Fludarabine, Cyclophosphamide, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Hematologic Cancer

NCT ID: NCT00134004

Last Updated: 2015-10-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 210 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-10-31
• Study Completion Date: 2015-01-31

Brief Summary

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and cyclophosphamide, and radiation therapy before a donor bone marrow transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops the patient's immune system from rejecting the donor's bone marrow stem cells. The donated stem cells may replace the patient's immune system cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation works in treating patients who are undergoing a donor bone marrow transplant for hematologic cancer.

Detailed Description

OBJECTIVES:

• Determine transplant-related mortality, risk of relapse, and progression-free survival of patients with standard- or high-risk hematologic malignancies undergoing nonmyeloablative conditioning comprising fludarabine, cyclophosphamide, and total-body irradiation followed by HLA-haploidentical allogeneic bone marrow transplantation.
• Determine donor hematopoietic chimerism in patients' peripheral blood at 30, 60, and 180 days after transplantation.
• Determine hematologic and nonhematologic toxic effects of this regimen in these patients.
• Determine, when feasible, surface expression of HLA molecules and death receptors, sensitivity to cytotoxic lymphocytes, and expression of anti-apoptotic genes (e.g., Bcl-2, Bcl-xL, X-IAP, and c-FLIP) in cancer cells from patients who relapse after treatment with this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to risk of relapse (standard [defined as ≤ 30% risk] vs high [defined as ≥ 70% risk]).

• Nonmyeloablative conditioning regimen: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients undergo total body irradiation on day -1.
• Allogeneic bone marrow transplantation: Patients undergo donor bone marrow infusion on day 0.
• Post-transplantation therapy: Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4.
• Graft-vs-host disease prophylaxis: Beginning on day 5, patients receive oral mycophenolate mofetil 3 times daily until day 35 and tacrolimus IV (then changing to orally) twice daily until day 180.

Treatment continues in the absence of disease progression.

After completion of study transplantation, patients are followed on days 30, 60, 100, and 180; at 1 year; and then annually for 4 additional years.

PROJECTED ACCRUAL: A total of 75-100 patients will be accrued for this study within 3-4 years.

Conditions

Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Mini-haplo Transplant

Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.

Group Type: EXPERIMENTAL

cyclophosphamide

Intervention Type: DRUG

fludarabine phosphate

Intervention Type: DRUG

mycophenolate mofetil

Intervention Type: DRUG

tacrolimus

Intervention Type: DRUG

allogeneic bone marrow transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Interventions

cyclophosphamide

Intervention Type: DRUG

fludarabine phosphate

Intervention Type: DRUG

mycophenolate mofetil

Intervention Type: DRUG

tacrolimus

Intervention Type: DRUG

allogeneic bone marrow transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

• LVEF < 45%
• FEV_1 or FVC < 50% of predicted (75% of predicted in patients with prior thoracic or mantle radiotherapy)
• Total bilirubin > 2.0 mg/dL (unless documented Gilbert's disease)
• Creatinine > 2.0 mg/dL
• Non-Hodgkin's lymphoma (NHL)

• Low-grade NHL allowed provided patient had a remission duration of < 1 year after administration of any established, multi-agent chemotherapy regimen (e.g., CVP, CHOP, or rituximab in combination with CHOP)
• Intermediate- or high-grade NHL allowed provided patient is ineligible for autologous SCT according to the criteria listed above
• Multiple myeloma
• Myelodysplastic syndromes
• Paroxysmal nocturnal hemoglobinuria
• Chronic myeloproliferative disorders other than CML, including any of the following:

• Chronic myelomonocytic leukemia
• Agnogenic myeloid metaplasia (or myeloid metaplasia with myelofibrosis), with hemoglobin < 10 g/dL OR WBC < 4,000/mm^3 or > 30,000/mm^3
• Polycythemia vera or essential thrombocythemia in "spent" phase, with a history of 2 of the following:

• Marrow fibrosis
• Splenomegaly
• Cytopenia (i.e., absolute neutrophil count < 1,500/mm^3, platelet count < 100,000/mm^3, hemoglobin < 10 g/dL)
• Polycythemia vera or essential thrombocythemia with transformation to myelodysplastic syndromes or acute myeloid leukemia (requires treatment to achieve < 20% blasts in marrow)
• No smoldering myeloma
• Patients with acute myeloid leukemia or myelodysplastic syndromes must have had comprehensive cytogenetic evaluation of bone marrow specimen during active disease
• Ineligible for or refused bone marrow transplantation from an HLA-matched sibling or unrelated donor
• Ineligible for or refused autologous SCT
• Must have an HLA mismatched (i.e., 3/6, 4/6, or 5/6) related (first-degree relative)* donor available

• Donor ≥ 18 years of age NOTE: *Patients with an inherited recombinant HLA haplotype may receive marrow from the parent in whose gamete the recombination occurred

NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

Age

• 6 months to 74 years

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• See Disease Characteristics
• Bilirubin < 3.1 mg/dL

Renal

• See Disease Characteristics

Cardiovascular

• See Disease Characteristics
• LVEF ≥ 35%

Pulmonary

• See Disease Characteristics
• FEV_1 or FVC ≥ 40% of predicted in patients without prior thoracic or mantle radiotherapy (60% of predicted in patients with prior thoracic or mantle radiotherapy)

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• Geographically accessible
• No debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment or follow-up

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• No prior transfusions from donor

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics

Surgery

• Not specified

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 74 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ephraim J. Fuchs, MD

Role: STUDY_CHAIR

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Locations

Blood and Marrow Transplant Program at Northside Hospital

Atlanta, Georgia, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Hahnemann University Hospital

Philadelphia, Pennsylvania, United States

Countries

United States

Other Identifiers

P01CA015396

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA006973

Identifier Type: NIH

Identifier Source: secondary_id

View Link

JHOC-J0457

Identifier Type: OTHER

Identifier Source: secondary_id

JHOC-04072704

Identifier Type: -

Identifier Source: secondary_id

J0457 CDR0000440990

Identifier Type: -

Identifier Source: org_study_id