Leukemia, Myeloid, Leukemia, Acute Myeloid Leukemia (AML)
Conditions
Brief summary
Acute myeloid leukemia (AML) is a cancer of the bone marrow that mostly affects older adults. Even with the best chemotherapy, two-year disease-free survival is achieved in a minority of patients. Bone marrow transplantation from a sibling donor may improve cure rates; however, patients over 50 years of age have a high risk of complications and therefore generally are excluded from this treatment option. Recently our group developed a transplantation strategy for older cancer patients that protects against transplant-associated complications, yet does not interfere with the ability of the transplanted donor cells to destroy cancer cells. With this new method, we can now safely evaluate transplantation as a curative therapy for AML patients over the age of 50. We have assembled clinical and scientific researchers throughout the state of California to study and compare bone marrow transplantation using our new approach with the best standard of care chemotherapy in AML patients over the age of 50. The results of this study have the potential to establish a new treatment standard that will improve survival of older AML patients.
Interventions
PROCEDUREAllogeneic HSCT
Allogeneic, 5+ of 6 HLA-matched PBSC transplant from sibling, mobilized to target of 5 x 10e6 CD34+ cells/kg and \< 7 x 10e8 CD3+ cells/kg.
1.5 mg/kg for 5 days by IV
6.25 mg/kg twice daily oral
DRUGMycophenolate mofetil (MMF)
15 mg/kg twice daily oral
RADIATIONTotal lymphoid irradiation (TLI)
80 cGy/fraction radiotherapy in 10 fractions.
DRUGMethylprednisolone sodium succinate
1.0 mg/kg for 5 days by IV
Intervention consist of: * Consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation) * Autologous transplantation * Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning * Umbilical cord blood transplantation * Haploidentical transplantation
Sponsors
Genzyme, a Sanofi Company
Stanford University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Treatment assignment was based on availability of an HLA-matched donor.
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* ≥ 50 years of age and ≤ 75 years of age. * De novo acute myelogenous leukemia (AML), based on FAB and WHO criteria. * Intermediate or unfavorable cytogenetic abnormalities based on Southwest Oncology Group (SWOG) Cytogenetic Criteria. * First morphologic complete remission (CR), or CRp (a complete remission but with low platelets) following 1 or 2 courses of induction therapy, documented no more than 8 weeks prior to the date of enrollment and confirmed at time of enrollment. * Karnofsky Performance Score ≥ 60. * Suitable for non-myeloablative transplantation or best treatment. * Able to understand and willing to sign a written informed consent document.
Exclusion criteria
* AML with favorable cytogenetic features based on SWOG Cytogenetic Criteria * AML, either treatment-related or MDS-related * Active CNS disease as identified by positive CSF cytospin at time of enrollment. * Prior or concurrent malignancies except localized non-melanoma skin malignancies or treated cervical carcinoma in situ. (EXCEPTION: Cancer treated with curative intent \> 5 years previously is allowed. EXCEPTION: Low grade lymphoma is allowed as long as active treatment is not required for control of disease) * Planned for allogeneic transplant using a full-dose conditioning * Life expectancy \< 1 year due to diseases other than malignancy * Pregnant or breastfeeding. * HIV-seropositive. * Uncontrolled infection (presumed or documented) with progression after appropriate therapy for greater than one month. * Symptomatic coronary artery disease or uncontrolled congestive heart failure. Left ventricular ejection fraction (LVEF) is not required to be measured, however if measured, exclusion if ejection fraction is \< 30%. * Requiring supplementary continuous oxygen. Diffusing capacity of the lungs for carbon monoxide (DLCO) is not required to be measured, however if it is measured, exclusion if DLCO \< 35%. * Fulminant liver failure * Cirrhosis with evidence of portal hypertension or bridging fibrosis * Alcoholic hepatitis * Esophageal varices * A history of bleeding esophageal varices * Hepatic encephalopathy * Uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time * Ascites related to portal hypertension * Chronic viral hepatitis with total serum bilirubin \> 3 mg/dL * Symptomatic biliary disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 2 years | Overall survival defined as the time interval between the date of attaining a first complete remission (CR) and the date of death from any cause. The outcome is reported as the number of participants alive (without dispersion). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non-relapse Mortality | 2 years | Non-relapse mortality is defined as death that occurs after therapy, from any cause except a cause associated with relapse. This will be reported as the number of participants experiencing non-relapse mortality (a number without dispersion). |
| Relapse Rate | 2 years | Relapse will be determined as ≥ 5% blast cells in the bone marrow, not secondary to regeneration after myelosuppressive therapy; OR emergence of extramedullary leukemia; OR the re-emergence of blasts in the peripheral blood. The outcome will be reported as the number and percentage of participants that meet these criteria (a number without dispersion). |
| Transplant-related Mortality | 100 days and 6 months | Transplant-related mortality will be assessed as any death occurring within 6 months post-transplant, from any cause except relapse. It will be measured at 100 day and 6 months after transplant. The outcome is expressed as at the number of participants experiencing transplant-related mortality (a number without dispersion). |
| Disease-free Survival (DFS) | 2 years | Disease-free survival is defined as the time interval between the date of attaining a first complete remission (CR) and the date of relapse. Disease free survival (DFS) will compared to conventional therapy vs Non-myeloablative Host Conditioning (NMA HCT). The outcome is reported as the number of participants which never experienced disease relapse (without dispersion). |
| Early Graft Loss | 2 years | Early graft loss means a failure to achieve donor T-cell chimerism of \> 5% at any time after transplant. The outcome is reported as the percentage of participants that experience early graft loss, a number without dispersion. |
| Patients Completing the Intended Therapy in Both Arms | 2 years | The assessment for completion of the intended therapy (in both arms) will be reported as the percentage of participants, a number without dispersion |
| Complete Donor Hematopoietic Cell Chimerism | 2 years | Complete donor hematopoietic cell chimerism was evaluated in transplant recipients. Complete donor chimerism will be assessed as the presence of \> 95% donor T-cells (CD3+) in the blood. The outcome is reported as the percentage of participants that achieve complete donor chimerism, a number without dispersion. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Allo-HSCT + TLI + ATG Participants achieving complete remission after consolidation therapy & who have 5 of 6 HLA-match sibling donor to provide PBSC harvest for transplant. Pre-transplant subjects receive:
* Total lymphoid radiation (TLI) Days -11 to -7, and Days -4 to -1 (2 fractions on day -1)
* Anti-thymocyte globulin (ATG) Days -11 to -7
* Methylprednisolone Days -11 to -7
* Cyclosporine (CSP) Days -4 to +2
* 5+ of 6 HLA-matched CD34+ cells on Day 0
* Mycophenolate mofetil (MMF), Day 0 to Day +28
Allogeneic HSCT: Allogeneic, 5+ of 6 HLA-matched PBSC transplant from sibling, mobilized to target of 5 x 10e6 CD34+ cells/kg and \< 7 x 10e8 CD3+ cells/kg.
Anti-thymocyte globulin (ATG): 1.5 mg/kg for 5 days by IV
Cyclosporine (CSP): 6.25 mg/kg twice daily oral
Mycophenolate mofetil (MMF): 15 mg/kg twice daily oral
Total lymphoid irradiation (TLI): 80 cGy/fraction radiotherapy in 10 fractions.
Methylprednisolone sodium succinate: 1.0 mg/kg for 5 days by IV | 25 |
| Best Standard Care Regular medical care for participants who achieve complete remission after standard consolidation therapy, but do not have a 5 of 6 HLA-match sibling donor. Treatment may consist of:
* Additional consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation)
* Autologous transplantation
* Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning
* Umbilical cord blood transplantation
* Haploidentical transplantation
Best standard care: Intervention consist of:
* Consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation)
* Autologous transplantation
* Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning
* Umbilical cord blood transplantation
* Haploidentical transplantation | 33 |
| Total | 58 |
Baseline characteristics
| Characteristic | Allo-HSCT + TLI + ATG | Best Standard Care | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 7 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 26 Participants | 46 Participants |
| Age, Continuous | 60 years STANDARD_DEVIATION 5.1 | 60 years STANDARD_DEVIATION 6 | 60 years STANDARD_DEVIATION 5.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 30 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 22 Participants | 21 Participants | 43 Participants |
| Region of Enrollment United States | 25 participants | 33 participants | 58 participants |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 22 Participants |
| Sex: Female, Male Male | 14 Participants | 22 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 16 / 25 | 20 / 33 |
| other Total, other adverse events | 0 / 25 | 0 / 33 |
| serious Total, serious adverse events | 20 / 25 | 24 / 33 |
Outcome results
Primary
Overall Survival (OS)
Overall survival defined as the time interval between the date of attaining a first complete remission (CR) and the date of death from any cause. The outcome is reported as the number of participants alive (without dispersion).
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Allo-HSCT + TLI + ATG | Overall Survival (OS) | 9 Participants |
| Best Standard Care | Overall Survival (OS) | 13 Participants |
Secondary
Complete Donor Hematopoietic Cell Chimerism
Complete donor hematopoietic cell chimerism was evaluated in transplant recipients. Complete donor chimerism will be assessed as the presence of \> 95% donor T-cells (CD3+) in the blood. The outcome is reported as the percentage of participants that achieve complete donor chimerism, a number without dispersion.
Time frame: 2 years
Population: Participants in the Best Standard Care arm did not receive transplant, and are not evaluable for transplant outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Allo-HSCT + TLI + ATG | Complete Donor Hematopoietic Cell Chimerism | 56 percentage of participants |
Secondary
Disease-free Survival (DFS)
Disease-free survival is defined as the time interval between the date of attaining a first complete remission (CR) and the date of relapse. Disease free survival (DFS) will compared to conventional therapy vs Non-myeloablative Host Conditioning (NMA HCT). The outcome is reported as the number of participants which never experienced disease relapse (without dispersion).
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Allo-HSCT + TLI + ATG | Disease-free Survival (DFS) | 5 Participants |
| Best Standard Care | Disease-free Survival (DFS) | 9 Participants |
Secondary
Early Graft Loss
Early graft loss means a failure to achieve donor T-cell chimerism of \> 5% at any time after transplant. The outcome is reported as the percentage of participants that experience early graft loss, a number without dispersion.
Time frame: 2 years
Population: Participants in the Best Standard Care arm did not receive transplant, and are not evaluable for transplant outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Allo-HSCT + TLI + ATG | Early Graft Loss | 4 percentage of participants |
Secondary
Non-relapse Mortality
Non-relapse mortality is defined as death that occurs after therapy, from any cause except a cause associated with relapse. This will be reported as the number of participants experiencing non-relapse mortality (a number without dispersion).
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Allo-HSCT + TLI + ATG | Non-relapse Mortality | 1 Participants |
| Best Standard Care | Non-relapse Mortality | 2 Participants |
Secondary
Patients Completing the Intended Therapy in Both Arms
The assessment for completion of the intended therapy (in both arms) will be reported as the percentage of participants, a number without dispersion
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Allo-HSCT + TLI + ATG | Patients Completing the Intended Therapy in Both Arms | 100 percentage of participants |
| Best Standard Care | Patients Completing the Intended Therapy in Both Arms | 81.8 percentage of participants |
Secondary
Relapse Rate
Relapse will be determined as ≥ 5% blast cells in the bone marrow, not secondary to regeneration after myelosuppressive therapy; OR emergence of extramedullary leukemia; OR the re-emergence of blasts in the peripheral blood. The outcome will be reported as the number and percentage of participants that meet these criteria (a number without dispersion).
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Allo-HSCT + TLI + ATG | Relapse Rate | 20 Participants |
| Best Standard Care | Relapse Rate | 24 Participants |
Secondary
Transplant-related Mortality
Transplant-related mortality will be assessed as any death occurring within 6 months post-transplant, from any cause except relapse. It will be measured at 100 day and 6 months after transplant. The outcome is expressed as at the number of participants experiencing transplant-related mortality (a number without dispersion).
Time frame: 100 days and 6 months
Population: Participants in the Best Standard Care arm did not receive transplant, and are not evaluable for transplant outcomes.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Allo-HSCT + TLI + ATG | Transplant-related Mortality | At 100 days | 0 Participants |
| Allo-HSCT + TLI + ATG | Transplant-related Mortality | At 6 months | 1 Participants |