PF279 BST‐236 ‐ A NOVEL SAFE AND EFFECTIVE FIRST‐LINE THERAPY FOR PATIENTS WITH ACUTE MYELOID LEUKEMIA UNFIT FOR STANDARD CHEMOTHERAPY. SUMMARY OF CLINICAL RESULTS TO DATE
Authors: Zuckerman T. , Altman J.K. , Ram R. , Burch M. , Wolach O. , Levi I. , Gourevitch A. , Flaishon L. , Tessler S. , Gengrinovitch S. , Ben Yakar R. , Rowe J.M. 
Published: June 2019

Background:Cytarabine is the backbone of acute myeloid leukemia (AML) treatment for decades. However, its use in older and medically unfit patients is limited due to its increased toxicity in this population. The backbone of therapy of older and unfit patients is therefore hypomethylating agents or low‐dose cytarabine, with limited efficacy and poor outcomes, especially in patients with secondary AML who were previously exposed to hypomethylating agents. BST‐236 is a prodrug of cytarabine, enabling high‐dose cytarabine treatment with reduced systemic toxicity, including in patients unfit for standard therapy. Data from a completed phase 1/2a trial and an ongoing phase 2b study in AML patients unfit for standard therapy demonstrate promising safety and efficacy in this challenging population.Aims:To evaluate the efficacy and safety of BST‐236 in AML patients unfit for standard induction therapy.Methods:Thirty acute leukemia patients (28 AML and 2 acute lymphoblastic leukemia) were treated to date with BST‐236 as a single agent. Twenty‐six patients, median age 77 years (range 26–90 years) were treated in a phase 1/2a dose‐escalation study (doses 0.3–6 g/m2/d), and 4 patients in an ongoing phase 2b study of BST‐236 (4.5 g/m2/d, equivalent to 3 g/m2/d cytarabine). Each BST‐236 treatment course (induction and consolidation) consists of 6 daily 1‐hour infusions.Results:The cumulative safety data of these 30 patients, 26 of them (22 in the phase 1/2a study and all patients in the ongoing phase 2b study) not eligible for standard induction therapy due to age or comorbidities, demonstrate that BST‐236 is safe and well‐tolerated in repeated‐course administrations, including in the older and unfit population, with no safety concerns. Adverse events include mainly hematological “on‐target” events with no mucositis or neurological toxicity.Fifteen patients (11 in the phase 1/2a study and all patients in the ongoing phase 2b study) had newly‐diagnosed AML, either de novo or secondary to myelodysplastic syndrome (MDS) and were not eligible for standard induction therapy (median age 78 years). Ten patients (67%) were ≥75 year‐old at diagnosis, and 6 patients (40%) were ≥80 year‐old. Nine patients (60%) had prior MDS, 6 (40%) were previously treated with hypomethylating agent, and 14 (93%) had intermediate or adverse cytogenetics. The median baseline bone marrow blast percentage was 80%.In spite of the poor prognostic factors, the combined durable complete remission (CR) rate is 33% (40% CR/CRp (CR with incomplete platelet recovery)) at all doses combined, and 50% in the 4.5–6 g/m2/d doses, with neutrophil and platelet recovery achieved by approximately day 30 of induction and consolidation courses. Notably, among the 5 patients who reached a CR (median age 77), 2 were previously treated with 5 or 10 courses of hypomethylating agents (Table 1).The median overall survival (OS) of the 11 unfit AML patients in the phase 1/2a study was 6.5 months, following only 1 or 2 induction courses. The median OS of the responders (CR/CRp) was not reached at data lock (>1 year). OS follow up including enrollment on the phase 2b study is ongoing.Updated data will be presented at the meeting.Table 1. Individual patient baseline characteristics and outcome.Summary/Conclusion:The emerging clinical data suggest that BST‐236 is safe and effective for the treatment of AML patients who are unfit for standard induction therapy, and may establish BST‐236 as a new therapeutic backbone, either as a single agent or in combination with targeted therapy.image