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

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 se...

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Bibliographic Details
Published in:	Haematologica (Roma) Vol. 108; no. 7; pp. 1768 - 1781
Main Authors:	Kuusanmäki, Heikki, Kytölä, Sari, Vänttinen, Ida, Ruokoranta, Tanja, Ranta, Amanda, Huuhtanen, Jani, Suvela, Minna, Parsons, Alun, Holopainen, Annasofia, Partanen, Anu, Kuusisto, Milla E L, 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
Format:	Journal Article
Language:	English
Published:	Italy Fondazione Ferrata Storti 01-07-2023 Ferrata Storti Foundation
Subjects:	Acute Myeloid Leukemia Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Bridged Bicyclo Compounds, Heterocyclic - pharmacology Bridged Bicyclo Compounds, Heterocyclic - therapeutic use Humans Leukemia, Myeloid, Acute - diagnosis Leukemia, Myeloid, Acute - drug therapy Prospective Studies
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Disclosures HK reports research funding from AbbVie and personal fees from Faron outside the submitted work. APart reports personal fees from AbbVie, Astra Zeneca, Janssen-Cilag, No-vartis, Sanofi, and Takeda outside the submitted work. KP reports personal fees from AbbVie, Astellas Pharma, BMS/Celgene, Incyte, Novartis, and Pfizer and research funding from AbbVie, BMS/Celgene, Incyte, Novartis, and Pfizer outside the submitted work. CAH reports research funding from Novartis, Orion Pharma, BMS/Celgene, Oncopeptides, and Kronos Bio Inc. and personal fees from Oncopeptides outside the submitted work. PE reports personal fees from Novartis, Pfizer, Amgen, and Sanofi outside the submitted work. MP reports personal fees from Pfizer, Novartis, and AbbVie outside the submitted work. JR reports personal fees from Astellas Pharma, AbbVie, Bristol-Myers Squibb, and Pfizer outside the submitted work. TS reports personal fees from Novartis, Bristol-Myers Squibb, Janssen-Cilag, AbbVie, and Takeda outside the submitted work. MK reports personal fees from Astellas Pharma, AbbVie, Bristol-Myers Squibb, Faron, Jazz Pharmaceuticals, Novartis and Pfizer and research funding from AbbVie outside the submitted work. The other authors have no disclosures to make. Contributions All data relevant to the study are included in the article or uploaded in the Online Supplementary Data. The datasets used and/or analyzed during the study are available from the Finnish AML Group upon reasonable request to the corresponding author. Initial requests should be directed to the principal investigator Mika Kontro (mika.kontro@helsinki.fi). HK and MK conceived and designed the study, acquired funding for the study and supervised it. SKy, MK, and HK were responsible for project administration and coordination. PE, JR, TS, and MP were principal investigators and were responsible for administration, coordination, supervision and resource management at sites. PE, JR, TS, MP, MK, SKy, AH, APart, MELK, SKo, RR, and MIR recruited and cared for patients and collected data. HK, IV, TR, AR, MS, and APars were responsible for sample processing and investigations. IMV developed the database for drug sensitivity data. JH and OD conducted the formal analysis of RNA sequencing data. CAH, SS, KP, and KW provided administrative, technical and material support. HK, MK, SKy, IV, AR, and TR were responsible for methodology, data curation, formal analysis, and visualization. HK, SKy, IV, TR, and MK wrote the original version of the manuscript. All authors contributed to reviewing and editing the manuscript and approved the final version. Data-sharing statement
ISSN:	0390-6078 1592-8721 1592-8721
DOI:	10.3324/haematol.2022.281692