Combination Chemotherapy and Total-Body Irradiation Followed by Peripheral Stem Cell or Bone Marrow Transplantation in Treating Patients With Acute Lymphoblastic Leukemia

OBJECTIVES:

• Determine if a one-year disease free survival of 40% and a day 200 transplant-related mortality of less than 25% can be achieved in patients with high-risk acute lymphoblastic leukemia in complete remission treated with a nonmyeloablative conditioning regimen comprising fludarabine and total body irradiation followed by allogeneic peripheral blood stem cell or bone marrow transplantation.
• Evaluate the efficacy and toxicity of donor lymphocyte infusion in the treatment of minimal residual disease after nonmyeloablative allografting in these patients.

OUTLINE: This is a multicenter study.

Patients receive a nonmyeloablative conditioning regimen comprising fludarabine IV on days -4 to -2 and total body irradiation (TBI) on day 0. Children undergo allogeneic peripheral blood stem cell transplantation (PBSCT) or bone marrow transplantation after TBI on day 0. Adults undergo filgrastim (G-CSF)-mobilized allogeneic PBSCT after TBI on day 0.

Patients also receive graft-versus-host disease (GVHD) prophylaxis therapy comprising oral cyclosporine twice daily on days -3 to 56 and then tapered and oral mycophenolate mofetil once at 5-10 hours after transplantation on day 0 and then twice daily on days 1-27.

Patients who have no evidence of grade 2 or greater acute GVHD or clinically extensive chronic GVHD, have been off GVHD prophylaxis therapy for 1-2 weeks, and have stable or increasing minimal residual disease after discontinuation of GVHD prophylaxis therapy receive donor lymphocyte infusion (DLI) IV over 30 minutes. DLI repeats every 4 weeks for a total of 3 doses (if necessary).

Patients without a history of CNS leukemia and patients with a history of CNS leukemia previously treated with prophylactic craniospinal irradiation receive methotrexate (MTX) or cytarabine (ARA-C) intrathecally (IT) for a total of 2 doses before transplantation and for a total of 6 doses beginning on day 32 after transplantation. Patients with a history of CNS leukemia not previously treated with craniospinal irradiation undergo craniospinal irradiation for 11 days before conditioning regimen and then MTX or ARA-C IT for a total of 6 doses beginning on day 32 after transplantation. Male patients also undergo testicular radiotherapy for 7 days.

Patients are followed at 1, 2, 3, 6, 12, 18, and 24 months.

PROJECTED ACCRUAL: A total of 30 patients (20 adults and 10 children) will be accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

• Diagnosis of acute lymphoblastic leukemia (ALL)
• Adult patients must meet 1 of the following criteria:

• Age 50 to 75 with high-risk ALL in complete remission (CR) (less than 5% blasts by morphology on bone marrow aspirate and absence of peripheral blasts) or ALL in second CR (CR2) or greater
• Age 18 to 50 with high-risk ALL in first CR (CR1) and either ineligible for conventional allogeneic transplantation (based on general medical condition) or refused conventional transplantation

• High-risk adult ALL in CR1 includes patients meeting 1 or more of the following criteria:

• Age 30 and over
• Non-T-cell phenotype
• Cytogenetic abnormalities including t(9;22), t(4;11), trisomy 8, or monosomy 7
• Failure to achieve CR after 4 weeks of induction chemotherapy
• Age 18 to 50 with ALL in CR2 or greater and ineligible for conventional allogeneic transplantation based on general medical condition
• Age 18 to 50 with high-risk ALL in CR2 or greater and refused conventional allogeneic transplantation
• Pediatric patients must meet 1 of the following criteria:

• Under age 18 with high-risk ALL in CR1 and ineligible for conventional allogeneic transplantation based on general medical condition

• High-risk pediatric ALL in CR1 includes patients meeting 1 or more of the following criteria:

• Cytogenetic abnormalities

• t(9;22) with WBC at least 25,000/mm3 at diagnosis
• t(4;11) in patients under age 1 or age 10 and over
• Hypodiploidy (no more than 45 chromosomes)
• Failure to achieve CR after 4 weeks of induction chemotherapy
• Persistent peripheral blasts after 1 week of induction chemotherapy
• Under age 18 with CR2 or greater and ineligible for conventional allogeneic transplantation based on general medical condition
• Age 12 and under allowed if approved by the principle investigator
• No active CNS disease
• Availability of a sibling donor (excluding an identical twin)

• HLA genotypically identical for at least 1 haplotype
• HLA-A, -B, -C, -DRB1, and -DQB1 genotypically or phenotypically identical

PATIENT CHARACTERISTICS:

Age:

• See Disease Characteristics
• 75 and under

Performance status:

• Karnofsky 50-100% (adults)
• Lansky 40-100% (children)

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• No fulminant liver failure
• No alcoholic hepatitis
• No history of bleeding esophageal varices
• No grade II or greater hepatic encephalopathy
• No hepatic synthetic dysfunction evidenced by prolongation of PT with INR greater than 2.5
• No intractable ascites related to portal hypertension
• No bacterial or fungal liver abscess
• No chronic viral hepatitis with bilirubin greater than 5 mg/dL
• No biliary obstruction with bilirubin greater than 5 mg/dL
• No concurrent symptomatic biliary disease

Renal:

• Not specified

Cardiovascular:

• Cardiac ejection fraction at least 30%

Pulmonary:

• No requirement for supplementary continuous oxygen

Other:

• HIV negative
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 1 year after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent posttransplantation growth factors during mycophenolate mofetil administration

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified