Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Acute Myeloid Leukemia in Remission, Childhood Chronic Myelogenous Leukemia, Childhood Myelodysplastic Syndromes, Chronic Phase Chronic Myelogenous Leukemia, de Novo Myelodysplastic Syndromes, Juvenile Myelomonocytic Leukemia, Previously Treated Myelodysplastic Syndromes, Recurrent Childhood Acute Lymphoblastic Leukemia, Secondary Myelodysplastic Syndromes
Conditions
Brief summary
This randomized phase III trial is studying donor bone marrow transplant with or without G-CSF to compare how well they work in treating young patients with hematologic cancer or other diseases. Giving chemotherapy and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer or abnormal cells. It also 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 methotrexate and tacrolimus or cyclosporine before and after transplant may stop this from happening. It is not yet known whether donor bone marrow transplant is more effective with or without G-CSF in treating hematologic cancer or other diseases.
Detailed description
PRIMARY OBJECTIVE: I. Compare improvement in event-free survival of patients with hematologic cancer or other diseases undergoing filgrastim (G-CSF)-stimulated bone marrow transplantation (BMT) vs conventional BMT. SECONDARY OBJECTIVES: I. Compare the incidence and time to engraftment in patients treated with these regimens. II. Compare rates of acute and chronic graft-vs-host disease (GVHD) in patients treated with these regimens. III. Correlate incidence of acute and chronic GVHD with absolute T-cell numbers, Th1 vs Th2 profile of T cells, dendritic cell populations, and T-regulatory cell content. IV. Assess the impact of G-CSF-stimulated BMT as a stem cell source on hospital stay and treatment-related mortality at day 100 in patients treated with this regimen. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to risk (high vs intermediate vs standard). CONDITIONING REGIMEN: Co-enrolled on COG-ASCT0431 or COG-AAML0531; Patients receive a conditioning regimen as defined on that treatment study. ACUTE LYMPHOBLASTIC LEUKEMIA (ALL): Patients undergo total-body irradiation (TBI) twice daily on days -8 to -6. Patients receive thiotepa IV on days -5 and -4 and high-dose cyclophosphamide IV over 1 hour on days -3 and -2. Some patients with CNS leukemia or very high-risk ALL in first complete remission receive cranial radiotherapy. ACUTE MYELOID LEUKEMIA, JUVENILE MYELOMONOCYTIC, CHRONIC MYELOGENOUS LEUKEMIA, OR MYELODYSPLASTIC SYNDROMES: (myeloid malignancies) Patients receive busulfan IV over 2 hours every 6 hours on days -9 to -6 and high-dose cyclophosphamide IV over 1 hour on days -5 to -2. GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Co-enrolled on COG-ASCT0431 or COG-AAML0531: Patients undergo GVHD prophylaxis as defined on that treatment study. ALL: Patients receive tacrolimus IV or orally beginning on day -2 and continuing until day 42, followed by a taper until day 98. Patients also receive methotrexate IV on days 1, 3, and 6. MYELOID MALIGNANCIES: Patients receive cyclosporine IV continuously or orally beginning on day -1 and continuing until day 42 or day 50, followed by a taper for 8-16 weeks. Patients also receive methotrexate IV on days 1, 3, 6, and 11. ALLOGENEIC BONE MARROW TRANSPLANTATION (BMT): Patients are randomized to 1 of 2 transplantation arms. ARM I: Patients undergo filgrastim (G-CSF) -stimulated allogeneic BMT on day 0. ARM II: Patients undergo conventional allogeneic BMT on day 0. After completion of study treatment, patients are followed at 1 year and then annually for 5-10 years.
Interventions
PROCEDUREallogeneic bone marrow transplantation
Patients undergo allogeneic BMT
OTHERlaboratory biomarker analysis
Correlative studies
BIOLOGICALfilgrastim
Given IV
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of hematologic cancer or other disease, including any of the following: * Chronic myelogenous leukemia in first or second chronic phase * Acute lymphoblastic leukemia (ALL), meeting any of the following criteria: * Relapsed ALL enrolled on a Children's Oncology Group (COG) relapse clinical trial OR received ≥ 1 round of reinduction therapy (4-6 weeks) and 1 round of intensive consolidation chemotherapy (3-6 weeks) * ALL in second complete remission (CR)\* after a bone marrow, extramedullary, or combined bone marrow and extramedullary relapse * Very high-risk ALL in first CR, defined as any of the following: * Philadelphia chromosome-positive ALL * Hypodiploidy (\< 44 chromosomes) * Mixed lineage leukemia rearrangement * Induction failure * Acute myeloid leukemia in first or second CR * Induction therapy must be completed * Juvenile myelomonocytic leukemia * Myelodysplastic syndromes * No clinically evident CNS or extramedullary disease * No blasts seen on cerebrospinal fluid cytospin * Post-relapse reinduction therapy must be completed * Not planning to receive reduced-intensity conditioning regimen * Not planning to receive a graft that has undergone T-cell depletion * No Down syndrome * Matched sibling donor must be available and must be enrolled on ASCT0631D companion study * Karnofsky performance status (PS) 60-100% (patients \> 16 years of age) OR Lansky PS 60-100% (patients ≤ 16 years of age) * AST or ALT \< 5 times upper limit of normal for age * Bilirubin \< 2.5 mg/dL (unless due to Gilbert's syndrome) * Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine base on age and/or gender as follows: * 0.4 mg/dL (1 month to \< 6 months of age) * 0.5 mg/dL (6 months to \< 1 year of age) * 0.6 mg/dL (1 to 2 years of age) * 0.8 mg/dL (2 to \< 6 years of age) * 1.0 mg/dL (6 to \< 10 years of age) * 1.2 mg/dL (10 to \< 13 years of age) * 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to \< 16 years of age) * 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age) * Shortening fraction ≥ 27% by echocardiogram OR LVEF ≥ 50% by radionuclide angiogram * FEV\_1, FVC, and DLCO ≥ 60% OR meets the following criteria (for patients unable to cooperate for pulmonary function tests): * No evidence of dyspnea at rest * No exercise intolerance * No requirement for supplemental oxygen therapy * Not pregnant or nursing * No known HIV * No known uncontrolled fungal, bacterial, or viral infections * Patients acquiring fungal disease during induction therapy may proceed if they have a significant response to antifungal therapy with no or minimal evidence of disease remaining by CT scan * No prior allogeneic or autologous stem cell transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Two-year Event-free Survival (EFS) | at 2 years | EFS is defined as relapse or treatment-related mortality (TRM). relapse is defined by either morphological or cytogenetic evidence of ALL consistent with pre-transplant features. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Graft Failure Rate | Up to 10 years | Primary graft failure is defined as the failure to achieve an absolute neutrophil count of more than 5000 per cubic millimeter for at least three consecutive days by Day +42. |
| Estimated Incidence of Grade III-IV Acute Graft-versus-host Disease (aGVHD) | Up to 3 months | Stage III-IV aGVHD is defined as: Stage 0-3 skin, with Stage 2-3 liver, or Stage 2-3 GI; OR Stage 4 skin, liver or GI involvement. |
| Estimated 100-day Transplant Related Mortality (TRM) Percentage | 100 days | Death in a patient after transplant due to protocol treatment is defined as an TRM. |
| Estimated Median Time to Neutrophil Engraftment | Up to 10 years | Median Time from transplant to neutrophil engraftment |
| Estimated Median Length of Initial Hospitalization | Up to 10 years | Estimated and compared between randomization arms using the Wilcoxon rank-sum test. |
| Estimated Percentage of Chronic Graft-versus-host Disease (cGVHD) | 18 months post-transplant | cGVHD definition is based on BMT CTN MOP SEPT. 2005; outlined in Protocol Appendix III. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Immune Reconstitution | Up to 1 year | Summarized graphically. Generalized estimating equation will be used to model the levels as a function of time and randomization assignment and to test the impact of G-CSF stimulation on immune reconstruction. |
| Infused Nucleated and CD34+ Cell Doses | Up to 10 years | Compared using the Wilcoxon rank-sum test. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Control BM Arm Conventional bone marrow transplant (BM) | 13 |
| Experimental G-BM Arm G-CSF (filgrastim) stimulated bone marrow (G-BM) | 14 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 3 |
| Overall Study | Missing Data | 2 | 0 |
| Overall Study | Relapse | 2 | 0 |
Baseline characteristics
| Characteristic | Control BM Arm | Total | Experimental G-BM Arm |
|---|---|---|---|
| Age, Continuous | 12 Whole year | 12 Whole year | 11 Whole year |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 22 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 19 Participants | 9 Participants |
| Region of Enrollment Australia | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment United States | 12 Participants | 26 Participants | 14 Participants |
| Sex: Female, Male Female | 5 Participants | 14 Participants | 9 Participants |
| Sex: Female, Male Male | 8 Participants | 13 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 13 | 7 / 13 |
| serious Total, serious adverse events | 1 / 13 | 0 / 13 |
Outcome results
Primary
Estimated Two-year Event-free Survival (EFS)
EFS is defined as relapse or treatment-related mortality (TRM). relapse is defined by either morphological or cytogenetic evidence of ALL consistent with pre-transplant features.
Time frame: at 2 years
Population: Early terminated study. One patient is inevaluable for EFS on experimental arm and is excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control BM Arm | Estimated Two-year Event-free Survival (EFS) | 66 Percentage of patients |
| Experimental G-BM Arm | Estimated Two-year Event-free Survival (EFS) | 83 Percentage of patients |
Secondary
Estimated 100-day Transplant Related Mortality (TRM) Percentage
Death in a patient after transplant due to protocol treatment is defined as an TRM.
Time frame: 100 days
Population: One patient is inevaluable and is excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control BM Arm | Estimated 100-day Transplant Related Mortality (TRM) Percentage | 0 percentage of patients |
| Experimental G-BM Arm | Estimated 100-day Transplant Related Mortality (TRM) Percentage | 7.69 percentage of patients |
Secondary
Estimated Graft Failure Rate
Primary graft failure is defined as the failure to achieve an absolute neutrophil count of more than 5000 per cubic millimeter for at least three consecutive days by Day +42.
Time frame: Up to 10 years
Population: One patient is inevaluable for EFS on experimental arm and is excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control BM Arm | Estimated Graft Failure Rate | 0 Percentage of patients |
| Experimental G-BM Arm | Estimated Graft Failure Rate | 0 Percentage of patients |
Secondary
Estimated Incidence of Grade III-IV Acute Graft-versus-host Disease (aGVHD)
Stage III-IV aGVHD is defined as: Stage 0-3 skin, with Stage 2-3 liver, or Stage 2-3 GI; OR Stage 4 skin, liver or GI involvement.
Time frame: Up to 3 months
Population: One patient is inevaluable and is excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control BM Arm | Estimated Incidence of Grade III-IV Acute Graft-versus-host Disease (aGVHD) | 7.69 Percentage of patients |
| Experimental G-BM Arm | Estimated Incidence of Grade III-IV Acute Graft-versus-host Disease (aGVHD) | 15.38 Percentage of patients |
Secondary
Estimated Median Length of Initial Hospitalization
Estimated and compared between randomization arms using the Wilcoxon rank-sum test.
Time frame: Up to 10 years
Population: Data regarding length of Initial Hospitalization are not collected for this study according to Study Chair.
Secondary
Estimated Median Time to Neutrophil Engraftment
Median Time from transplant to neutrophil engraftment
Time frame: Up to 10 years
Population: One patient was inevaluable and excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control BM Arm | Estimated Median Time to Neutrophil Engraftment | 23 Days |
| Experimental G-BM Arm | Estimated Median Time to Neutrophil Engraftment | 20 Days |
Secondary
Estimated Percentage of Chronic Graft-versus-host Disease (cGVHD)
cGVHD definition is based on BMT CTN MOP SEPT. 2005; outlined in Protocol Appendix III.
Time frame: 18 months post-transplant
Population: Included only patients survived beyond 100 days.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control BM Arm | Estimated Percentage of Chronic Graft-versus-host Disease (cGVHD) | 7.69 percentage of patients |
| Experimental G-BM Arm | Estimated Percentage of Chronic Graft-versus-host Disease (cGVHD) | 0 percentage of patients |
Other Pre-specified
Immune Reconstitution
Summarized graphically. Generalized estimating equation will be used to model the levels as a function of time and randomization assignment and to test the impact of G-CSF stimulation on immune reconstruction.
Time frame: Up to 1 year
Population: Data are not collected for this study.
Other Pre-specified
Infused Nucleated and CD34+ Cell Doses
Compared using the Wilcoxon rank-sum test.
Time frame: Up to 10 years
Population: Data are not collected for this study.