Combination Chemotherapy Plus PSC-833 in Treating Children With Refractory or Relapsed Acute Leukemia

OBJECTIVES:

I. Determine the maximum tolerated dose of PSC-833 in combination with mitoxantrone and etoposide in children with refractory or relapsed acute leukemia.

II. Determine the effects of PSC-833 on mitoxantrone and etoposide pharmacokinetics.

III. Quantify MDR1 gene expression and MDR1 P-glycoprotein expression and function in patient-derived leukemia cells.

OUTLINE: This is a dose escalation study of PSC-833.

Patients undergo induction therapy consisting of etoposide IV and mitoxantrone IV on days 1-5. Patients then receive PSC-833 IV over 124 hours beginning on day 2. A second course is administered no sooner than 21 days from the start of the first course if the marrow is hypocellular after the first course. Patients with persistent disease after 2 induction courses are removed from the study. Patients receive a total of 3 courses of etoposide/mitoxantrone. Patients who achieve complete remission after 1 induction course receive 2 courses of etoposide/mitoxantrone with PSC-833 as consolidation, beginning within 4 weeks of attainment of complete remission. Patients who achieve complete remission after 2 induction courses receive 1 course of etoposide/mitoxantrone with PSC-833 as consolidation. Cohorts of 3-6 patients receive escalating doses of PSC-833 until the maximum tolerated dose is determined. Patients are followed every 6 months.

DISEASE CHARACTERISTICS:

• Acute myeloid leukemia (AML) in one of the following categories:
• First relapse if initial CR less than 6 months
• Refractory to first or second induction with daunomycin, cytarabine, and thioguanine (DAT) or other anthracycline-containing regimens
• Relapse following bone marrow transplantation provided good trilineage engraftment followed transplant and greater than 6 months since transplant
• Presentation with secondary AML or AML evolving from myelodysplastic syndrome --Acute lymphocytic leukemia in one of the following categories:
• In second or subsequent relapse or failed second or later induction attempts regardless of prior remissions
• Relapsed following bone marrow transplantation provided good trilineage engraftment followed transplant and greater than 6 months since transplant
• No isolated CNS or extramedullary relapse

PATIENT CHARACTERISTICS:

• Age: Under 22 at diagnosis
• Performance status: Karnofsky 50-100% (ECOG 0-2)
• Lansky 40-100% (in patients under 12 years of age)
• Life expectancy: At least 8 weeks
• Bilirubin less than 1.5 mg/dL
• ALT less than twice normal
• Creatinine normal for age (within 2 standard deviations) OR glomular filtration rate at least 70 mL/min
• Albumin at least 3 g/dL
• Ejection fraction greater than 50% at rest or with 5% increase with exercise OR shortening fraction greater than 27% by echocardiogram
• No history of clinical heart failure
• No uncontrolled infection
• No anticonvulsant therapy
• No history of allergic reactions or anaphylaxis to etoposide not remediable by premedication
• Not pregnant or nursing
• Fertile patients must use effective contraception
• Third percentile weight for height

PRIOR CONCURRENT THERAPY:

• At least 4 weeks since chemotherapy and recovered
• Prior cumulative anthracycline dose no greater than 360 mg per square meter
• Hydroxyurea therapy allowed just prior to study for rapidly rising blast count