A phase I trial of a single high dose of idarubicin combined with high-dose cytarabine as induction therapy in relapsed or refractory adult patients with acute lymphoblastic leukemia

Abstract

Relapsed or refractory adult acute lymphoblastic leukemia (ALL) carries a grave prognosis. The most promising strategy for curing these patients is through re-induction chemotherapy followed by successful allogeneic transplant. We studied a new high-dose induction regimen inorder to improve the outcome for these patients. Eighteen adult patients with relapsed/ refractory ALL were treated on a phase I study of high-dose cytarabine combined with a single escalating dose of idarubicin. Five patients had primary refractory disease and 13 were treated in refractory relapse. Nine patients (50%) had Ph⁺ ALL. The induction regimen was cytarabine 3 g/m²/day intravenously days 1–5 and idarubicin as a single intravenous dose on day 3. G-CSF 5 μg/kg subcutaneously every 12 h was started on day 7. The initial idarubicin dose was 20 mg/m² with dose escalations of 10 mg m². Cohorts of three patients were treated at each idarubicin dose level. Unacceptable toxicity was encountered at 50 mg/m² with one death from infection and one death from cardiotoxicity in a patient with significant prior anthracycline exposure. There were no instances of grade 4 non-hematologic toxicity encountered at idarubicin doses of 20 mg/m², 30 mg/m², or 40 mg/m². The data suggest a dose–response relationship for increasing doses of idarubicin with 0/3 complete responses (CR) at 20 mg/m², 1/3 CR at 30 mg/m², and 7/12 (58%) CR at idarubicin doses ⩾40 mg/m². We conclude that concomitant administration of cytarabine 3 g/m²/day × 5 and high-dose idarubicin at 40 mg/m² as a single dose on day 3 can be administered safely to patients with refractory and relapsed ALL.