A1 Refereed original research article in a scientific journal
Ex vivo venetoclax sensitivity testing predicts treatment response in acute myeloid leukemia
Authors: Kuusanmäki Heikki, Kytölä Sari, Vänttinen Ida, Ruokoranta Tanja, Ranta Amanda, Huuhtanen Jani, Suvela Minna, Parsons Alun, Holopainen Annasofia, Partanen Anu, Kuusisto Milla EL, Koskela Sirpa, Räty Riikka, Itälä-Remes Maija, Västrik Imre, Dufva Olli, Siitonen Sanna, Porkka Kimmo, Wennerberg Krister, Heckman Caroline A, Ettala Pia, Pyörälä Marja, Rimpiläinen Johanna, Siitonen Timo, Kontro Mika
Publisher: Ferrata-Storti Foundation
Publication year: 2023
Journal: Haematologica
Journal name in source: Haematologica
Journal acronym: Haematologica
Volume: 108
Issue: 7
ISSN: 0390-6078
eISSN: 1592-8721
DOI: https://doi.org/10.3324/haematol.2022.281692
Web address : https://haematologica.org/article/view/haematol.2022.281692
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/178010784
The BCL2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) patients not benefitting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly for relapsed or refractory (R/R) 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 2 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 (NCT04267081). Participants with de novo AML ineligible for intensive chemotherapy, R/R AML, or secondary AML were included. The primary endpoint was the treatment response in ex vivo sensitive participants 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 predictive accuracy. Blast-specific venetoclax sensitivity measured in conditioned medium most accurately correlated with treatment outcomes; 88% of sensitive participants achieved treatment response. Median survival was significantly longer for ex vivo sensitive participants (14. 6 months for s ensitive, 3. 5 for insensitive, p < 0 . 001). T his analysis illustrates the feasibility of integrating drug-response profiling into clinical practice and demonstrates excellent predictivity.
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