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

NCT ID: NCT00110058

Last Updated: 2011-11-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-02-28
• Study Completion Date: 2006-07-31

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.

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.

Conditions

Leukemia

Study Design

• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

recombinant interferon alfa

Intervention Type: BIOLOGICAL

therapeutic allogeneic lymphocytes

Intervention Type: BIOLOGICAL

cyclosporine

Intervention Type: DRUG

fludarabine phosphate

Intervention Type: DRUG

imatinib mesylate

Intervention Type: DRUG

mycophenolate mofetil

Intervention Type: DRUG

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

• 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

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Principal Investigators

Brenda Sandmaier, MD

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Center

Locations

City of Hope Comprehensive Cancer Center

Duarte, California, United States

Seattle Cancer Care Alliance

Seattle, Washington, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Countries

United States

References

Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, Shizuru J, Franke GN, Maris MB, Boyer M, Bruno B, Sahebi F, Langston AA, Hari P, Agura ED, Lykke Petersen S, Maziarz RT, Bethge W, Asch J, Gutman JA, Olesen G, Yeager AM, Hubel K, Hogan WJ, Maloney DG, Mielcarek M, Martin PJ, Flowers MED, Georges GE, Woolfrey AE, Deeg JH, Scott BL, McDonald GB, Storb R, Sandmaier BM. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021 Jun 1;106(6):1599-1607. doi: 10.3324/haematol.2020.248187.

Reference Type: DERIVED

PMID: 32499241 (View on PubMed)

Other Identifiers

FHCRC-1954.00

Identifier Type: -

Identifier Source: secondary_id

CDR0000423314

Identifier Type: REGISTRY

Identifier Source: secondary_id

1954.00

Identifier Type: -

Identifier Source: org_study_id