Paediatric acute myeloid leukaemia (AML) is the second most common childhood leukaemia. Most treatment regimens utilise four to five courses of intensive myelosuppressive chemotherapy followed by hematopoietic stem cell transplantation, leaving patients with lifelong toxicity. However, 30-40% AML patients ultimately relapse with only a ~35% chance of survival. Hence, safer and more effective strategies are urgently needed to improve the outcome of paediatric AML patients.
Venetoclax, a selective BCL-2 inhibitor, has emerged as a promising therapeutic agent for treating blood cancers, including paediatric AML. However, in vitro drug sensitivity testing on Australia’s largest panel of paediatric AML patient-derived xenografts (PDXs) from Children’s Cancer Institute, revealed distinct resistant and sensitive subpopulations in response to venetoclax monotherapy. Follow-up in vivo testing against 19 AML PDXs revealed that venetoclax efficacy in vitro positively correlates with its in vivo efficacy, and single-agent venetoclax induced more than 50% leukaemia burden regression in 58% of PDXs (11/19) tested. Interestingly, a cohort of PDXs (7/12) that were resistant to venetoclax in vitro exhibited sensitivity in vivo. By leveraging next-generation sequencing data generated in our PDX models, this venetoclax preclinical sensitivity dataset provides a valuable opportunity to further elucidate gene signatures that may identify paediatric AML patients who are likely to respond to venetoclax clinically.
To identify novel therapies to overcome venetoclax resistance, unbiased in vitro combination high-throughput drug combination screens (HTS) were conducted using a well-established 150-drug library tailored for paediatric precision medicine in 3 venetoclax-resistant PDXs. Our HTS result demonstrated a strong synergy (Bliss Score ≥15) between venetoclax and vorinostat in two PDX models. In vivo validation of the efficacy of this combination is currently underway.
In summary, we generated a venetoclax preclinical dataset, facilitating the identification of gene signatures predictive of venetoclax sensitivity to inform real-time clinical decision-making and recommend venetoclax to paediatric AML patients. Through our combination HTS, we have also identified novel venetoclax-based regimens to overcome venetoclax resistance. These findings provide compelling preclinical evidence to support the development of chemotherapy-free therapeutic strategies incorporating venetoclax, with direct translational relevance to personalised paediatric AML treatment and future clinical trial design.