow immune recovery Graft failure Strategies: Selection of large units Double cord transplantation (expensive) Expansion and homing techniques (in development, often requires two units) 29 4/18/216 A Comprehensive Model for Registry Match Rates N Engl J Med 214;371:339-48 3 5
8/8 match likelihoods by year-end using current donor availability, extending recruitment trends to 217 4/18/216 31 4/18/216 32 5/6 CBU match rates for children by year Cell Dose 2.5 x 1^7 per Kg 5/6 CBU match rates for adults by year Cell Dose 2.5 x 1^7 per Kg 4/18/216 33 4/18/216 34 The New Alternative Haploidentical In Europe, haploidentical transplants using T-cell depleted peripheral blood grafts have been used for a small but important proportion of transplants In the US, very few haploidentical transplants were performed until the last five years No approved CD34 selection or T-cell depletion device available Introduction of the Johns Hopkins approach using post-transplant cyclophosphamide increased interest Technically simple Costs similar to HLA-identical sibling transplant Cyclophosphamide-induced tolerance anti-hsv anti-cmv Proliferating ALLOREACTIVE cells are killed anti-cmv anti-hsv Non-proliferating non-alloreactive cells are spared 35 6
Number of Transplants BMT CTN PROTOCOL #63 A Phase II Trial of Reduced Intensity Conditioning and Transplantation of Partially HLA-Mismatched Bone for Patients with Hematologic Malignancies BMT CTN PROTOCOL #64 A Phase II Trial of Reduced Intensity Conditioning and Transplantation of Umbilical Cord Blood from Unrelated Donors in Patients with Hematologic Malignancies Brunstein, Fuchs, et al Blood 211 Parallel Designs Age 7 Diseases Leukemia: high risk, in remission Lymphoma Hodgkin, mantle cell, or large cell: chemosensitive relapse, not eligible for autologous SCT Follicular or marginal zone: multiply relapsed Adequate organ function, performance score >6% N=5 in each trial Primary endpoint: 6-month survival 38 AGVHD 4/25% CGVHD 25% AGVHD 4/% CGVHD 13% 1 Comparisons of clinical outcomes: UCB vs Haplo (BMT CTN 63/64) Overall survival 84% Progression-free survival 1 8 68% 8 6 4 2 74% 52% haplo 54% 54% cord 46% 39% 6 4 2 haplo: 4% cord: 36% cord: 38% haplo: 35% Brunstein, et al 211 39 12 24 36 Months Post Transplant 12 24 36 Months Post Transplant Eapen, et al BBMT 214 16 14 12 1 8 6 4 2 Haplo-Identical Transplantations Hematologic Malignancy Other centers Years of 63/64 trial CTN 63 centers Year 63/64 paper was published 28 29 21 211 212 213 Distribution of Alternative (not an HLAmatched adult donor) Graft Sources 25% 2% 21 N=1646 14% 41% 14% 18% 214 N=196 31% 37% Mism unrelated Haploident Single Cord Double Cord 42 7
1 Overall Survival Adjusted for age, Disease Risk, secondary AML 8 6 4 2 Myeloablative 1245 MUD/14 Haplo MUD 5% (47-53) HAPLO 45% (36-54) HR.93 (95% CI.7 1.22), p=.58 1 2 3 Years Reduced Intensity 737 MUD/88 Haplo HAPLO 46% (35-56) MUD 44% (4-47) 1 8 6 4 2 HR 1.6 (95% CI.79 1.43), p=.7 1 2 3 Years Ciurea, et al Blood 215 Limitation of this Analysis - POWER COMPARISONS OF 3-Year SURVIVAL Matched Unrelated Myeloablative: 1245 MUD/14 Haplo Point Estimate Lower Bound Upper Bound Reduced Intensity: 737 MUD/88 Haplo Point Estimate Lower Bound Upper Bound 5% 47% 53% 44% 4% 47% Haploidentical 45% 36% 54% 46% 35% 56% 44 Some Unknowns About Haplos with Post-Transplant Cyclophosphamide Long-term control of malignancy Engraftment/outcomes in non-malignant diseases Outcomes in Children Suitability of Older Donors More graft failure Clonal hematopoiesis more common with older donors uncertain significance Able to donate bone marrow? Question: might results be better using posttransplant Cy with younger mismatched unrelated bone marrow donors with appropriate CMV/KIR status? Summary Few patients will lack an acceptable donor/graft source All donor/graft types (8/8 or 7/8 adult, haplo, cord) produce survival outcomes that, if not identical, are in the same range Maximum differences in survival, compared to 8/8 adult donor, are in the range of 1%-15% Outcomes now more driven by patient and disease factors 45 46 How Universal Donor Availability Might Change Things HCT more likely to impact treatment of a disease since it is available to more people Choice of donor/graft will depend on factors other than HLA Availability Other donor characteristics: age, CMV status, etc. Disease recurrence risk Infection risk Planned conditioning regimen Cost 47 Relative risks and benefits of different cell sources: acquisition issues Suitable HLA match available Availability UD Cord Haplo 9% Caucasian Much lower for other ancestries Variable Donor attrition Increased chance (especially rarer tissue types) Predictable Usually, but other donor characteristics might not be optimal Generally predictable Speed of acquisition Medium Fast Fast Cell dose Predictable Low High Second donations/dli Cost Possible Not possible Possible Higher than sibling Much higher Equal to sibling 8
Relative risks and benefits of different cell sources: clinical outcomes UD Cord Haplo* Engraftment Fast Slow Fast Graft failure Rare More common Slightly more common GvHD Relapse High (esp with mismatch) Possibly lower than sibling Lower than expected with mismatch Possibly lower than sibling Low due to techniques used Higher A Side Note: Implications of Better Chronic GVHD Prevention Possible with both CD34 selection and post-transplant cyclophosphamide in both myeloablative and reduced intensity settings Makes allogeneic transplantation more attractive for non-malignant diseases such as Sickle cell disease Inborn errors of metabolism Lower risk MDS * In adults with malignancy 5 Conclusions HCT as a therapy should be considered early based on relative efficacy/toxicity compared to non-hct therapy not donor availability Timing should be optimized Randomized comparisons (rather than biologic assignment, ie., donor vs no donor) of HCT vs non-hct therapy are now possible in many situations, particularly in adults with hematologic malignancies, and should be pursued Thank You! 51 52 9