Prolonged high dose ARA-C infusions in acute leukemia.

Area of Science:

• Oncology
• Pharmacology

Background:

• Acute leukemia and chronic myelogenous leukemia (CML) in blast phase represent advanced hematologic malignancies.
• Cytosine arabinoside (ara-C) is a chemotherapy agent used in leukemia treatment.
• High-dose chemotherapy regimens are explored to overcome treatment resistance in relapsed or refractory leukemia.

Purpose of the Study:

• To evaluate the efficacy and toxicity of high-dose cytosine arabinoside (ara-C) administered via continuous infusion.
• To determine an appropriate Phase II dose for this treatment regimen.
• To assess the pharmacokinetic profile of ara-C and its metabolite ara-U during continuous infusion.

Main Methods:

• Continuous infusion of high-dose cytosine arabinoside (ara-C) at 250 mg/M2/hr for 36 to 72 hours.
• Dose escalation and toxicity assessment to establish a Phase II dose.
• Monitoring of plasma levels of ara-C and ara-U.
• Evaluation of objective responses and duration of remission in patients with acute leukemia and CML in blast phase.

Main Results:

• Major toxicities included myelosuppression, diarrhea, and abdominal pain; gastrointestinal toxicity was dose-limiting.
• A Phase II dose was established at 250 mg/M2/hr for 60-72 hours.
• Four patients achieved objective responses, including two CML patients returning to chronic phase and two acute myelogenous leukemia patients achieving complete remission.
• Plasma levels of ara-C and ara-U did not accumulate during infusion.

Conclusions:

• Continuous infusion of high-dose ara-C demonstrates potential utility in treating acute leukemia and CML in blast crisis.
• The established Phase II dose appears to induce responses with manageable, albeit significant, toxicities.
• Further investigation into this high-dose continuous infusion strategy for acute leukemias is warranted.