Clinical trial NCT00450450: Donor Bone Marrow Transplant With or Without G-CSF in Treating Young Patients With Hematologic Cancer or Other Diseases
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: 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
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-03-22
Enrollment: 27
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Estimated Two-year Event-free Survival (EFS)
timeFrame: at 2 years
Secondary outcomes:
measure: Estimated Graft Failure Rate
timeFrame: Up to 10 years
measure: Estimated Incidence of Grade III-IV Acute Graft-versus-host Disease (aGVHD)
timeFrame: Up to 3 months
measure: Estimated 100-day Transplant Related Mortality (TRM) Percentage
timeFrame: 100 days
measure: Estimated Percentage of Chronic Graft-versus-host Disease (cGVHD)
timeFrame: 18 months post-transplant
measure: Estimated Median Time to Neutrophil Engraftment
timeFrame: Up to 10 years
measure: Estimated Median Length of Initial Hospitalization
timeFrame: Up to 10 years
Other outcomes:
measure: Immune Reconstitution
timeFrame: Up to 1 year
measure: Infused Nucleated and CD34+ Cell Doses
timeFrame: Up to 10 years
Locations:
city: Arcadia
country: United States
facility: Children's Oncology Group
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center-Parnassus
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Chicago
country: United States
facility: Childrens Memorial Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Medical Center
state: Indiana
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Kansas City
country: United States
facility: The Childrens Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
Study officials:
affiliation: Children's Oncology Group
name: Stephan A. Grupp, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: