In a phase I trial reported in The Lancet Oncology, Karol et al found that the combination of the BCL2 inhibitor venetoclax and the chemotherapeutic agent cytarabine with or without idarubicin produced responses in pediatric patients with relapsed or refractory acute myeloid leukemia.

As noted by the investigators, venetoclax has shown activity in combination with hypomethylating agents and low-dose cytarabine in older adults with newly diagnosed acute myeloid leukemia for whom chemotherapy is not suitable.

Study Details

The dose-escalation study, performed at three sites in the United States, enrolled 38 patients 3 to 22 years old with relapsed or refractory acute myeloid leukemia or acute leukemia of ambiguous lineage. Dose escalation consisted of venetoclax once per day in continuous 28-day cycles at either 240 mg/m² or 360 mg/m² in combination with cytarabine every 12 hours at either 100 mg/m² for 20 doses or 1,000 mg/m² for 8 doses. A single dose of idarubicin 12 mg/m² was given to 9 of 20 patients receiving venetoclax at 360 mg/m² plus cytarabine at 1,000 mg/m² every 12 hours for 8 doses.

Key Findings

All dose levels were tolerated, with only one dose-limiting toxicity observed (prolonged hematopoietic recovery in one patient receiving venetoclax at 240 mg/m² and cytarabine at 100 mg/m²).

The recommended phase II dose of venetoclax was determined to be 360 mg/m² (maximum = 600 mg) combined with cytarabine (1,000 mg/m² per dose for eight doses) with or without idarubicin (12 mg/m² as a single dose).

Overall, 36 patients received combination therapy with dose escalation, with a median follow-up of 7.1 months. Response was observed in 24 (69%) of 35 patients who were evaluable after cycle 1. Among the 20 patients treated with the recommended phase II dose, 14 (70%) had a complete response with or without complete hematologic recovery, and 2 (10%) had a partial response; complete response with or without complete hematologic recovery occurred in 8 of 11 patients who did not receive idarubicin and 6 of 9 who received idarubicin. Duration of response could not be assessed because 80% of patients with complete response with or without complete hematologic recovery proceeded to receipt of allogeneic stem cell transplantation.

Among all 38 patients, the most common grade 3 or 4 adverse events were febrile neutropenia (n = 22), bloodstream infections (n = 6), and invasive fungal infections (n = 6). Treatment-related death occurred in one patient due to colitis and sepsis. Serious adverse events occurred in two patients during cycle 1, including sepsis in one patient and the colitis/sepsis noted above. Tumor lysis syndrome was observed in one patient with rapidly progressive disease.

The investigators concluded, “The safety and activity of venetoclax plus chemotherapy in pediatric patients with heavily relapsed and refractory acute myeloid leukemia suggests that this combination should be tested in newly diagnosed pediatric patients with high-risk acute myeloid leukemia.”

Jeffrey E. Rubnitz, MD, of St. Jude Children’s Research Hospital, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the National Institutes of Health, American Lebanese Syrian Associated Charities, AbbVie, and Gateway for Cancer Research. For full disclosures of the study authors, visit thelancet.com.