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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


Phase 2
N/A
N/A
Not Enrolling
Both
Leukemia

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Trial Information

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


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.

Inclusion Criteria


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

Type of Study:

Interventional

Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Safety Issue:

No

Principal Investigator

Brenda Sandmaier, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center

Authority:

United States: Federal Government

Study ID:

1954.00

NCT ID:

NCT00110058

Start Date:

February 2005

Completion Date:

July 2006

Related Keywords:

  • Leukemia
  • accelerated phase chronic myelogenous leukemia
  • childhood chronic myelogenous leukemia
  • chronic phase chronic myelogenous leukemia
  • Philadelphia chromosome positive chronic myelogenous leukemia
  • relapsing chronic myelogenous leukemia
  • Leukemia
  • Leukemia, Myeloid
  • Leukemia, Myeloid, Accelerated Phase
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Name

Location

Fred Hutchinson Cancer Research CenterSeattle, Washington  98109
City of Hope Comprehensive Cancer CenterDuarte, California  91010
Seattle Cancer Care AllianceSeattle, Washington  98109