Pharmacogenomic profiling of paediatric AML informs precision medicine

Intensive anthracycline- and cytarabine-based chemotherapy with or without haematopoietic stem cell transplantation (HSCT) has remained the standard of care (SoC) for paediatric AML for decades. [Blood 2021;138:1009-1018] However, recent genomic discoveries showed that up to 14 percent of children with high-risk or relapsed/refractory leukaemias could receive matched targeted therapies. [Cancer Discov 2021;11:1424-1439]

Although direct drug-response profiling of patients’ biopsies complements static genetic measurements and allows increasingly precise treatment, most studies assessing drug-sensitivity patterns of AML have been conducted in the adult arena, and multdimensional gene-drug clinical data for pediatric AML are currently lacking. [Nat Med 2017;23:1028-1035]

The data set of the current CUHK study was based on 61 specimens taken from a cohort of 52 children (median age, 9 years) diagnosed with AML (n=47; 90.4 percent), mixed phenotype acute leukaemia (MPAL; n=3; 5.8 percent) or myelodysplastic syndrome (MDS; n=2; 3.8 percent). Primary haematopoetic cells’ response was tested ex vivo against a collection of 45 bioactive agents (39 targeted and six chemotherapeutics), which were selected based on their molecular targets, stages of clinical development, and relevance to haematologic malignancies. [Blood Cancer Discov 2022;3:516-535]

The researchers were able to divide the tested agents into clusters, based on their activity. Cluster A comprised seven highly active compounds (median half-maximal inhibitory concentration [IC₅₀] <70 nmol/L), namely, the proteasome inhibitors bortezomib, carfilzomib, and oprozomib, HDAC inhibitor panobinostat, survivin inhibitor YM155, HSP90 inhibitor elesclomol, and BCL-2 inhibitor navitoclax. Cluster B comprised 14 generally active compounds (median IC₅₀ <700 nmol/L), including the cytotoxic agents cytarabine, daunorubicin, fludarabine, and mitoxantrone, as well as inhibitors against BCL-2, HSP90, proteasome, and tyrosine kinases. Venetoclax, dasatinib, methotrexate, and sunitinib were placed in clusters C and D as they exhibited bimodal activities, with extreme sensitivity in some cases and complete resistance in others. Cluster E comprised 12 generally inactive compounds with sporadic responses. Cluster F comprised eight essentially inactive compounds, notably including several approved drugs for adult AML, such as decitabine, enasidenib, and ivosidenib.

“By profiling the response of myeloblasts from children to a clinically relevant drug panel through an optimized ex vivo culture system, we showed that several approved targeted agents and investigational drugs, including bortezomib, carfilzomib, oprozomib, elesclomol, panobinostat, navitoclax, and YM155, are more potent than chemotherapeutics at clinically achievable concentrations. Our data delivered a wealth of opportunistic drug candidates that deserve to be prioritized in upcoming clinical trials,” commented the researchers.

The researchers also demonstrated the feasibility of drug screening–guided treatment for children with high-risk AML in the clinical setting. Screening-guided treatment was given to five children with relapsed disease who failed successive salvage therapies. Encouragingly, two of the evaluable patients achieved remission and bridged to curative HSCT.

“We propose incorporating drug profiling into upcoming clinical trials to determine its predictive potential and prioritize patients most likely to benefit. In addition, our analyses in serial samples revealed dynamic changes in drug responses and genomic/transcriptomic landscapes. Therefore, in order to empower precision medicine, individual genomic profiling should be a continuous process,” suggested the researchers. “However, adopting nonstandard pharmacogenomic profiling in children would require tumour board recommendation, careful consideration of potential toxicity and drug cost, and paediatric experience with particular agents.”