Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Secondary Acute Myeloid Leukemia
Conditions
Brief summary
This phase II trial studies how well reduced intensity donor peripheral blood stem cell (PBSC) transplant works in treating patients with de novo or secondary acute myeloid leukemia (AML) in remission. Giving low doses of chemotherapy, such as fludarabine phosphate, and total-body irradiation (TBI) before a donor PBSC transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening
Detailed description
PRIMARY OBJECTIVES: I. To determine if a one-year disease free survival of \>= 35% can be achieved among patients \>= 55 years old with de novo and secondary AML in first complete remission (CR1) who undergo nonmyeloablative hematopoietic stem cell transplant (HSCT) from human leukocyte antigen (HLA) identical related donors. II. To determine if a day +200 nonrelapse related mortality of \< 15% can be achieved among patients \>= 55 years old with de novo and secondary AML in CR1 who undergo nonmyeloablative HSCT from HLA identical related donors. OUTLINE: CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo TBI on day 0. TRANSPLANT: Patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine (CSP) orally (PO) twice daily (BID) on days -3 to 56 with taper to day 77. Patients also receive mycophenolate mofetil (MMF) PO BID on days 0-27. After completion of study treatment, patients are followed up on days 28, 56, and 84; months 6, 12, 18, and 24; and then yearly for 5 years.
Interventions
Undergo TBI
Given PO
Given PO
Undergo nonmyeloablative allogeneic PBSC transplant
Undergo nonmyeloablative allogeneic PBSC transplant
Given IV
Sponsors
Study design
Eligibility
Inclusion criteria
* Patients with de novo AML (French-American-British \[FAB\] MO-M2, M4-M7) or secondary AML who achieve CR1 after induction chemotherapy and one or two cycles of consolidation chemotherapy * Transplant conditioning must occur within 6 months of diagnosis * Patient enrollment must be approved by the Fred Hutchinson Cancer Research Center (FHCRC) principal investigator (PI) or the PI's designee * DONOR: Related donor who is genotypically or phenotypically identical * DONOR: Age \>= 12 years * DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis * DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)
Exclusion criteria
* AML FAB M3 * AML involvement of the central nervous system (CNS) as defined by a positive cytospin of cerebral spinal fluid at the time of enrollment * Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology * Human immunodeficiency virus (HIV) seropositivity * Fungal infections with radiographic progression after receipt of amphotericin B or active triazole for greater than one month * Diffusion capacity of carbon monoxide (DLCO) corrected \< 40% * Total lung capacity (TLC) \< 40% * Forced expiratory volume in one second (FEV1) \< 40% or requiring supplementary oxygen * The FHCRC principal investigator of the study must approve enrollment of all patients with pulmonary nodules * Cardiac ejection fraction \< 40% * Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3mg/dL, or symptomatic biliary disease * Karnofsky Performance Score \< 70 * Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment * Females who are pregnant or breastfeeding * No intensive chemotherapy can be given within three weeks (or the interval in which a cycle of standard chemotherapy would be administered in a non-transplant setting) prior to initiating the nonmyeloablative transplant conditioning * Patients with active non-hematologic malignancies (except non-melanoma skin cancers) * Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a \> 20% risk of disease recurrence * Patients with active bacterial or fungal infections unresponsive to medical therapy * DONOR: Identical twin * DONOR: Pregnancy * DONOR: HIV seropositivity * DONOR: Inability to achieve adequate venous access * DONOR: Known allergy to G-CSF * DONOR: Current serious systemic illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival-incidence of Survival Without Relapse | By 1 year after transplant | Sufficient evidence will be taken to be an observed rate of DFS at one year after transplant that corresponds to a one-sided 95% confidence interval with an upper limit lower than 35%. |
| Nonrelapse Mortality (NRM)-Incidence of Nonrelapse Death | 200 days after transplant | Defined as death without morphologic evidence of disease. Sufficient evidence will be taken to be an observed rate of NRM within 200 days of transplant that corresponds to a one-sided 80% confidence interval with a lower limit greater than 15%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | By 1 year after transplant | Percent patients surviving. |
| Incidence of Relapse | By 1 year after transplant | Percent patients with relapsed disease post-transplant. |
| Incidence of Rejection | By 1 year after transplant | Percent patients who developed infections post-transplant. |
| Incidence of Acute and Chronic GVHD | aGVHD: 100 days after transplant; cGVHD: 1 Year after transplant. | Percent patients with acute/chronic GVHD |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Nonmyeloablative Donor PBSC Transplant) Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI & allogeneic PBSC transplant on day 0. Patients also receive CSP PO BID on days -3 to 56 with taper to day 77, and MMF PO BID on days 0-27.
Nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant
Fludarabine phosphate: Given IV
Total-body irradiation: Undergo total-body irradiation
Cyclosporine: Given PO
Mycophenolate mofetil: Given PO
Peripheral blood stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | Treatment (Nonmyeloablative Donor PBSC Transplant) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 7 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 64.8 years |
| Region of Enrollment United States | 17 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 17 |
| serious Total, serious adverse events | 5 / 17 |
Outcome results
Disease-free Survival-incidence of Survival Without Relapse
Sufficient evidence will be taken to be an observed rate of DFS at one year after transplant that corresponds to a one-sided 95% confidence interval with an upper limit lower than 35%.
Time frame: By 1 year after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Nonmyeloablative Donor PBSC Transplant) | Disease-free Survival-incidence of Survival Without Relapse | 47 percentage of participants |
Nonrelapse Mortality (NRM)-Incidence of Nonrelapse Death
Defined as death without morphologic evidence of disease. Sufficient evidence will be taken to be an observed rate of NRM within 200 days of transplant that corresponds to a one-sided 80% confidence interval with a lower limit greater than 15%.
Time frame: 200 days after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Nonmyeloablative Donor PBSC Transplant) | Nonrelapse Mortality (NRM)-Incidence of Nonrelapse Death | 6 percentage of participants |
Incidence of Acute and Chronic GVHD
Percent patients with acute/chronic GVHD
Time frame: aGVHD: 100 days after transplant; cGVHD: 1 Year after transplant.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Nonmyeloablative Donor PBSC Transplant) | Incidence of Acute and Chronic GVHD | Grade II-IV aGVHD | 35.3 percentage of participants |
| Treatment (Nonmyeloablative Donor PBSC Transplant) | Incidence of Acute and Chronic GVHD | cGVHD | 35.3 percentage of participants |
Incidence of Rejection
Percent patients who developed infections post-transplant.
Time frame: By 1 year after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Nonmyeloablative Donor PBSC Transplant) | Incidence of Rejection | 0 percentage of participants |
Incidence of Relapse
Percent patients with relapsed disease post-transplant.
Time frame: By 1 year after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Nonmyeloablative Donor PBSC Transplant) | Incidence of Relapse | 41.2 percentage of participants |
Overall Survival
Percent patients surviving.
Time frame: By 1 year after transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Nonmyeloablative Donor PBSC Transplant) | Overall Survival | 70.6 percentage of participants |