Donor Bone Marrow Transplant With or Without G-CSF in Treating Young Patients With Hematologic Cancer or Other Diseases

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase III Randomized Trial of G-CSF Stimulated Bone Marrow vs. Conventional Bone Marrow as a Stem Cell Source In Matched Sibling Donor Transplantation

Conditions
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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

Intervention / Treatment
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* Procedure: allogeneic bone marrow transplantation
* Other: laboratory biomarker analysis
* Biological: filgrastim


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients undergo filgrastim (G-CSF)-stimulated allogeneic bone marrow transplantation on day 0. | Procedure: allogeneic bone marrow transplantation<br>* Patients undergo allogeneic BMT<br>* Other names: transplantation, allogenic bone marrow;Other: laboratory biomarker analysis<br>* Correlative studies<br>Biological: filgrastim<br>* Given IV<br>* Other names: NSC #614629;|
| Active Comparator: Arm II<br>Patients undergo conventional allogeneic bone marrow transplantation on day 0. | Procedure: allogeneic bone marrow transplantation<br>* Patients undergo allogeneic BMT<br>* Other names: transplantation, allogenic bone marrow;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | at 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 10 years | 
| 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. | Up to 3 months | 
| Estimated 100-day Transplant Related Mortality (TRM) Percentage | Death in a patient after transplant due to protocol treatment is defined as an TRM. | 100 days | 
| Estimated Percentage of Chronic Graft-versus-host Disease (cGVHD) | cGVHD definition is based on BMT CTN MOP SEPT. 2005; outlined in Protocol Appendix III. | 18 months post-transplant | 
| Estimated Median Time to Neutrophil Engraftment | Median Time from transplant to neutrophil engraftment | Up to 10 years | 
| Estimated Median Length of Initial Hospitalization | Estimated and compared between randomization arms using the Wilcoxon rank-sum test. | Up to 10 years |