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

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

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.

Study Overview

• Status: Completed
• Conditions: Juvenile Myelomonocytic Leukemia; Childhood Acute Myeloid Leukemia in Remission; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Childhood Acute Lymphoblastic Leukemia; Secondary Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes
• Intervention / Treatment: Other: laboratory biomarker analysis; Biological: filgrastim; Procedure: allogeneic bone marrow transplantation

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.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Arcadia, California, United States, 91006-3776
      • Children's Oncology Group
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center-Parnassus
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Childrens Memorial Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Medical Center
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kosair Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287-8936
      • Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • The Childrens Mercy Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients undergo filgrastim (G-CSF)-stimulated allogeneic bone marrow transplantation on day 0.	Other: laboratory biomarker analysis; Correlative studies; Biological: filgrastim; Given IV; Other Names: G-CSF; Granulocyte Colony-Stimulating Factor; r-metHuG-CSF; Neupogen; NSC #614629; Procedure: allogeneic bone marrow transplantation; Patients undergo allogeneic BMT; Other Names: bone marrow therapy, allogeneic; bone marrow therapy, allogenic; transplantation, allogeneic bone marrow; transplantation, allogenic bone marrow
Active Comparator: Arm II; Patients undergo conventional allogeneic bone marrow transplantation on day 0.	Other: laboratory biomarker analysis; Correlative studies; Procedure: allogeneic bone marrow transplantation; Patients undergo allogeneic BMT; Other Names: bone marrow therapy, allogeneic; bone marrow therapy, allogenic; transplantation, allogeneic bone marrow; transplantation, allogenic bone marrow

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 1 year
Infused Nucleated and CD34+ Cell Doses	Compared using the Wilcoxon rank-sum test.	Up to 10 years

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Stephan A. Grupp, MD PhD, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2007
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): March 31, 2022

Study Registration Dates

• First Submitted: March 20, 2007
• First Submitted That Met QC Criteria: March 20, 2007
• First Posted (Estimate): March 22, 2007

Study Record Updates

• Last Update Posted (Actual): April 28, 2022
• Last Update Submitted That Met QC Criteria: April 1, 2022
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Preleukemia; Leukemia, Myelomonocytic, Juvenile; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; Lenograstim
• Other Study ID Numbers: ASCT0631; U10CA098543 (U.S. NIH Grant/Contract); NCI-2009-01069 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); COG-ASCT0631 (Other Identifier: Children's Oncology Group); COG-PBMTC-STC051 (Other Identifier: Children's Oncology Group); CDR0000532926 (Other Identifier: Clinical Trials.gov)