Combination Chemotherapy in Treating Young Patients With Relapsed or Refractory Acute Leukemia

OBJECTIVES:

• Determine the maximum tolerated dose of clofarabine when administered in combination with topotecan hydrochloride, vinorelbine ditartrate, thiotepa, and dexamethasone in young patients with relapsed or refractory acute leukemia.
• Evaluate the antileukemic potential of this regimen in these patients.
• Evaluate the incidence and severity of treatment-related morbidity and mortality in patients treated with this regimen.
• Develop a new reinduction treatment regimen that will result in a patient clinical response with as little residual disease as possible to permit a bone marrow transplantation while in subsequent remission; maintain the response long enough to identify an appropriate stem cell donor; and permit the patient to undergo a stem cell transplantation free of infections and without vital organ dysfunction.

OUTLINE: This is a nonrandomized, prospective, dose-escalation study of clofarabine.

Patients receive topotecan hydrochloride IV continuously over 120 hours on days 0-4; vinorelbine ditartrate over 6-10 minutes on days 0, 7, and 14; thiotepa IV over 4 hours on day 2; clofarabine IV over 2 hours on days 3-7; and oral or IV dexamethasone 3 times daily on days 3 and 7-13 and then on day 3 only thereafter. Patients also receive filgrastim (G-CSF) subcutaneously once daily beginning on day 8 and continuing until blood counts recover. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of clofarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of 6 patients experience dose-limiting toxicity OR the dose preceding that at which 2 of 3 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.

After completion of study treatment, patients are followed once a week for 4 weeks, twice a month for 6 months, and then once a month for 2 years.

PROJECTED ACCRUAL: A total of 23 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Must have 1 of the following diagnoses:

• Acute lymphoblastic leukemia (ALL) meeting 1 of the following criteria:

• Refractory to initial induction with two or more standard regimens
• Relapsed < 24 months after first complete response on a high-risk protocol OR refractory to one standard reinduction regimen
• Second or greater relapse
• Acute myeloid leukemia, acute biphenotypic leukemia, or acute undifferentiated leukemia meeting 1 of the following criteria:

• Refractory to initial induction
• First or greater relapse
• Must have > 20% bone marrow blasts, or evidence of recurrent disease at an extramedullary site
• No symptomatic CNS disease

• Patients with asymptomatic CNS disease are eligible with the approval of the principal investigator

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 70-100% OR Lansky PS 70-100%
• AST and ALT < 4 times upper limit of normal
• Bilirubin < 2.0 mg/dL (unless liver involvement)
• Creatinine within normal range for age OR creatinine clearance > 60 mL/min/1.73 m^2
• Adequate cardiac function (either asymptomatic with no prior risk factors, or if symptomatic, left ventricular ejection fraction > 50% at rest)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No active uncontrolled viral, bacterial, or fungal infection

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior clofarabine
• More than 2 weeks since prior systemic chemotherapy

• At least 7 days since prior chemotherapy for patients with rapidly progressive disease and recovered