Posted: Monday, April 27, 2020
Findings presented in the journal Blood indicate nine drug combinations beyond the simple pairing of venetoclax plus azacitidine may exceed the ex vivo activity of the BLC2 inhibitor used to treat elderly patients with acute myeloid leukemia (AML) who are considered unfit for standard chemotherapy. Stephen E. Kurtz, PhD, of the Knight Cancer Institute, Portland, Oregon, and colleagues also recognized clinical, mutational, and expression-based biomarker patterns that may be associated with sensitivity and resistance to the additional drug combinations.
“An understanding of the biology underlying the efficacy of each specific combination will offer an opportunity to fine-tune their clinical application toward the AML subsets most likely to benefit from each combination strategy and may also propel testing of these combinations in other malignancies,” the authors concluded.
A series of venetoclax combinations were examined via a functional genomics approach applied directly to more than 350 patients diagnosed with AML. The patients’ mononuclear cells were plated ex vivo with a panel of 10 venetoclax combinations and the represented single agents.
In line with clinical findings, venetoclax plus azacitidine demonstrated “significantly” enhanced efficacy in AML samples ex vivo, with evidence of enhanced efficacy when compared with each single agent. After this benchmark, the authors found nine venetoclax combinations that exceeded ex vivo activity and enhanced the efficacy of venetoclax plus azacitidine: (venetoclax paired with ruxolitinib, palbociclib, ARRY-382, doramapimod, trametinib, sorafenib, dasatinib, JQ1, and panobinostat.
With ruxolitinib plus venetoclax as the lead example, the investigators noted that the combination demonstrated similarly enhanced ex vivo efficacy in specimens from patients with newly diagnosed and relapsed or refractory AML, compared with venetoclax plus azacitidine. At the genetic level, the sensitivity of ruxolitinib plus venetoclax included not only specimens with highly frequent FLT3-ITD and NPM1 mutations, but also those with TP53 mutations, which are associated with venetoclax resistance.
Disclosure: For full disclosures of the study authors, visit ashpublications.org.