Ex vivo venetoclax sensitivity predicts clinical response in acute myeloid leukemia in the prospective VenEx trial
Abstract
Abstract The B-cell lymphoma 2 inhibitor venetoclax has shown promise for treating acute myeloid leukemia (AML). However, identifying patients likely to respond remains a challenge, especially for those with relapsed/refractory (R/R) disease. We evaluated the utility of ex vivo venetoclax sensitivity testing to predict treatment responses to venetoclax-azacitidine in a prospective, multicenter, phase 2 trial. The trial recruited 104 participants with previously untreated (n = 48), R/R (n = 39), or previously treated secondary AML (sAML) (n = 17). The primary end point was complete remission or complete remission with incomplete hematologic recovery (CR/CRi) rate in ex vivo sensitive trial participants during the first 3 therapy cycles. The key secondary end points included the correlations between ex vivo drug sensitivity, responses, and survival. Venetoclax sensitivity was successfully assessed in 102 of 104 participants, with results available within a median of 3 days from sampling. In previously untreated AML, ex vivo sensitivity corresponded to an 85% (34/40) CR/CRi rate, with a median overall survival (OS) of 28.7 months, compared with 5.5 months for ex vivo resistant patients (P = .002). For R/R/sAML, ex vivo sensitivity resulted in a 62% CR/CRi rate (21/34) and median OS of 9.7 vs 3.3 months for ex vivo resistant patients (P < .001). In univariate and multivariate analysis, ex vivo venetoclax sensitivity was the strongest predictor for a favorable treatment response and survival. This trial demonstrates the feasibility of integrating ex vivo drug testing into clinical practice to identify patients with AML, particularly in the R/R setting, who benefit from venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT04267081.
Article Details
Authors (24)
Sari Kytölä
1Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Ida Vänttinen
2Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland
Tanja Ruokoranta
1Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Anu Partanen
3Department of Medicine, Kuopio University Hospital, Kuopio, Finland
Annasofia Holopainen
3Department of Medicine, Kuopio University Hospital, Kuopio, Finland
Joseph Saad
2Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland
Milla E. L. Kuusisto
4Department of Hematology, University of Oulu, Oulu, Finland
Sirpa Koskela
5Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
Riikka Räty
1Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Maija Itälä-Remes
6Turku University Hospital, Turku, Finland
Imre Västrik
2Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland
Minna Suvela
1Institute for Molecular Medicine Finland - FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
Alun Parsons
2Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland
Kimmo Porkka
43Helsinki University Hospital Comprehensive Cancer Center, Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland
Krister Wennerberg
Caroline A. Heckman
Tero Jalkanen
8EstiMates Ltd, Turku, Finland
Teppo Huttunen
8EstiMates Ltd, Turku, Finland
Pia Ettala
58Department of Clinical Hematology and Stem Cells Transplantation Unit, Turku University Hospital and University of Turku, Turku, Finland
Johanna Rimpiläinen
4Tampere University Hospital, Deparment of Internal Medicine, Tampere, Finland
Timo Siitonen
6Cancer Center, Oulu University Hospital, Oulu, Finland
Marja Pyörälä
5Kuopio University Hospital, Kuopio, Finland
Heikki Kuusanmäki
Mika Kontro