TY - JOUR
T1 - Clinical Correlates of Venetoclax-Based Combination Sensitivities to Augment Acute Myeloid Leukemia Therapy
AU - Eide, Christopher A.
AU - Kurtz, Stephen E.
AU - Kaempf, Andy
AU - Long, Nicola
AU - Joshi, Sunil Kumar
AU - Nechiporuk, Tamilla
AU - Huang, Ariane
AU - Dibb, Charles A.
AU - Taylor, Akosha
AU - Bottomly, Daniel
AU - McWeeney, Shannon K.
AU - Minnier, Jessica
AU - Lachowiez, Curtis A.
AU - Saultz, Jennifer N.
AU - Swords, Ronan T.
AU - Agarwal, Anupriya
AU - Chang, Bill H.
AU - Druker, Brian J.
AU - Tyner, Jeffrey W.
N1 - Publisher Copyright:
©2023 American Association for Cancer Research.
PY - 2023
Y1 - 2023
N2 - The BCL2 inhibitor venetoclax combined with the hypomethylating agent azacytidine shows significant clinical benefit in a subset of patients with acute myeloid leukemia (AML); however, resistance limits response and durability. We prospectively profiled the ex vivo activity of 25 venetoclax-inclusive combinations on primary AML patient samples to identify those with improved potency and synergy compared with venetoclax + azacytidine (Ven + azacytidine). Combination sensitivities correlated with tumor cell state to discern three patterns: primitive selectivity resembling Ven + azacytidine, monocytic selectivity, and broad efficacy independent of cell state. Incorporation of immunophenotype, mutation, and cytogenetic features further stratified combination sensitivity for distinct patient subtypes. We dissect the biology underlying the broad, cell state–independent efficacy for the combination of venetoclax plus the JAK1/2 inhibitor ruxolitinib. Together, these findings support opportunities for expanding the impact of venetoclax-based drug combinations in AML by leveraging clinical and molecular biomarkers associated with ex vivo responses. SIGNIFICANCE: By mapping drug sensitivity data to clinical features and tumor cell state, we identify novel venetoclax combinations targeting patient subtypes who lack sensitivity to Ven + azacytidine. This provides a framework for a taxonomy of AML informed by readily available sets of clinical and genetic features obtained as part of standard care.
AB - The BCL2 inhibitor venetoclax combined with the hypomethylating agent azacytidine shows significant clinical benefit in a subset of patients with acute myeloid leukemia (AML); however, resistance limits response and durability. We prospectively profiled the ex vivo activity of 25 venetoclax-inclusive combinations on primary AML patient samples to identify those with improved potency and synergy compared with venetoclax + azacytidine (Ven + azacytidine). Combination sensitivities correlated with tumor cell state to discern three patterns: primitive selectivity resembling Ven + azacytidine, monocytic selectivity, and broad efficacy independent of cell state. Incorporation of immunophenotype, mutation, and cytogenetic features further stratified combination sensitivity for distinct patient subtypes. We dissect the biology underlying the broad, cell state–independent efficacy for the combination of venetoclax plus the JAK1/2 inhibitor ruxolitinib. Together, these findings support opportunities for expanding the impact of venetoclax-based drug combinations in AML by leveraging clinical and molecular biomarkers associated with ex vivo responses. SIGNIFICANCE: By mapping drug sensitivity data to clinical features and tumor cell state, we identify novel venetoclax combinations targeting patient subtypes who lack sensitivity to Ven + azacytidine. This provides a framework for a taxonomy of AML informed by readily available sets of clinical and genetic features obtained as part of standard care.
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U2 - 10.1158/2643-3230.BCD-23-0014
DO - 10.1158/2643-3230.BCD-23-0014
M3 - Article
C2 - 37698624
AN - SCOPUS:85175878441
SN - 2643-3230
VL - 4
SP - 452
EP - 467
JO - Blood cancer discovery
JF - Blood cancer discovery
IS - 6
ER -