Maximizing cell death in leukemias: bcl-2 and beyond

BCL-2 inhibitor Venetoclax (Ven) combined with hypomethylating agents (HMA) is a new standard of care for newly diagnosed patients with AML who are 75 years or older, or unfit for intensive chemotherapy. While AML blasts are generally BCL-2-dependent, adaptive resistance occurs, with selection of AML clones harboring specific genomic lesions. Therapy escapes in clones with “signaling mutations” such as FLT3 and RAS, is commonly associated with MCL-1 dependency that can be managed with inhibitors of upstream regulators of MCL-1 stability (such as kinase inhibitors) or direct MCL-1 inhibitors. JAK-2 mutated AML progressing post exhibit BCL-XL dependency and are sensitive to BCL-XL inhibitors and degraders. While these are other combinations are being tested in clinical trials, other novel approaches are needed in particular in refractory AML. Transcriptomic analysis of samples from AML patients with relapsed AML undergoing HMA/Ven therapy showed association of pre-treatment immune signatures and response. HMA/Ven therapy upregulated the expression of the immune checkpoint PD-1 in T cells while preserving CD4+ and CD8+ memory T cells in AML patients, and in vitro PD-1 inhibition potentiated the anti-leukemia response. We further demonstrated that HMA/Ven increased macrophage-induced phagocytosis in parental, venetoclax-resistant and in isogenic TP53-mutant AML MOLM13 cells, and the combination of 5F9 and VEN/AZA resulted in elimination of circulating blasts and significant extension of survival in AML PDX. Further understanding of molecular events driving interplay of leukemia and immune system will facilitate design of novel combinatorial approaches targeting cell death machinery and immune system in leukemia. BCL-2 inhibitor Venetoclax (Ven) combined with hypomethylating agents (HMA) is a new standard of care for newly diagnosed patients with AML who are 75 years or older, or unfit for intensive chemotherapy. While AML blasts are generally BCL-2-dependent, adaptive resistance occurs, with selection of AML clones harboring specific genomic lesions. Therapy escapes in clones with “signaling mutations” such as FLT3 and RAS, is commonly associated with MCL-1 dependency that can be managed with inhibitors of upstream regulators of MCL-1 stability (such as kinase inhibitors) or direct MCL-1 inhibitors. JAK-2 mutated AML progressing post exhibit BCL-XL dependency and are sensitive to BCL-XL inhibitors and degraders. While these are other combinations are being tested in clinical trials, other novel approaches are needed in particular in refractory AML. Transcriptomic analysis of samples from AML patients with relapsed AML undergoing HMA/Ven therapy showed association of pre-treatment immune signatures and response. HMA/Ven therapy upregulated the expression of the immune checkpoint PD-1 in T cells while preserving CD4+ and CD8+ memory T cells in AML patients, and in vitro PD-1 inhibition potentiated the anti-leukemia response. We further demonstrated that HMA/Ven increased macrophage-induced phagocytosis in parental, venetoclax-resistant and in isogenic TP53-mutant AML MOLM13 cells, and the combination of 5F9 and VEN/AZA resulted in elimination of circulating blasts and significant extension of survival in AML PDX. Further understanding of molecular events driving interplay of leukemia and immune system will facilitate design of novel combinatorial approaches targeting cell death machinery and immune system in leukemia.