Venetoclax with Cytarabine in Children with Relapsed or Refractory AML

A recent study has found that the BCL-2 agonist venetoclax, combined with cytarabine or cytarabine with idarubicin, is active and well-tolerated in pediatric patients with relapsed or refractory acute myeloid leukemia (AML).

Investigators from the St. Jude Children’s Research Hospital in Memphis, TN presented the results of the phase 1 trial, which examined the use of venetoclax combined with cytarabine or cytarabine idarubicin in pediatric patients, at the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting.

While venetoclax has demonstrated activity in adults with newly diagnosed or relapsed AML, investigators sought to describe the first use of venetoclax in combination with high-dose cytarabine and idarubicin in patients between 2 and 22 years of age with relapsed AML. Patients with relapsed or refractory AML to at least 2 course of induction therapy were enrolled in the study, which had a rolling-6 design.

All patients within the study received venetoclax at doses of 240mg/m2 or 360 mg/m2 on days 1-28 and low-dose (100 mg/m2 every 12 hours with 20 doses) or high-dose (1000 mg/m2 every 12 hours with 8 doses) cytarabine beginning on day 8. Authors noted that patients who had previously received less than 270 mg/m2 of doxorubicin equivalents were also given idarubicin 12mg/m2 on day in dose level 4 — other patients were enrolled on the expansion cohort data dose level 3. Non-hematologic common terminology criteria for adverse events (CTCAE) grade 3 or higher toxicities were intensity limiting (ILT), excluding those anticipated with high-use cytarabine.

Investigators found that, among 18 evaluable patients, a single ILT was observed. Additionally, toxicities were consistent with underlying cytotoxic chemotherapy, with 14 of the patients experiencing a total of 40 grade 3 toxicities. Within those 40 was 6 documented infections, 23 episodes of febrile neutropenia, and 1 case of grade 4 fungal sepsis.

Authors noted that the recommended phase 2 dose of venetoclax was 360mg/m2 (max 600mg) when combined with high-dose cytarabine or high-dose cytarabine with idarubicin. A total of 12 patients achieved reduction of 50% or greater in blasts following the 7-day venetoclax window therapy. In that group, end-of-cycle marrow responses included 7 who achieved complete remission or complete remission with incomplete hematologic recovery and 3 had partial response. A group of 4 patients had minimal residual disease negative remissions.

Based on the results, authors concluded that venetoclax combined with cytarabine or cytarabine with idarubicin is active and well tolerated in pediatric patients with relapsed or refractory AML. Additionally, the authors noted that a phase 2 expansion of both dose levels 3 and 4 to further characterize the activity of these combinations are underway.

This study, titled “Safety and activity of venetoclax in combination with high-dose cytarabine in children with relapsed or refractory acute myeloid leukemia,” was presented at ASCO 2019.