Safety and activity of venetoclax in combination with high-dose cytarabine in children with relapsed or refractory acute myeloid leukemia.

Abstract

10004 Background: Venetoclax is an orally available BCL-2 antagonist with demonstrated activity in adults with newly diagnosed or relapsed acute myeloid leukemia (AML). Here, we describe the first use of venetoclax 1) in combination with high-dose cytarabine and idarubicin 2) in patients 2-22 years old with relapsed AML. Methods: Patients with relapsed AML or AML refractory to at least two courses of induction therapy were enrolled in this Phase 1 study with a rolling-six design. All patients received venetoclax (240 or 360 mg/m2) on days 1-28 and low-dose (LD: 100 mg/m2 every 12 hours x 20 doses) or high-dose (HD: 1000 mg/m2 every 12 hours x 8 doses) cytarabine beginning on day 8 (Table). Patients who had previously received < 270 mg/m2 of doxorubicin equivalents also received idarubicin 12 mg/m2 on day 8 in dose level 4; other patients were enrolled on the expansion cohort at dose level 3. Non-hematologic CTCAE grade 3 or higher toxicities were intensity limiting (ILT), excluding those anticipated with HD cytarabine. Results: Among 18 evaluable patients, a single ILT (prolonged hematological suppression beyond day 50) was observed (Table). Toxicities were consistent with the underlying cytotoxic chemotherapy, with 14 patients experiencing a total of 40 grade 3 toxicities including 6 documented infections and 23 episodes of febrile neutropenia. There was 1 grade 4 fungal sepsis. The recommended phase 2 dose of venetoclax was 360 mg/m2 (max 600 mg) when combined with HD cytarabine or HD cytarabine/idarubicin. Of the 12 patients with > 50% reduction in blasts following the 7-day venetoclax window therapy, end-of-cycle marrow responses included 7 CR/CRi and 3 PR. Minimal residual disease negative remissions occurred in 4 patients. BH3 profiling of samples and a phase 2 expansion of both dose levels 3 and 4 to further characterize the promising activity of these combinations are underway. Conclusions: Venetoclax combined with cytarabine or cytarabine/idarubicin is active and well tolerated in pediatric patients with relapsed/ refractory AML. Clinical trial information: NCT03194932. [Table: see text]