Fludarabine and Radiation Therapy in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Chronic Phase or Accelerated Phase Chronic Myelogenous Leukemia
Fludarabine and Radiation Therapy in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Chronic Phase or Accelerated Phase Chronic Myelogenous Leukemia
RATIONALE: Giving low doses of chemotherapy, such as fludarabine, and radiation therapy
 before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells.
 It also stops the patient's immune system from rejecting the donor's stem cells. The donated
 stem cells may replace the patient's immune system and help destroy any remaining cancer
 cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor
 lymphocyte infusion) or interferon alfa after the transplant may help increase this effect.
 Sometimes the transplanted cells from a donor can also make an immune response against the
 body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may
 stop this from happening.

 PURPOSE: This phase II trial is studying how well giving fludarabine together with radiation
 therapy works in treating patients who are undergoing donor stem cell transplant for chronic
 phase or accelerated phase chronic myelogenous leukemia.
OBJECTIVES:

 Primary

 -  Determine the disease-free survival rate in patients with chronic or accelerated phase
 chronic myelogenous leukemia that failed or inadequately responded to prior imatinib
 mesylate treated with nonmyeloablative conditioning comprising fludarabine and low-dose
 total-body irradiation followed by allogeneic peripheral blood stem cell
 transplantation.

 Secondary

 -  Determine the complete cytogenetic and molecular response rates in patients treated with
 this regimen.

 -  Determine overall survival of patients treated with this regimen.

 -  Determine non-relapse mortality in patients treated with this regimen.

 -  Determine the incidence of serious infection, graft-versus-host disease, and
 myelosuppression in patients treated with this regimen.

 OUTLINE: This is a multicenter study.

 -  Conditioning treatment: Patients receive fludarabine IV on days -4 to -2. Patients
 undergo low-dose total-body irradiation (TBI) on day 0.

 -  Allogeneic peripheral blood stem cell transplantation: After TBI, patients undergo
 allogeneic peripheral blood stem cell transplantation on day 0.

 -  Immunosuppression: Patients receive oral cyclosporine twice daily on days -3 to 56
 followed by a taper to day 180 in the absence of graft-versus-host disease (GVHD).
 Patients also receive oral mycophenolate mofetil twice daily on days 0-27.

 -  Post-transplant treatment: Patients experiencing disease persistence or progression AND
 low donor chimerism discontinue immunosuppression. Patients with disease persistence or
 progression after discontinuing immunosuppression receive oral imatinib mesylate once
 daily. Patients who have disease improvement after day 28 of imatinib mesylate treatment
 AND who have no evidence of disease after day 84 of imatinib mesylate treatment continue
 imatinib mesylate in the absence of disease progression or unacceptable toxicity.
 Patients who fail to improve after day 28 of imatinib mesylate treatment OR who have
 residual disease after day 84 of imatinib mesylate treatment receive donor lymphocytes
 IV over 15-30 minutes once every 1-4 months for up to 4 infusions. Patients ineligible
 to receive donor lymphocytes (e.g., patients with evidence of GVHD) receive interferon
 alfa subcutaneously 3 times a week for up to 12 months in the absence of disease
 progression or unacceptable toxicity.

 After completion of study treatment, patients are followed at 6, 9, 12, 18, and 24 months,
 and then annually for 5 years.

 PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.
DISEASE CHARACTERISTICS:

 -  Diagnosis of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia,
 meeting 1 of the following criteria:

 -  Chronic phase

 -  Ph+ by cytogenetics or fluorescent in situ hybridization (FISH) assay

 -  Accelerated phase, meeting any of the following criteria:

 -  More than 10% but < 30% myeloblasts and promyelocytes in marrow or
 peripheral blood

 -  Any additional clonal cytogenetic abnormalities

 -  Increasing splenomegaly

 -  Extramedullary tumor

 -  WBC, platelet count, or hematocrit perturbations not controlled by therapy
 with hydroxyurea, interferon, or imatinib mesylate

 -  Persistent unexplained fever or bone pain

 -  Less than 5% blasts in the marrow at time of transplantation

 -  Not eligible for OR refused conventional myeloablative allogeneic stem cell
 transplantation

 -  Failed OR suboptimal response to prior imatinib mesylate, as defined by 1 of the
 following:

 -  Absence of complete hematologic response after > 3 months of treatment with
 imatinib mesylate

 -  Absence of cytogenetic response, as defined by 1 of the following:

 -  Absence of any cytogenetic response (< 95% Ph+ or BCR/ABL+ cells by
 cytogenetic or FISH analysis, respectively) after 6 months of treatment with
 imatinib mesylate

 -  Absence of major cytogenetic response (< 35% Ph+ or BCR/ABL+ cells by
 cytogenetic or FISH analysis, respectively) after 1 year of treatment with
 imatinib mesylate

 -  Absence of complete cytogenetic response (no Ph+ cells by cytogenetic
 analysis OR BCR/ABL+ cells within normal limits by FISH analysis) after 18
 months of treatment with imatinib mesylate

 -  Hematologic evidence of disease progression

 -  Cytogenetic evidence of disease progression

 -  Increase in Ph+ cells or BCR/ABL+ cells by > 20% with at least 1 month
 between sequential testing

 -  Molecular evidence of disease progression

 -  More than 10-fold increase in BCR/ABL mRNA levels by quantitative polymerase
 chain reaction (Q-PCR) with at least 1 month between 2 sequential tests

 -  Experienced adverse events during treatment with imatinib mesylate that precluded
 further administration of the drug

 -  No CNS disease refractory to intrathecal chemotherapy

 -  HLA identical related donor available

 -  Phenotypically matched at HLA-A, -B, -C, DRQ1, and DBQ1

 -  No presence of circulating leukemic blasts by standard pathology

 PATIENT CHARACTERISTICS:

 Age

 -  Any age

 Performance status

 -  Karnofsky 70-100% OR

 -  Lansky 70-100%

 Life expectancy

 -  Not specified

 Hematopoietic

 -  See Disease Characteristics

 Hepatic

 -  No fulminant liver failure

 -  No cirrhosis of the liver with evidence of portal hypertension or bridging fibrosis

 -  No alcoholic hepatitis

 -  No esophageal varices

 -  No history of bleeding esophageal varices

 -  No hepatic encephalopathy

 -  No uncorrectable hepatic synthetic dysfunction evidenced by prolongation of PT

 -  No ascites related to portal hypertension

 -  No bacterial or fungal liver abscess

 -  No biliary obstruction

 -  No chronic viral hepatitis AND bilirubin > 3 mg/dL

 -  No symptomatic biliary disease

 Renal

 -  Renal failure allowed

 Cardiovascular

 -  No symptomatic coronary artery disease

 -  Ejection fraction ≥ 35%

 -  No other cardiac failure requiring therapy

 -  No poorly controlled hypertension (blood pressure ≥ 150/90 mm Hg) on standard
 medication

 Pulmonary

 -  DLCO ≥ 30%

 -  Total lung capacity ≥ 30%

 -  FEV_1 ≥ 30%

 -  No requirement for continuous supplementary oxygen

 -  No fungal pneumonia with radiological progression after treatment with amphotericin or
 mold-active azoles for > 1 month

 Other

 -  Not pregnant or nursing

 -  Fertile patients must use effective barrier contraception during and for 12 months
 after completion of study treatment

 -  HIV negative

 -  No other disease that severely limits life expectancy

 -  No other active malignancy except localized nonmelanoma skin cancer

 -  No nonhematologic malignancy within the past 5 years that is currently in complete
 remission and has a > 20% risk of disease recurrence except for nonmelanoma skin
 cancer

 -  No systemic uncontrolled infection

 -  No active bacterial or fungal infection unresponsive to medical therapy

 PRIOR CONCURRENT THERAPY:

 Biologic therapy

 -  See Disease Characteristics

 Chemotherapy

 -  See Disease Characteristics

 Endocrine therapy

 -  Not specified

 Radiotherapy

 -  Not specified

 Surgery

 -  Not specified

 Other

 -  At least 48 hours since prior imatinib mesylate