Venetoclax Plus High-Dose Cytarabine With or Without Idarubicin Well Tolerated in Pediatric AML

In a small study of children and young adults with relapsed or refractory acute myeloid leukemia (AML), venetoclax plus cytarabine chemotherapy, with or without idarubicin, was safe and associated with a relatively high response rate. Results from this phase I trial were published in Lancet Oncology by Seth Karol, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and colleagues. The authors noted that these findings offer first-time evidence for the potential combined use of BCL2 inhibition and intensive chemotherapy in pediatric patients with AML.

Thirty-eight patients between ages 2 and 22 (median age = 10 years) with relapsed or refractory AML or AML of ambiguous lineage were recruited from three U.S. research hospitals. In the trial’s dose-escalation phase, participants received once-daily oral venetoclax 240 to 360 mg/m2 in continuous 28-day cycles. Venetoclax was combined with intravenous twice-daily cytarabine at either 100 mg/m2 for 20 doses (intermediate-dose) or 1,000 mg/m2 for 8 doses (high dose). Using a rolling accrual strategy, some patients also received a single dose of intravenous idarubicin 12 mg/m2.

Identifying the recommended phase II dose of venetoclax plus chemotherapy was the study’s primary endpoint. Secondary endpoints included the proportion of patients who achieved either complete response (CR; defined as measurable residual disease <5%) or CR with incomplete hematologic recovery (CRi) with the recommended phase II dose. Bone marrow evaluations were performed between days 35 and 49 of treatment to evaluate treatment response.

All dose levels were tolerated, with no patients requiring a dose reduction or discontinuation because of venetoclax-associated toxicity.

Of the 38 participants, 21 (55%) had a prior CR to one therapy, and 12 (34%) had a previous response to two or more therapies.

All but 2 patients received the planned combination therapy with dose escalation. Nonreceipt of combination therapy was related to rapid disease progression and infection.

In the remaining 36 patients, the median follow-up was 7.1 months (interquartile range = 5.1-11.2). One dose-limiting toxicity was observed (prolonged hematopoietic recovery in a participant receiving venetoclax 240 mg/m2, twice daily cytarabine 100 mg/m2, and no idarubicin). However, the authors wrote that all dose levels were tolerated, with no patients requiring a dose reduction or discontinuation because of venetoclax-associated toxicity. Based on these findings, the investigators identified the recommended phase II regimen as: venetoclax 360 mg/m2 (to a maximum 600 mg/m2) plus cytarabine 1,000 mg/m2 per dose, with or without idarubicin 12 mg/m2.

Looking at the efficacy of this treatment combination, the authors reported that 24 of 35 evaluable patients (69%) had a response after cycle one. The response rates were as follows:

  • CR: 46% (n=16)
  • CRi: 11% (n=4)
  • partial response (PR): 11% (n=4)

Out of the 20 patients who were treated with the recommended phase II dose, 14 (70%) demonstrated a CR with hematologic recovery or CRi (95% CI 46–88), and 2 patients (10%) had a PR. For a detailed breakdown of response rates across different dosing groups, see the TABLE.

Among the high-dose cytarabine group, 16 (70%) had a CR or CRi, and 2 patients had a PR, for an overall response rate of 78%.

During the first therapy cycle, patients experienced a median of two grade ≥3 toxicities. Two patients experienced serious adverse events (AEs) during cycle 1, including sepsis and toxic death.

Of the 65 observed toxicities in this cohort, infectious toxicities accounted for 65% (n=42), and nearly one-third of these (29%; n=11) were grade 3 or 4. Other common grade 3/4 AEs included:

  • febrile neutropenia (66%)
  • bloodstream infections (16%)
  • invasive fungal infections (16%)

The heterogenous patient population in regard to prior therapy and genetics represents one limitation of this study. The small sample size further limits the implications of these findings.

Despite the limitations, the study authors wrote that their results suggest that the combination treatment should be tested in newly diagnosed patients with high-risk AML and should be further evaluated to validate leukemic blast reduction and BH3 dependencies as biomarkers of response to combination therapy.


Karol SE, Alexander TB, Budhraja A, et al. Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. Lancet Oncol. 2020;21:551-560.