Aspacytarabine for the treatment of patients with AML unfit for intensive chemotherapy: a phase 2 study.

High-dose cytarabine is associated with gastrointestinal and cerebellar toxicity, precluding its use for older or unfit patients with acute myeloid leukemia (AML). Aspacytarabine, an inactive prodrug of cytarabine, was evaluated as monotherapy in a phase 2b study of patients unfit for intensive chemotherapy (NCT03435848). Sixty-five patients with AML were treated with aspacytarabine 4.5 g/m2 per day (equimolar to 3 g/m2 per day cytarabine) for 6 doses per treatment. The median age was 75 years; 60.6% of patients had de novo AML, 28.8% had AML secondary to myelodysplastic syndrome, and 10.6% had therapy-related AML. Overall, 36.9% achieved complete remission (CR) with full count recovery. CR rates in patients with secondary AML, patients with prior treatment with hypomethylating agents, and patients with TP53 mutation were 26.7%, 25%, and 36%, respectively. Median overall survival was 9 months (range, 6-15.9) and was not reached among responders. Hematologic recovery was observed in all responding patients by day 26 without prolonged cytopenias. Adverse events typically precluding the use of high-dose cytarabine in older or unfit patients were not observed. These data suggest that aspacytarabine may be an effective regimen with a reduction in the attendant toxicities associated with high-dose cytarabine, an important consideration when treating AML and other hematologic disorders that use high-dose cytarabine. This trial was registered at www.clinicaltrials.gov as #NCT03435848.

BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a study.

High-dose cytarabine is the backbone of acute myeloid leukemia (AML) treatment. Nevertheless, its use in older patients is considerably limited due to increased toxicity. BST-236 (INN aspacytarabine) is a novel cytarabine prodrug designed to deliver high-dose cytarabine to target cells with reduced systemic exposure to free cytarabine. This phase 1/2a dose-escalation study was designed to evaluate BST-236 safety, pharmacokinetics, and efficacy in older or unfit-for-intensive-therapy patients with acute leukemia. Twenty-six patients, unfit for standard therapy, who were either relapsed/refractory or newly diagnosed, received BST-236 in 6 dose-escalating cohorts (range 0.3 to 6 g/m2 per day). BST-236 was administered intravenously once daily over 60 minutes for 6 consecutive days. The median age was 76.5 (26 to 90), with 84.6% of patients ≥70 years. BST-236 was safe and well tolerated. The maximal tolerated dose was 6 g/m2 per day. Overall response rate was 29.6%. A subgroup analysis of newly diagnosed patients with AML, de novo or secondary to myelodysplastic syndrome, unfit for standard induction (median age 78), demonstrated overall response of 45.5%. The median overall survival was 6.5 months and was not reached in patients achieving complete remission. The findings of this phase 1/2 study suggest that BST-236 safely delivers high and efficacious cytarabine doses to older patients who are unfit for standard induction and lays the foundation for further studies of BST-236 in AML. This trial was registered at www.clinicaltrials.gov as #NCT02544438.