Venetoclax May Be an Option for Children With R/R AML, MDS

Pediatric patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) may benefit from venetoclax (Venclexta), a new study suggests.

The report comes from a single-center study in which 12 patients were given venetoclax-based regimens under a compassionate use program. The report was published in the British Journal of Haemaotology.¹

There is no universal standard of care in R/R AML, noted corresponding author Sophie Cousson, MD, of the Robert Debré Academic Hospital, in Paris, and colleagues. The BCL-2 inhibitor venetoclax has become a first-line option in combination with hypomethylating agents (HMAs) or low-dose cytarabine in certain adults with newly diagnosed AML, gaining FDA approval in 2018.

“This authorization has sparked interest in exploring venetoclax-based regimens for pediatric R/R leukemia,” Cousson and colleagues wrote.

They noted that a 2020 report found venetoclax plus chemotherapy led to an overall response rate (ORR) of 80% (95% CI, 56%-94%) and a complete response (CR) rate of 70% (95% CI, 46%-88%) in pediatric patients with heavily relapsed and refractory AML treated with the recommended phase 2 dose of venetoclax of 360 mg/m².²

Subsequent research into pediatric use of venetoclax has shown that the therapy works best when combined with other therapeutic agents, has a favorable safety profile, and could be used as a bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT), Cousson and colleagues said.¹

In the new report, the investigators analyzed the cases of 12 patients, ranging in age from 2 to 12 years, who were given venetoclax-based regimens for R/R myeloid malignancies. Eight of the patients had previously experienced relapse, 5 patients were given venetoclax after allo-HSCT, and 3 patients had refractory AML, the authors said. One patient had MDS-related AML (MDS-AML), and the remainder had R/R AML.

The patients received either venetoclax plus HMAs (5 patients) or chemotherapy (5 patients) or venetoclax alone (2 patients). At a median follow-up of 11 months, the investigators said the ORR for the cohort was 41.6% and 33% of patients achieved CR.

The CR rate was best (60%) in patients who received venetoclax plus cytotoxic agents. In those receiving venetoclax plus HMAs, just 1 patient achieved a complete response with incomplete recovery. Neither of the 2 patients on venetoclax monotherapy responded.

The 1-year overall survival rate was 50% (95% CI, 28%-88%), and 1-year event-free survival rate was 25% (95% CI, 9.4%-67%).

By the end of follow-up, 11 patients had died. Most of the patients died as a result of progression or relapse (10 patients), but 1 patient died due to an infection associated with transplantation.

Cousson and colleagues said the single-center nature of the study limits the conclusions that can be drawn from it, but they said the data still provide valuable insights. For instance, they noted that 4 patients achieved CR without using anthracyclines, and 3 of those patients were able to undergo HSCT.

“This regimen could be particularly beneficial for heavily pretreated patients, allowing for less intensive treatment options,” they wrote.

They said their experience suggests a venetoclax-cytarabine-based regimen is a favorable bridging strategy to HSCT. In addition, they argued that more research is needed to understand molecular determinants of response to venetoclax-based regimens, and they said resistance-management strategies will need to be developed.

“BLC2-inhibitors like venetoclax are promising targeted therapy in treating R/R myeloid disorders but significant research efforts and multicenter clinical trials are warranted to refine treatment strategies in these patients,” they concluded.

References

1. Cousson S, Calvo C, Goldwirt L, et al. Monocentric experience of venetoclax-based regimen in paediatric refractory and relapsed AML/MDS. Br J Haematol. Published online October 24, 2024. doi:10.1111/bjh.19849
2. 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(4):551-560. doi:10.1016/S1470-2045(20)30060-7