Leukemia, Myelocytic, Acute
Conditions
Brief summary
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.
Detailed description
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.
Interventions
BIOLOGICALCD34+ 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
Sponsors
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patients with AML with or without prior history of myelodysplastic syndrome based on the World Health Organization criteria at the following stages: * First morphologic complete remission (CR) * Second morphologic CR * If prior history of central nervous system (CNS) involvement, no evidence of active CNS leukemia during the pre-transplant evaluation (no evidence of leukemic blasts in cerebrospinal fluid) * First or second CR was achieved after no more than two cycles of induction (or re-induction for patients in second CR) chemotherapy * No more than 6 months elapsed from documentation of CR to transplant for patients in first CR, or 3 months for patients in second CR. * A 6/6 HLA antigen (A, B, DRB1)-compatible sibling donor; the match may be determined at serologic level for HLA-A and HLA-B loci; DRB1 must be matched at least at low-resolution using DNA typing techniques; HLA-C will be typed at the serologic level, but not included in the match algorithm * Karnofsky performance status greater than 70% * Life expectancy greater than 8 weeks * Diffusing capacity of the lung for carbon monoxide (DLCO) of at least 40% (corrected for hemoglobin) with no symptomatic pulmonary disease * Left ventricular ejection fraction (LVEF) by Multi Gated Acquisition Scan (MUGA) or echocardiogram greater than 40% * Serum creatinine greater than 2 mg/dL, bilirubin greater than 2 mg/dL, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at least 3 times the upper limit of normal at time of enrollment * Willingness of both the patient and the donor to participate
Exclusion criteria
* M3-AML (acute promyelocytic leukemia) in first CR * Acute leukemia following blast transformation of prior chronic myelogenous leukemia (CML) or other myeloproliferative disease * M4Eo-AML with inv 16 in first CR * AML with t(8;21) in first CR * Participation in other clinical trials that involve investigational drugs or devices except with permission from the Medical Monitor * Evidence of active Hepatitis B or C infection or evidence of cirrhosis * HIV positive * Uncontrolled diabetes mellitus * If proven or probable invasive fungal infection, infection must be controlled; patients may be on prophylactic anti-fungal agents, but are not permitted to be on anti-fungal agents for therapeutic purposes (i.e., active treatment for disease) * Uncontrolled viral or bacterial infection (currently taking medication without clinical improvement) * Documented allergy to iron dextran or murine proteins * Pregnant or breastfeeding; women of childbearing age must avoid becoming pregnant while in the study * Prior autologous or allogeneic hematopoietic stem cell transplantation (HSCT)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Disease-free Survival (DFS) at 6 Months Post-transplant (Death or Relapse Will be Considered Events for This Endpoint) | 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Leukemia Relapse | Months 12 and 36 | 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 | 28 day | 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 | 6 Months | 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 | Day 100 | 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) | Day 100 | Incidence and severity of acute GVHD will be graded according to the BMT CTN MOP. |
| Chronic Graft Versus Host Disease (GVHD) | Year 2 | Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP. |
| Transplant Related Mortality | Months 12, 24, and 36 | Death occurring in a patient in continuing complete remission. |
| Determination of Infusional Toxicity | 28 day | — |
| Disease-free Survival (DFS) | Months 6, 12, and 36 | 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 | Months 12 and 36 | Overall survival is defined as time from transplant to death or last follow-up. |
| CD34+ and CD3+ Cell Doses | Day 0 | Total CD34+ and CD3+ cell doses will be calculated based on results of flow cytometric analysis. |
| Post-transplant Lymphoproliferative Disorder (PTLD) | Year 2 | PTLD is defined as increased Epstein Barr Virus viremia requiring clinical intervention. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from October2005 through December 2008
Participants by arm
| Arm | Count |
|---|---|
| T Cell Depletion T cell depletion using Miltenyi device for patients with AML in first or second complete remission | 44 |
| Total | 44 |
Baseline characteristics
| Characteristic | T Cell Depletion |
|---|---|
| Age, Customized <20 | 0 participants |
| Age, Customized 20-29 | 7 participants |
| Age, Customized 30-39 | 4 participants |
| Age, Customized 40-49 | 14 participants |
| Age, Customized 50-59 | 19 participants |
| Cytogenetic risk Favorable | 1 participants |
| Cytogenetic risk Intermediate | 28 participants |
| Cytogenetic risk Unfavorable | 14 participants |
| Cytogenetic risk Unknown | 1 participants |
| Karnofsky Performance Status 100% | 17 participants |
| Karnofsky Performance Status 70% | 2 participants |
| Karnofsky Performance Status 80% | 8 participants |
| Karnofsky Performance Status 90% | 17 participants |
| Leukemia stage CR1 | 37 participants |
| Leukemia stage CR2 | 7 participants |
| Race/Ethnicity, Customized Other | 2 participants |
| Race/Ethnicity, Customized White | 42 participants |
| Recipient CMV Status Negative | 27 participants |
| Recipient CMV Status Positive | 17 participants |
| Region of Enrollment United States | 44 participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 47 |
| serious Total, serious adverse events | 0 / 47 |
Outcome results
Primary
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
Population: All transplanted patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 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 percentage of patients |
Secondary
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T Cell Depletion | Acute Graft Versus Host Disease (GVHD) | Grades II - IV | 22.7 percentage of participants |
| T Cell Depletion | Acute Graft Versus Host Disease (GVHD) | Grades III - IV | 4.5 percentage of participants |
Secondary
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
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| T Cell Depletion | CD34+ and CD3+ Cell Doses | CD34+ (x10^6) | 7.9 cells per kilogram |
| T Cell Depletion | CD34+ and CD3+ Cell Doses | CD3+ (x10^3) | 6.6 cells per kilogram |
Secondary
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T Cell Depletion | Chronic Graft Versus Host Disease (GVHD) | Limited/extensive | 19.0 percentage of participants |
| T Cell Depletion | Chronic Graft Versus Host Disease (GVHD) | Extensive only | 6.8 percentage of participants |
Secondary
Determination of Infusional Toxicity
Time frame: 28 day
Population: No data collected
Secondary
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T Cell Depletion | Disease-free Survival (DFS) | 6 months | 81.8 percentage of participants |
| T Cell Depletion | Disease-free Survival (DFS) | 12 months | 66 percentage of participants |
| T Cell Depletion | Disease-free Survival (DFS) | 36 months | 53 percentage of participants |
Secondary
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T Cell Depletion | Graft Failure | Primary Graft Failure | 0 participants |
| T Cell Depletion | Graft Failure | Secondary Graft Failure | 1 participants |
Secondary
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T Cell Depletion | Leukemia Relapse | 12 months | 20.6 percentage of participants |
| T Cell Depletion | Leukemia Relapse | 36 months | 23.7 percentage of participants |
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T Cell Depletion | Neutrophil Engraftment | 12 days |
Secondary
Overall Survival
Overall survival is defined as time from transplant to death or last follow-up.
Time frame: Months 12 and 36
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T Cell Depletion | Overall Survival | 12 months | 77 percentage of participants |
| T Cell Depletion | Overall Survival | 36 months | 56 percentage of participants |
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T Cell Depletion | Platelet Engraftment | 16 days |
Secondary
Post-transplant Lymphoproliferative Disorder (PTLD)
PTLD is defined as increased Epstein Barr Virus viremia requiring clinical intervention.
Time frame: Year 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T Cell Depletion | Post-transplant Lymphoproliferative Disorder (PTLD) | 8 participants |
Secondary
Transplant Related Mortality
Death occurring in a patient in continuing complete remission.
Time frame: Months 12, 24, and 36
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T Cell Depletion | Transplant Related Mortality | 12 months | 14 percentage of participants |
| T Cell Depletion | Transplant Related Mortality | 24 months | 20 percentage of participants |
| T Cell Depletion | Transplant Related Mortality | 36 months | 23.2 percentage of participants |