Ex vivo venetoclax sensitivity testing predicts treatment response in acute myeloid leukemia.

Autor:	Kuusanmäki H; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark; Foundation for the Finnish Cancer Institute, Helsinki., Kytölä S; Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki., Vänttinen I; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki., Ruokoranta T; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki., Ranta A; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki., Huuhtanen J; Hematology Research Unit, University of Helsinki, Helsinki., Suvela M; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki., Parsons A; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki., Holopainen A; Department of Medicine, Kuopio University Hospital, Kuopio., Partanen A; Department of Medicine, Kuopio University Hospital, Kuopio., Kuusisto MEL; Department of Medicine, Oulu University Hospital, Oulu, Finland; Department of Hematology, University of Oulu, Oulu., Koskela S; Department of Internal Medicine, Tampere University Hospital, Tampere., Räty R; Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki., Itälä-Remes M; Department of Clinical Hematology, Turku University Hospital, Turku., Västrik I; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki., Dufva O; Hematology Research Unit, University of Helsinki, Helsinki., Siitonen S; Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital., Porkka K; Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; Hematology Research Unit, University of Helsinki, Helsinki., Wennerberg K; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen., Heckman CA; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki., Ettala P; Department of Clinical Hematology, Turku University Hospital, Turku., Pyörälä M; Department of Medicine, Kuopio University Hospital, Kuopio., Rimpiläinen J; Department of Internal Medicine, Tampere University Hospital, Tampere., Siitonen T; Department of Medicine, Oulu University Hospital, Oulu., Kontro M; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Foundation for the Finnish Cancer Institute, Helsinki, Finland; Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki. mika.kontro@helsinki.fi.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2023 Jul 01; Vol. 108 (7), pp. 1768-1781. Date of Electronic Publication: 2023 Jul 01.
DOI:	10.3324/haematol.2022.281692
Abstrakt:	The BCL-2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) in patients not benefiting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly for relapsed or refractory AML. Ex vivo drug sensitivity testing may correlate with outcomes, but its prospective predictive value remains unexplored. Here we report the results of the first stage of the prospective phase II VenEx trial evaluating the utility and predictiveness of venetoclax sensitivity testing using different cell culture conditions and cell viability assays in patients receiving venetoclax-azacitidine. Participants with de novo AML ineligible for intensive chemotherapy, relapsed or refractory AML, or secondary AML were included. The primary endpoint was the treatment response in participants showing ex vivo sensitivity and the key secondary endpoints were the correlation of sensitivity with responses and survival. Venetoclax sensitivity testing was successful in 38/39 participants. Experimental conditions significantly influenced the predictive accuracy. Blast-specific venetoclax sensitivity measured in conditioned medium most accurately correlated with treatment outcomes; 88% of sensitive participants achieved a treatment response. The median survival was significantly longer for participants who were ex vivo-sensitive to venetoclax (14.6 months for venetoclax-sensitive patients vs. 3.5 for venetoclax-insensitive patients, P<0.001). This analysis illustrates the feasibility of integrating drug-response profiling into clinical practice and demonstrates excellent predictivity. This trial is registered with ClinicalTrials.gov identifier: NCT04267081.
Databáze:	MEDLINE
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