Comparison of Hematopoietic cell Transplantation with CD34-selected T cell depletion to Unmanipulated Grafts for AML Marcelo C. Pasquini, MD, MS
Rationale Single center studies show reduced GVHD without increased relapse rates in AML patients receiving T cell depleted (TCD) allografts in CR 1-3 One randomized, prospective, multi-center TCD trial showed no increase in relapse in AML patients receiving TCD allografts 4 1 Aversa et al. Blood Cells Mol and Disease 28 2 Pappadopoulos et al, Blood, 1998 3 Soiffer et al; Blood 1997 4 Wagner, J. et al. Lancet 25 27
Randomized, Prospective, Multi-center T Cell Depletion Trial Wagner et al., Lancet 366:733, 25 T-cell depletion (TCD) Methods include Elutriation and T1B9 + Methotrexate Cyclosporine A + Methotrexate (M/C)
HLA-Identical Sibling-Matched, CD34 + Selected, T cell Depleted Peripheral Blood Stem Cells Following Myeloablative Conditioning For First or Second Remission Acute Myeloid Leukemia (AML): Results of Blood and Marrow Transplant Clinical Trials Network* (BMT CTN) Protocol 33 S Devine, S Carter, R Soiffer, M Pasquini, P Hari, A Stein, H Lazarus, C Linker, E Stadtmauer, E Alyea, C Keever-Taylor, and R O'Reilly * Devine, S et al; BBMT, 211
BMT CTN 33 Study Eligibility AML in CR1 or CR2 Age 18-65 HLA-identical sibling available No more than 2 induction cycles of chemotherapy required to induce remission No more than six months from CR to transplant (three months for CR2) Other standard organ function criteria No uncontrolled bacterial/fungal/viral infections Karnofsky performance status > 7% 3
BMT CTN 33 Patient Conditioning Regimen TBI 1375 cgy* Day of Tx -9-8 -7-6 -5-4 -3-2 -1 11 total doses; administered on days -9 through -6 Thiotepa @ 5mg/kg Thymoglobulin @ 2.5 mg/kg Cyclophosphamide @ 6mg/kg CliniMACS CD34-enriched cells Stem Cell Infusion
Post Processing Outcomes 7-AAD All centers were able to process grafts that met the study criteria
CD3 + Cells Infused per kg Upper limit of CD3 + dose No patients received more than 1.x1 5 /kg CD3 + cells
Final Cellular Product Summary Parameter Median CD34 + dose Range Median CD3 + dose Range Result 7.92 x 1 6 /kg 2.4-3.3 x 1 6 /kg.7 x 1 4 /kg.1 1.8 x 1 4 /kg Median Log 1 TCD 4.9 logs Range 3.2 5.9 logs All gram stains/14 day cultures were negative All endotoxin < 5. EU/kg No significant infusion related toxicities observed
Primary Endpoint 6 Month Disease-Free Survival of >75% 1..8 Probability.6.4 81.8% @ 6 months (95% CI 66.9-9.5).2 N=44. 2 4 6 8 1 12 14 16 18 2 22 24 Months Post Transplant
Secondary Endpoint Cumulative Incidence of EBV Reactivation All Patients By CR1/CR2 1. N=44 1. First CR (N=37) Second CR (N=7).8.8 Probability.6.4 13.6% (95% CI: 3.4-23.8) 18.2% @ 2 yrs Probability.6.4 18.9% @ 2 yrs.2.2. 2 4 6 8 1 12 14 16 18 2 22 24 Months Post Transplant 14.3% @ 2 yrs. 2 4 6 8 1 12 14 16 18 2 22 24 Months Post Transplant 8 patients treated for EBV DNA levels >1 copies/ml One case of PTLD with subsequent death
A Single Arm, Multi-center Phase II Trial of Transplants of HLA- Matched, 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 Morphologic Complete Remission (BMT CTN) Protocol 33 A Randomized Double-blind Trial of Fluconazole V.s Voriconazole for the Prevention of Invasive Fungal Infections in Allogeneic Blood and Marrow Transplant Patients (BMT CTN) Protocol 11 Pasquini et al, JCO in press
Enrollment Period BMT CTN 11 versus CTN 33 23 26 11 33 25 28 Enrolling Centers by Protocol, and Their Contribution to Each Study 15 3 5 23% of 11 47.5% of 33
Patients Randomized N=6 Patient Selection BMT CTN 11 BMT CTN 33 Patients Enrolled N=47 No Transplant N=1 Received Transplant N=599 Received Transplant N=44 No Transplant N=3 Eligibility Criteria: Age 18-65 HLA Match-Sibling PBSC AML in CR1 or CR2 IST Cohort Patients meeting eligibility N=84 Patients meeting eligibility N=44 TCD Cohort AML CR1 N=65 AML CR2 N=19 AML CR1 N=37 AML CR2 N=7
Demographics IST (n=84) TCD (n=44) P- value Male 56% 34%.4 Age (years) 5 > 5 57 (68%) 27 (32%) 25 (57%) 19 (43%).22 Median Age 45 48.14 Performance Score > 9 68 (81%) 34 (77%).36 Disease Status CR1 CR2 65 (77%) 19 (23%) 37 (84%) 7 (16%).37 Median follow up, months 48 (1-69) 24 (12-47) -
Cytogenetic Risk Categories by Protocol IST (n=84) TCD (n=44) P- value Favorable 9 (11%) 2 (4%).34 Intermediate 55 (65%) 28 (64%) Unfavorable 12 (14%) 11 (25%) Unknown 8 (1%) 3 (7%)
Transplant Characteristics Conditioning Regimens Cy/TBI/Thio/ATG Cy+TBI Bu+Cy Bu+Flu TBI+VP16 GvHD Prophylaxis T-cell depletion FK56+MTX MTX+CsA IST (n=84) 35 (42%) 27 (31%) 14 (17%) 9 (1%) 48 (54%) 36 (46%) TCD (n=44) 44 (1%) 44 (1%)
Neutrophil Engraftment by Graft Manipulation 1 9 TCD, 1% @ Day 3 1 9 Probability, % 8 7 6 5 4 3 IST, 96% @ Day 3 8 7 6 5 4 3 2 1 P=.2 1 2 3 4 5 6 Weeks 2 1 BMTCTN33-11-11_1.ppt
Cumulative Incidence of Platelet Engraftment by Graft Manipulation 1 9 8 TCD, 98% @ Day 1 IST, 88% @ Day 1 1 9 8 Probability, % 7 6 5 4 3 7 6 5 4 3 2 2 1 P=.2 1 2 3 4 5 6 Months 1 BMTCTN33-11-11_2.ppt
Cumulative Incidence of Grades II-IV IV Acute GVHD 1 9 8 P=.7 1 9 8 Probability, % 7 6 5 4 3 IST, 39% @ Day 1 7 6 5 4 3 2 2 1 TCD, 23% @ Day 1 1 2 4 6 8 1 12 14 Weeks BMTCTN33-11-11_3.ppt
Cumulative Incidence of III-IV IV Acute GVHD 1 9 8 P=.3 1 9 8 Probability, % 7 6 5 4 3 7 6 5 4 3 2 1 TCD, 4% @ Day 1 IST, 9% @ Day 1 2 1 2 4 6 8 1 12 14 Weeks BMTCTN33-11-11_4.ppt
Cumulative Incidences of Chronic GVHD 1 1 9 P<.1 9 8 8 Probability, % 7 6 5 4 3 2 IST, 5% @ 2 years TCD, 19% @ 2 years 7 6 5 4 3 2 1 1 1 2 3 Years BMTCTN33-11-11_5.ppt
Cumulative Incidence of Leukemia Relapse 1 9 P=.57 1 9 8 8 Probability, % 7 6 5 4 3 IST, 27% @ 2 years 7 6 5 4 3 2 TCD, 24% @ 2 years 2 1 1 1 2 3 Years BMTCTN33-11-11_6.ppt
Cumulative Incidence of Treatment-related related Mortality 1 9 8 P=.95 1 9 8 Probability, % 7 6 5 4 3 TCD, 21% @ 2 years 7 6 5 4 3 2 1 IST, 19% @ 2 years 2 1 1 2 3 Years BMTCTN33-11-11_8.ppt
Overall Survival 1 1 9 9 8 8 Probability, % 7 6 5 4 3 IST, 65% @ 2 years TCD, 59% @ 2 years 7 6 5 4 3 2 2 1 P=.96* 1 2 3 * Log rank p-value Years 1 BMTCTN33-11-11_9.ppt
Disease-Free Survival 1 1 9 9 8 8 Probability, % 7 6 5 4 3 TCD, 55% @ 2 years IST, 54% @ 2 years 7 6 5 4 3 2 2 1 P=.6 1 1 2 3 Years BMTCTN33-11-11_1.ppt
Probability of GVHD-free Survival after HCT, by Protocol 1 1 9 9 8 8 Probability, % 7 6 5 4 3 TCD, 42% @ 2 years 7 6 5 4 3 2 2 1 P<.6 IST, 19% @ 2 years 1 2 3 Years 1
TCD vs IST Comparison Conclusions TCD with myeloablative in early risk AML shows lower rates of chronic GVHD and comparable: OS, LFS, engraftment, acute GVHD, TRM and relapse.
BMT CTN 33 Team Robert Soiffer Steven Devine Richard O Reilly Adam Mendizabal Carolyn Keever-Taylor Shelly Carter Miltenyi Biotec Patients Participant Transplant Center Acknowledgements BMT CTN Mary M. Horowitz Brent Logan BMTCTN GVHD Committee Joseph Antin Daniel Weisdorf Richard Jones John Levine Amin Alousi Steven Pavletic Mary Flowers Daniel Couriel David Porter David Jacobs
BMT CTN Centers, 212 >115 centers have enrolled >42 patients since 23 = Core Centers = PBMTC Centers = Affiliate Centers Mmh11_9.ppt