Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), recurrent adult acute myeloid leukemia, adult acute myeloid leukemia in remission, recurrent childhood acute myeloid leukemia, recurrent adult acute lymphoblastic leukemia, recurrent childhood acute lymphoblastic leukemia, blastic phase chronic myelogenous leukemia, refractory anemia with excess blasts in transformation, refractory anemia with excess blasts, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes
Brief summary
RATIONALE: Giving chemotherapy and total-body irradiation before a donor stem cell transplant or a donor bone marrow transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving mycophenolate mofetil and cyclosporine before and after transplant may stop this from happening. PURPOSE: This phase II trial is studying the side effects and best way to give busulfan together with etoposide and total-body irradiation and to see how well they work in treating patients who are undergoing a donor stem cell or bone marrow transplant for advanced hematologic cancer.
Detailed description
OBJECTIVES: * To determine the efficacy of a preparative regimen comprising dose targeted busulfan, etoposide, and fractionated total-body irradiation followed by allogeneic hematopoietic stem cell or bone marrow transplantation in patients with advanced hematologic malignancies. * To determine the efficacy of this regimen in patients with acute myeloid leukemia in first remission with unfavorable cytogenetics. * To evaluate the early and late toxicities of this regimen. OUTLINE: * Preparative chemotherapy regimen: Patients receive busulfan IV over 2 hours once every 6 hours on days -14 to -8 for a total of 16 doses and etoposide IV on day -3.\* NOTE: \*Patients also receive oral or IV dilantin 1-3 times daily on days -18 to -5 for prophylaxis of grand mal seizures. * Fractionated total-body irradiation (FTBI): Patients undergo FTBI on days -7 to -4 for a total of 10 fractions. * Allogeneic transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. * Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV or orally on days -1 to 50 followed by a taper to day 180 in the absence of GVHD. Patients also receive mycophenolate mofetil orally or IV over 2 hours twice daily on days 0-27, followed by a taper until day 56. After completion of study treatment, patients are followed annually for 2 years.
Interventions
DRUGbusulfan
DRUGcyclosporine
DRUGetoposide
DRUGmycophenolate mofetil
PROCEDUREallogeneic bone marrow transplantation
PROCEDUREallogeneic hematopoietic stem cell transplantation
PROCEDUREperipheral blood stem cell transplantation
RADIATIONtotal-body irradiation
Sponsors
City of Hope Medical Center
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of 1 of the following: * Acute myeloid leukemia (AML) * Failed remission induction therapy or in relapse beyond second remission * In first remission with poor risk cytogenetics (e.g., 11q abnormalities, -7, -5, complex abnormalities \[i.e., \> 3 abnormalities, 6;9 translocation and 3q abnormalities del (7q), del (5q), complex abnormalities ≥ abnormalities, 9q, 20q, 21q, 17q, t(9;21)\]) * Acute lymphoblastic leukemia (ALL) * Failed remission induction therapy or in relapse beyond second remission * Blastic phase chronic myelogenous leukemia * Refractory anemia with excess blasts * Refractory anemia with excess blasts in transformation * HLA -A, -B, -C, -DR identical sibling donor match available * No relapse after prior bone marrow transplantation PATIENT CHARACTERISTICS: * Cardiac ejection fraction ≥ 50% * Serum creatinine ≤ 1.2 times upper limit of normal (ULN) or creatinine clearance \> 80 mL/min * Bilirubin ≤ 1.5 times ULN * AST and ALT \< 5 times ULN * FEV\_1 ≥ 50% of predicted normal * DLCO ≥ 50% of predicted normal * No psychological or medical condition that would preclude allogeneic transplantation (in the opinion of the treating physician) * Not pregnant * Negative pregnancy test PRIOR CONCURRENT THERAPY: * See Disease Characteristics * At least 28 days since prior induction or reinduction therapy * Prior etoposide and busulfan allowed * No prior radiation therapy that would exclude total-body irradiation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival at 5 Years Post-Transplant. | Date of Transplant to Five Years post-Transplant | Kaplan-Meier estimate of an event of death estimated at five years post-transplant. 95% confidence intervals were calculated from the logit transform of the Greenwood variance. The transformation was necessary to keep the estimate within the probability space of 0 to 100%. |
| Disease-free Survival at Five Years Post-transplant | Date of transplant to five years post-transplant | Kaplan-Meier estimate of an event of relapse or death estimated at five years post-transplant. 95% confidence intervals were calculated from the logit transform of the Greenwood variance. The transformation was necessary to keep the estimate within the probability space of 0 to 100%. |
| Overall Survival Comparing Diagnosis Groups | Date of Transplant to Five Years post-Transplant | Kaplan-Meier estimate of an event of death estimated at five years post-transplant. 95% confidence intervals were calculated from the logit transform of the Greenwood variance. The transformation was necessary to keep the estimate within the probability space of 0 to 100%. |
| Cumulative Incidence of Relapse With Transplant-related Death as the Competing Risk: Diagnosis Groups Are Compared. | Date of Transplant to Five Years post-Transplant. Estimate is at Five Years post-Transplant. | Fine and Gray estimate of cumulative incidence of Relapse, with Death as the competing risk. Estimate is at five years post-transplant. Ninety-five percent confidence interval is by logit transformation of Greenwood variance to keep the interval within the probability space of 0% to 100%. |
Contacts
STUDY_CHAIRAnthony S. Stein, MD
City of Hope Medical Center
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Busulfan, FTBI and VP16 IV Busulfan + 12 cGy FTBI + VP16 prior to allogeneic Bone Marrow Transplant
busulfan
cyclosporine
etoposide
mycophenolate mofetil
allogeneic bone marrow transplantation
allogeneic hematopoietic stem cell transplantation
peripheral blood stem cell transplantation
total-body irradiation | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Busulfan, FTBI and VP16 |
|---|---|
| Age, Continuous | 37 years |
| Cytogenetics Indeterminate | 1 Participants |
| Cytogenetics Intermediate | 14 Participants |
| Cytogenetics Unfavorable | 15 Participants |
| Disease Status at Transplant ALL in First Relapse | 1 Participants |
| Disease Status at Transplant ALL in Induction Failure | 4 Participants |
| Disease Status at Transplant ALL in Second Relapse | 1 Participants |
| Disease Status at Transplant AML in First Complete Remission | 6 Participants |
| Disease Status at Transplant AML in First Relapse | 6 Participants |
| Disease Status at Transplant AML in Induction Failure | 10 Participants |
| Disease Status at Transplant untreated RAEB-t | 2 Participants |
| Patient Assessment of Mortality (PAM) Score | 26 units on a scale |
| Percent Blasts in Bone Marrow | 16.5 percent of leukocytes |
| Percent Blasts in Peripheral Blood | 3.5 percent of leukocytes |
| Race/Ethnicity, Customized Asian | 6 Participants |
| Race/Ethnicity, Customized Hispanic | 2 Participants |
| Race/Ethnicity, Customized White, Not Hispanic | 22 Participants |
| Region of Enrollment United States | 30 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 15 Participants |
| Stem Cell Source Bone Marrow | 1 Participants |
| Stem Cell Source Peripheral Blood | 29 Participants |
| WBC pre-conditioning | 3.4 x10^9 cells/L |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 18 / 30 |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 2 / 30 |
Outcome results
Primary
Cumulative Incidence of Relapse With Transplant-related Death as the Competing Risk: Diagnosis Groups Are Compared.
Fine and Gray estimate of cumulative incidence of Relapse, with Death as the competing risk. Estimate is at five years post-transplant. Ninety-five percent confidence interval is by logit transformation of Greenwood variance to keep the interval within the probability space of 0% to 100%.
Time frame: Date of Transplant to Five Years post-Transplant. Estimate is at Five Years post-Transplant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Busulfan, FTBI and VP16 | Cumulative Incidence of Relapse With Transplant-related Death as the Competing Risk: Diagnosis Groups Are Compared. | 0 percentage of relapse probability |
| AML/R1 | Cumulative Incidence of Relapse With Transplant-related Death as the Competing Risk: Diagnosis Groups Are Compared. | 0 percentage of relapse probability |
| AML/IF | Cumulative Incidence of Relapse With Transplant-related Death as the Competing Risk: Diagnosis Groups Are Compared. | 30 percentage of relapse probability |
| Active ALL | Cumulative Incidence of Relapse With Transplant-related Death as the Competing Risk: Diagnosis Groups Are Compared. | 50 percentage of relapse probability |
Comparison: Gray's estimate. (Fine and Gray). Null hypothesis is all four groups are statistically from the same population. Alternative hypothesis is that at least one of the groups is from a population different from the remaining groups. Anticipated sample-sizes comparing Active ALL (anticipated N= 12) with the combined AML patients (anticipated N=38) was deemed to be too small for formal hypothesis testingp-value: >0.05Gray's Test
Primary
Disease-free Survival at Five Years Post-transplant
Kaplan-Meier estimate of an event of relapse or death estimated at five years post-transplant. 95% confidence intervals were calculated from the logit transform of the Greenwood variance. The transformation was necessary to keep the estimate within the probability space of 0 to 100%.
Time frame: Date of transplant to five years post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Busulfan, FTBI and VP16 | Disease-free Survival at Five Years Post-transplant | 40 percentage of survival probability |
Primary
Overall Survival at 5 Years Post-Transplant.
Kaplan-Meier estimate of an event of death estimated at five years post-transplant. 95% confidence intervals were calculated from the logit transform of the Greenwood variance. The transformation was necessary to keep the estimate within the probability space of 0 to 100%.
Time frame: Date of Transplant to Five Years post-Transplant
Population: The Full Study Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Busulfan, FTBI and VP16 | Overall Survival at 5 Years Post-Transplant. | 40 percentage of survival probability |
Primary
Overall Survival Comparing Diagnosis Groups
Kaplan-Meier estimate of an event of death estimated at five years post-transplant. 95% confidence intervals were calculated from the logit transform of the Greenwood variance. The transformation was necessary to keep the estimate within the probability space of 0 to 100%.
Time frame: Date of Transplant to Five Years post-Transplant
Population: Study cohort separated into four disease groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Busulfan, FTBI and VP16 | Overall Survival Comparing Diagnosis Groups | 67 percentage of survival probability |
| AML/R1 | Overall Survival Comparing Diagnosis Groups | 50 percentage of survival probability |
| AML/IF | Overall Survival Comparing Diagnosis Groups | 30 percentage of survival probability |
| Active ALL | Overall Survival Comparing Diagnosis Groups | 33 percentage of survival probability |
Comparison: Log-rank test. (Mantel-Haenszel test). Null hypothesis is all four groups are statistically from the same population. Alternative hypothesis is that at least one of the groups is from a population different from the remaining groups. Anticipated sample-sizes comparing Active ALL (anticipated N= 12) with the combined AML patients (anticipated N=38) was deemed to be too small for formal hypothesis testing.p-value: >0.05Log Rank