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Fludarabine and Low-Dose TBI Dose Escalation to Determine the Optimal Regimen for Achieving High Rates Engraftment of Unrelated Donor Peripheral Blood Stem Cell in Patients With Chronic Myeloid Leukemia - A Multi-Center Trial


Phase 1/Phase 2
N/A
N/A
Not Enrolling
Both
Leukemia

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Trial Information

Fludarabine and Low-Dose TBI Dose Escalation to Determine the Optimal Regimen for Achieving High Rates Engraftment of Unrelated Donor Peripheral Blood Stem Cell in Patients With Chronic Myeloid Leukemia - A Multi-Center Trial


OBJECTIVES:

Primary

- Determine whether increasing the intensity of a nonmyeloablative conditioning regimen
comprising fludarabine and total body irradiation allows achievement of a donor T-cell
chimerism level of > 40% on day 28 post-transplantation in 90% or more of patients with
chronic myelogenous leukemia undergoing allogeneic peripheral blood stem cell
transplantation and immunosuppression comprising cyclosporine and mycophenolate
mofetil.

- Determine the feasibility of reducing the day 84 graft rejection rate/graft failure to
< 10% in patients treated with this regimen.

- Determine the feasibility of maintaining the incidence of grade 4 acute
graft-versus-host disease at < 10% in patients treated with this regimen.

- Determine the feasibility of maintaining the day 200 nonrelapse mortality rate at < 15%
in patients treated with this regimen.

Secondary

- Determine the rate of complete cytogenetic remission in patients treated with this
regimen.

- Determine the probability of actuarial disease-free survival of patients treated with
this regimen.

- Determine the pharmacokinetics of mycophenolate mofetil and fludarabine in these
patients.

OUTLINE: This is a multicenter, dose-escalation study of fludarabine and total-body
irradiation (TBI).

- Nonmyeloablative conditioning regimen: Patients receive fludarabine IV on days -4 to -2
OR days -6 to -2. Patients undergo TBI on day 0.

- Allogeneic peripheral blood stem cell transplantation (PBSCT): After the completion of
TBI, patients undergo allogeneic PBSCT on day 0.

- Immunosuppression: Patients receive oral cyclosporine twice daily on days -3 to 100
followed by a taper to day 177 in the absence of graft-versus-host disease (GVHD).
Beginning within 4-6 hours after the completion of PBSCT, patients receive oral
mycophenolate mofetil 2-3 times daily on days 0-40 followed by a taper to day 96 in the
absence of GVHD.

Cohorts of 5-25 patients receive cumulative doses of fludarabine and escalating doses of TBI
until 2 of 5, 3 of 10-15, 4 of 20, or 5 of 25 patients experience a day 28 post-transplant
T-cell chimerism level ≤ 40% and/or a day 84 post-transplant graft rejection rate of > 10%.

After completion of study transplantation, patients are followed 3 times weekly for 3
months, at 6, 12, and 18 months, annually for 5 years, and then periodically thereafter.

PROJECTED ACCRUAL: A total of 5-75 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Diagnosis of chronic myelogenous leukemia (CML), meeting 1 of the following criteria:

- First or second chronic phase

- Philadelphia chromosome-positive (Ph+) disease by cytogenetics or
fluorescent in situ hybridization (FISH)

- First accelerated phase, meeting any of the following criteria:

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

- Any additional clonal cytogenetic abnormalities

- Increasing splenomegally

- Extramedullary tumor

- WBC, platelet count, or hematocrit pertubations not controlled by therapy
with hydroxyurea, interferon, or imatininb mesylate

- Persistent unexplained fever or bone pain

- Less than 5% blasts in marrow at time of transplant

- No blast crisis

- No other curative therapy exists

- Received prior imatinib mesylate AND meets ≥ 1 of the following criteria:

- Hematologic evidence of disease progression

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

- Cytogenetic evidence of disease progression, defined as an increase in Ph+ cells
or BCR/ABL-positive (BCR/ABL+) cells of > 25%

- Lack of complete cytogenetic remission (no Ph+ cells by cytogenetic analysis or
BCR/ABL+ cells by FISH) after 1 year of treatment with imatinib mesylate

- At least 65% Ph+ cells by cytogenetic analysis or BCR/ABL+ cells by FISH after 6
months of treatment with imatinib mesylate

- Less than 3-log reduction in BCR/ABL mRNA levels by quantitative polymerase
chain reaction (Q-PCR) compared to a standard baseline level after 1 year of
treatment with imatinib mesylate

- Molecular evidence of disease progression, defined as > 1 log increase in
BCR/ABL mRNA levels by Q-PCR, detected in 2 samples

- Experienced adverse events with imatinib mesylate treatment that would preclude
further administration of the drug

- Patient refused further treatment with imatinib mesylate despite lack of disease
progression

- Refused conventional myeloablative allogeneic stem cell transplantation OR at high
risk for regimen-related toxicity due to pre-existing medical conditions (for
patients < 50 years of age)

- Unrelated donor available

- Matched at HLA-A, -B, -C, -DRB1, and -DQB1 by high-resolution typing

- A single allele* disparity for HLA-A, -B, or -C allowed

- Negative anti-donor cytotoxic crossmatch

- Not a marrow donor NOTE: *Patient and donor pairs homozygous at a mismatched
allele (e.g., the patient is A*0101 and the donor is A*0201) are considered a
two-allele mismatch and are not allowed

- No CNS involvement with disease that is refractory to intrathecal chemotherapy

PATIENT CHARACTERISTICS:

Age

- Any age

Performance status

- Karnofsky 70-100%

- Lanksy 50-100% (for pediatric patients)

Life expectancy

- Not specified

Hematopoietic

- See Disease Characteristics

Hepatic

- No fulminant liver failure

- No cirrhosis of the liver with evidence of portal hypertension

- 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

- Not specified

Cardiovascular

- Ejection fraction ≥ 40%

- No cardiac failure requiring therapy

- No poorly controlled hypertension (i.e., blood pressure ≥ 150/90 mm Hg despite
standard medication)

Pulmonary

- DLCO ≥ 35% (corrected)

- No requirement for supplementary continuous oxygen

- Pulmonary nodules allowed at the discretion of the principal investigator

Immunologic

- HIV negative

- No uncontrolled systemic infection

- No fungal infection with radiological progression after treatment with amphotericin B
or active triazole for > 1 month

Other

- Not pregnant or nursing

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

- No other active malignancy except nonmelanoma skin cancer

- No prior localized malignancy at high risk (≥ 20%) of recurrence

PRIOR CONCURRENT THERAPY:

Biologic therapy

- See Disease Characteristics

- See Chemotherapy

Chemotherapy

- See Disease Characteristics

- More than 3 weeks since prior cytotoxic chemotherapy

- Imatinib mesylate and interferon are not considered cytotoxic chemotherapy

Endocrine therapy

- Not specified

Radiotherapy

- Not specified

Surgery

- Not specified

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

Increase number of patients with donor T-cell chimerism from > 40% to 90% on day 28 post-transplant

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:

1939.00

NCT ID:

NCT00119340

Start Date:

April 2005

Completion Date:

November 2007

Related Keywords:

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

Name

Location

Fred Hutchinson Cancer Research CenterSeattle, Washington  98109
Veterans Affairs Medical Center - SeattleSeattle, Washington  98108
Seattle Cancer Care AllianceSeattle, Washington  98109