Acute Myeloid Leukemia T Cell Depletion to Improve Transplants in Adults With Acute Myeloid Leukemia (BMT CTN 0303)
This study is a single arm Phase II, multicenter trial. It is designed to determine whether the anticipated endpoints for a T cell depleted transplant arm of a planned prospective randomized trial comparing T cell depleted and unmodified hematopoietic allografts are likely to be achieved in a multicenter study conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN or Network). The study population is patients with acute myeloid leukemia (AML) in first or second morphologic complete remission. The enrollment is 45 patients.
Based on published results of unmodified transplants from HLA-matched siblings applied to patients with AML in first or second morphologic complete remission, a significant improvement in results with a graft modified as specified in this protocol would be expected if disease-free survival (DFS) at 6 months was greater than 75%, the true incidence of transplant-related mortality at 1 year was less than 30%, and the DFS rate at 2 years was greater 70% for patients transplanted in first remission and less than 60% for patients transplanted in second remission. Additional secondary endpoints include the following: graft failure rate and incidences of acute grade II-IV and chronic graft-versus-host disease (GVHD). Additionally, the trial will have target specific doses of CD34+ progenitors and CD3+ T cells to be obtained following fractionation with the CliniMACS system. Based on the results of this trial, a Phase III trial comparing T cell depleted peripheral blood stem cell transplants (PBSCT) with unmanipulated bone marrow or unmanipulated PBSCT will be designed.
Leukemia, Myelocytic, Acute
Device: CD34+ selection with CliniMACS device
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Single Arm, Multicenter 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 #0303)|
- Probability of Disease-free Survival (DFS) at 6 Months Post-transplant (Death or Relapse Will be Considered Events for This Endpoint) [ Time Frame: 6 months ] [ Designated as safety issue: No ]The primary analysis will consist of estimating the 6-month DFS (from day of enrollment) probability based on the Kaplan-Meier product limit estimator. The 6-month DFS probability and confidence interval will be calculated. All registered patients will be considered for this analysis.
- Leukemia Relapse [ Time Frame: Months 12 and 36 ] [ Designated as safety issue: Yes ]To assess the incidence of acute leukemia relapse from day of transplant, a cumulative incidence curve will be computed along with a 95% confidence interval. Death prior to relapse will be considered as a competing risk.
- Neutrophil Engraftment [ Time Frame: 28 day ] [ Designated as safety issue: Yes ]Time to neutrophil engraftment is measured by determining the first of three consecutive measurements of absolute neutrophil count ≥ 500/uL following conditioning regimen induced nadir, starting from Day 0.
- Platelet Engraftment [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]Time to platelet engraftment is measured by determining the first of three consecutive measurements of platelet count ≥ 20,000/uL without platelet transfusion support for seven days, starting from Day 0.
- Graft Failure [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]Primary graft failure is defined as the failure to achieve an ANC > 500 cells/µL by Day +30. Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in neutrophil counts < 500 cells/µL, unresponsive to growth factor therapy.
- Acute Graft Versus Host Disease (GVHD) [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]Incidence and severity of acute GVHD will be graded according to the BMT CTN MOP.
- Chronic Graft Versus Host Disease (GVHD) [ Time Frame: Year 2 ] [ Designated as safety issue: Yes ]Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP.
- Transplant Related Mortality [ Time Frame: Months 12, 24, and 36 ] [ Designated as safety issue: Yes ]Death occurring in a patient in continuing complete remission.
- Determination of Infusional Toxicity [ Time Frame: 28 day ] [ Designated as safety issue: Yes ]
- Disease-free Survival (DFS) [ Time Frame: Months 6, 12, and 36 ] [ Designated as safety issue: Yes ]DFS is defined as the minimum time interval of times to relapse/recurrence, to death or to the last follow-up, from the time of transplant.
- Overall Survival [ Time Frame: Months 12 and 36 ] [ Designated as safety issue: Yes ]Overall survival is defined as time from transplant to death or last follow-up.
- CD34+ and CD3+ Cell Doses [ Time Frame: Day 0 ] [ Designated as safety issue: No ]Total CD34+ and CD3+ cell doses will be calculated based on results of flow cytometric analysis.
- Post-transplant Lymphoproliferative Disorder (PTLD) [ Time Frame: Year 2 ] [ Designated as safety issue: Yes ]PTLD is defined as increased Epstein Barr Virus viremia requiring clinical intervention.
|Study Start Date:||June 2005|
|Study Completion Date:||December 2013|
|Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
Experimental: CD34+ selection with CliniMACS device
T cell depletion using Miltenyi device
Device: CD34+ selection with CliniMACS device
CD34+ cell selection will be performed according to procedures given in the CliniMACS Users Operating Manual and institutional Standard Operating Procedures (SOPs) in place and validated at the study sites. CliniMACS (Miltenyi device) to target CD34+ >5 x 10*6/kg and CD3+ < 1 x 10*5/kg
Other Name: T Cell Depletion
Allogeneic hematopoietic cell transplantation is an accepted therapy for AML. Transplants of unmodified HLA-matched related bone marrow or peripheral blood stem cells following conditioning with total body irradiation (TBI) and cyclophosphamide or VP-16 or busulfan and cyclophosphamide have led to sustained DFS rates of 45-60% for adults transplanted in first complete remission (CR1) and 40-53% for patients transplanted in second complete remission (CR2). In several single center and multicenter cooperative group prospective trials comparing HLA-matched allogeneic transplants to chemotherapy in the treatment of AML in CR1, DFS rates for the transplant arm were almost invariably superior; however, these advantages were statistically significant in only a minority of the cooperative group studies conducted. In each study, the risk of relapse was significantly lower for patients receiving allogeneic transplants. However, this advantage was counterbalanced by transplant-related mortality, principally reflecting infections complicating GVHD and its treatment.
Despite increased risks of infection, development of effective T cell depletion (TCD) techniques for prevention of GVHD and tolerable modifications of regimens for pre-transplant cytoreduction that secure consistent engraftment offer the potential for significant decreases in transplant-related mortality. Furthermore, the use of TCD transplants in the treatment of patients with AML is not associated with substantial increases in the incidence of relapse. Several single center trials indicate highly encouraging long-term results, particularly for patients with AML in CR1 or CR2. Although the number of cases in each single center series is limited, the consistency of the results suggests that the use of an effective technique for TCD together with an adequate cytoreductive regimen might yield transplant results superior to those achieved with unmodified grafts.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00201240
|United States, California|
|City of Hope National Medical Center|
|Duarte, California, United States, 91010|
|University of California, San Francisco|
|San Francisco, California, United States, 94143|
|United States, Massachusetts|
|Dana Farber Cancer Institute/Brigham & Women's Hospital|
|Boston, Massachusetts, United States, 02114|
|United States, New York|
|Memorial Sloan-Kettering Cancer Center|
|New York City, New York, United States, 10021|
|United States, Ohio|
|University Hospitals of Cleveland/Case Western|
|Cleveland, Ohio, United States, 44106|
|Ohio State/Arthur G. James Cancer Hospital|
|Columbus, Ohio, United States, 43210|
|United States, Pennsylvania|
|University of Pennsylvania Cancer Center|
|Philadelphia, Pennsylvania, United States, 19104|
|United States, Wisconsin|
|Medical College of Wisconsin|
|Milwaukee, Wisconsin, United States, 53211|
|Study Chair:||Steven Devine, MD||Ohio State/Arthur G. James Cancer Hospital|
|Principal Investigator:||Parameswaran Hari, MD||Medical College of Wisconsin|
|Principal Investigator:||Hillard Lazarus, MD||University Hospitals of Cleveland/Case Western|
|Principal Investigator:||Lloyd Damon, MD||University of California, San Francisco|
|Study Chair:||Richard O'Reilly, MD||Memorial Sloan Kettering Cancer Center|
|Principal Investigator:||Robert Soiffer, MD||Dana Farber Cancer Institute/Brigham & Women's Hospital|
|Principal Investigator:||Anthony Stein, MD||City of Hope National Medical Center|
|Principal Investigator:||John DiPersio, MD, PhD||Washington University/Barnes Jewish Hospital|
|Principal Investigator:||Edward Stadtmauer, MD||University of Pennsylvania|