A Phase 2 interventional study of CD34+ selection with CliniMACS device in Leukemia, Myelocytic, Acute, sponsored by National Heart, Lung, and Blood Institute (NHLBI). Completed at 8 sites in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2021-11-01.
Sponsored by National Heart, Lung, and Blood Institute (NHLBI) · Phase 2, Interventional, and Treatment
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.
BACKGROUND:
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.
DESIGN NARRATIVE:
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.
5,441 studies on the registry are indexed under Leukemia; 636 are open to participants now.
This study's enrollment of 47 is above the median of 38 across 4,247 interventional studies indexed under Leukemia.
Browse Leukemia studies →National Heart, Lung, and Blood Institute (NHLBI) is the lead sponsor of 1,117 studies on the registry; 71 are open to participants now.
Of its 57 completed or terminated interventional studies of FDA-regulated products, 49 (86%) have results posted.
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Patients with AML with or without prior history of myelodysplastic syndrome based on the World Health Organization criteria at the following stages:
Exclusion Criteria:
T cell depletion using Miltenyi device
Biological: 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
Also known as: T Cell Depletion
Probability of Disease-free Survival (DFS) at 6 Months Post-transplant (Death or Relapse Will be Considered Events for This Endpoint)
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.
Time frame: 6 months
Leukemia Relapse
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.
Time frame: Months 12 and 36
Neutrophil Engraftment
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.
Time frame: 28 day
Platelet Engraftment
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.
Time frame: 6 Months
Graft Failure
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.
Time frame: Day 100
Acute Graft Versus Host Disease (GVHD)
Incidence and severity of acute GVHD will be graded according to the BMT CTN MOP.
Time frame: Day 100
Chronic Graft Versus Host Disease (GVHD)
Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP.
Time frame: Year 2
Transplant Related Mortality
Death occurring in a patient in continuing complete remission.
Time frame: Months 12, 24, and 36
Determination of Infusional Toxicity
Time frame: 28 day
Disease-free Survival (DFS)
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.
Time frame: Months 6, 12, and 36
Overall Survival
Overall survival is defined as time from transplant to death or last follow-up.
Time frame: Months 12 and 36
CD34+ and CD3+ Cell Doses
Total CD34+ and CD3+ cell doses will be calculated based on results of flow cytometric analysis.
Time frame: Day 0
Post-transplant Lymphoproliferative Disorder (PTLD)
PTLD is defined as increased Epstein Barr Virus viremia requiring clinical intervention.
Time frame: Year 2
Patients were recruited from October2005 through December 2008
| Milestone | T Cell Depletion |
|---|---|
| Started | 47 |
| Completed | 44 |
| Not completed | 3 |
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.
| percentage of patients | T Cell Depletion |
|---|---|
| Probability of Disease-free Survival (DFS) at 6 Months Post-transplant (Death or Relapse Will be Considered Events for This Endpoint) | 81.8 (70.3 to 93.4) |
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.
| percentage of participants | T Cell Depletion |
|---|---|
| 12 months | 20.6 (8.4 to 32.8) |
| 36 months | 23.7 (10.5 to 37.0) |
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.
| days | T Cell Depletion |
|---|---|
| Neutrophil Engraftment | 12 (9 to 19) |
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.
| days | T Cell Depletion |
|---|---|
| Platelet Engraftment | 16 (13 to 159) |
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.
| participants | T Cell Depletion |
|---|---|
| Primary Graft Failure | 0 |
| Secondary Graft Failure | 1 |
Incidence and severity of acute GVHD will be graded according to the BMT CTN MOP.
| percentage of participants | T Cell Depletion |
|---|---|
| Grades II - IV | 22.7 (10.2 to 35.3) |
| Grades III - IV | 4.5 (0 to 10.8) |
Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP.
| percentage of participants | T Cell Depletion |
|---|---|
| Limited/extensive | 19.0 (6.8 to 31.1) |
| Extensive only | 6.8 (0 to 14.4) |
Death occurring in a patient in continuing complete remission.
| percentage of participants | T Cell Depletion |
|---|---|
| 12 months | 14 (3.4 to 24) |
| 24 months | 20 (7.1 to 32.7) |
| 36 months | 23.2 (9.3 to 37.1) |
No measurements were reported for this outcome.
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.
| percentage of participants | T Cell Depletion |
|---|---|
| 6 months | 81.8 (70.3 to 93.4) |
| 12 months | 66 (52 to 80) |
| 36 months | 53 (37 to 69) |
Overall survival is defined as time from transplant to death or last follow-up.
| percentage of participants | T Cell Depletion |
|---|---|
| 12 months | 77 (65 to 90) |
| 36 months | 56 (40 to 73) |
Total CD34+ and CD3+ cell doses will be calculated based on results of flow cytometric analysis.
| cells per kilogram | T Cell Depletion |
|---|---|
| CD34+ (x10^6) | 7.9 (2.4 to 31.3) |
| CD3+ (x10^3) | 6.6 (1.1 to 84.9) |
PTLD is defined as increased Epstein Barr Virus viremia requiring clinical intervention.
| participants | T Cell Depletion |
|---|---|
| Post-transplant Lymphoproliferative Disorder (PTLD) | 8 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| T Cell Depletion | — | 0/47 (0%) | 0/47 (0%) |
| Age, Customized(participants) | T Cell Depletion |
|---|---|
| <20 | 0 |
| 20-29 | 7 |
| 30-39 | 4 |
| 40-49 | 14 |
| 50-59 | 19 |
| Sex: Female, Male(Participants) | T Cell Depletion |
|---|---|
| Female | 28 |
| Male | 16 |
| Race/Ethnicity, Customized(participants) | T Cell Depletion |
|---|---|
| White | 42 |
| Other | 2 |
| Region of Enrollment(participants) | T Cell Depletion |
|---|---|
| United States | 44 |
| Karnofsky Performance Status(participants) | T Cell Depletion |
|---|---|
| 100% | 17 |
| 90% | 17 |
| 80% | 8 |
| 70% | 2 |
| Leukemia stage(participants) | T Cell Depletion |
|---|---|
| CR1 | 37 |
| CR2 | 7 |
| Cytogenetic risk(participants) | T Cell Depletion |
|---|---|
| Favorable | 1 |
| Intermediate | 28 |
| Unfavorable | 14 |
| Unknown | 1 |
| Recipient CMV Status(participants) | T Cell Depletion |
|---|---|
| Positive | 17 |
| Negative | 27 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
Supporting information: Study protocol, Icf
This study is completed, as verified in Aug 2017. You cannot join it, but the record below documents what was studied.
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