Venetoclax Plus High-Dose Cytarabine Active, Safe in Children with Relapsed/Refractory AML

Venetoclax (Venclexta, Genentech) in combination with high-dose cytarabine demonstrated activity and tolerability in pediatric patients with relapsed/refractory acute myeloid leukemia (AML), according to an abstract presented at the 2019 American Society of Clinical Oncology Annual Meeting.

Currently, venetoclax is approved for use in combination with azacytidine, or decitabine, or low-dose cytarabine for the treatment of adults with newly-diagnosed AML who are 75 years of age or older or who have other medical conditions that prevent the use of standard chemotherapy. Venetoclax is also indicated for the treatment of adults with chronic lymphocytic leukemia or small lymphocytic lymphoma.

At an oral abstract session held at the conference on May 31, study investigators described the first use of venetoclax in combination with high-dose cytarabine and idarubicin and in patients 2- to 22-years old with relapsed AML.

The phase 1 study included patients with relapsed AML or refractory AML to at least 2 courses of induction therapy. For the study design, all patients received venetoclax (240 or 360 mg/m2) on days 1 to 28 and low-dose (100 mg/m² every 12 hours x 20 doses) or high-dose (1000 mg/m² every 12 hours x 8 doses) cytarabine beginning on day 8. Additionally, patients who had previously received <270 mg/m² of doxorubicin equivalents also received idarubicin 12 mg/m² on day 8 in dose level 4, according to the abstract. Other patients were enrolled on the expansion cohort at dose level 3. The primary endpoints of the study are the recommended phase 2 doses of venetoclax plus cytarabine and venetoclax plus cytarabine and idarubicin.

Among 18 evaluable patients, a single ILT (prolonged hematological suppression beyond day 50) was observed. The results showed that toxicities were consistent with underlying cytotoxic chemotherapy. Overall, 14 patients experienced a total of 40 grade 3 toxicities, including 6 documented infections and 23 episodes of febrile neutropenia.

When combined with high-dose cytarabine or cytarabine/idarubicin, the recommended phase 2 dose of venetoclax was 360 mg/m² (max 600 mg), according to the findings. Of the 12 patients with >50% reduction in blasts following the 7-day venetoclax window therapy, end-of-cycle marrow responses included 7 complete remission/complete remission with incomplete count recovery/partial remission and 3 partial remission. Minimal residual disease negative remissions occurred in 4 patients.

Currently, BH3 profiling of samples and a phase 2 expansion of both dose levels 3 and 4 are underway to further characterize the promising activity of these combinations, the investigators noted.

Overall, the results concluded that venetoclax combined with cytarabine or cytarabine/idarubicin demonstrated safety and activity in children with relapsed/refractory AML.

Reference

Karol SE, Alexander T, Gupta SD, et al. Safety and activity of venetoclax in combination with high-dose cytarabine in children with relapsed or refractory acute myeloid leukemia. J Clin Oncol 37, 2019 (suppl; abstr 10004).