Fludarabine and Radiation Therapy in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Chronic Phase or Accelerated Phase Chronic Myelogenous Leukemia

Sponsor

Fred Hutchinson Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00110058

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

16.9

Duration (Months)

13.3

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Biological: recombinant interferon alfa Biological: therapeutic allogeneic lymphocytes Drug: cyclosporine Drug: fludarabine phosphate Drug: imatinib mesylate Drug: mycophenolate mofetil Procedure: peripheral blood stem cell transplantation Radiation: radiation therapy	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Multi-Center Phase II Study of Nonmyeloablative Conditioning With TBI and Fludarabine for HLA-Matched Related Hematopoietic Cell Transplantation for Treatment of Chronic Myeloid Leukemia in Chronic and Accelerated Phase

Study Start Date :

Feb 1, 2005

Actual Study Completion Date :

Jul 1, 2006

Outcome Measures

Primary Outcome Measures

Progression-free survival []

Secondary Outcome Measures

Rate of complete molecular response []
Late nonrelapse mortality []
Incidence and severity of graft-vs-host disease (GVHD) []
Incidence of serious infections []
Myelosuppression []
Overall survival and disease-free survival []

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010-3000
2	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109-1023
3	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109-1024