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.
| Original language | English |
|---|---|
| Journal | Blood |
| DOIs | |
| Publication status | E-pub ahead of print - 2024 |
| Publication type | A1 Journal article-refereed |
Funding
This study received funding from the Finnish Medical Foundation , Cancer Foundation Finland , Helsinki University Hospital Comprehensive Cancer Center , Helsinki University , iCAN\u2013Digital Precision Medicine, and FiCAN South. H.K. and M.K. are supported by the Foundation for the Finnish Cancer Institute . S. Kyt\u00F6l\u00E4 and I.V. received support from the Finnish Medical Foundation . The authors thank the patients, their families, and physicians for their participation in the trial. The authors especially thank the VenEx study nurses and coordinators Sari Nikkola, P\u00E4ivi Pellikka, Satu M\u00E4\u00E4tt\u00E4-Halonen, Kirsi Kvist-M\u00E4kel\u00E4, Elina Ellil\u00E4, Jenni Raali, and Saara Vaalas, as well as coordinating medical monitor Leena Partanen. The authors acknowledge the personnel FIMM High Throughput Biomedicine Unit, which is hosted by the University of Helsinki and supported by HiLIFE and Biocenter Finland , for their expert technical assistance. The authors thank the patients, their families, and physicians for their participation in the trial. They especially thank the VenEx study nurses and coordinators Sari Nikkola, P\u00E4ivi Pellikka, Mari Tengstr\u00F6m, Satu M\u00E4\u00E4tt\u00E4-Halonen, Kirsi Kvist-M\u00E4kel\u00E4, Elina Ellil\u00E4, Jenni Raali, and Saara Vaalas, as well as coordinating medical monitor Leena Partanen. The authors acknowledge the personnel of the FIMM High Throughput Biomedicine Unit, which is hosted by the University of Helsinki and supported by HiLIFE and Biocenter Finland, for their expert technical assistance. This study was supported by the Finnish Medical Foundation, Cancer Foundation Finland, Helsinki University Hospital Comprehensive Cancer Center, Helsinki University, iCAN\u2013Digital Precision Medicine, and FiCAN South. H.K. and M.K. are supported by the Foundation for the Finnish Cancer Institute. S. Kyt\u00F6l\u00E4 and I. V\u00E4nttinen received support from the Finnish Medical Foundation. Contribution: H.K. and M.K. conceptualized the study, performed study design, acquired funding, and supervised the study; S. Kyt\u00F6l\u00E4, M.K. and H.K. performed project administration and coordination; P.E. J.R. T.S. M.P. and M.K. performed administration, coordination, supervision, and resource management at sites; P.E. J.R. T.S. M.P. M.K. S. Kyt\u00F6l\u00E4, A.H. A. Partanen, M.E.L.K. S. Koskela, R.R. and M.I.-R. performed patient recruitment, patient care, and data collection; H.K. I. V\u00E4nttinen, T.R. M.S. and A. Parsons performed sample processing and investigation; I. V\u00E4strik performed development of the database for drug sensitivity data; C.A.H. K.P. and K.W. provided administrational, technical, and material support; S. Kyt\u00F6l\u00E4, T.H. T.J. I. V\u00E4nttinen, J.S. M.K. H.K. and T.R. performed methods, data curation, formal analysis, and visualization; S. Kyt\u00F6l\u00E4, I. V\u00E4nttinen, T.R. H.K. and M.K. wrote the original manuscript; and all authors contributed to the reviewing and editing and approved the final manuscript.
| Funders | Funder number |
|---|---|
| Foundation for the Finnish Cancer Institute | |
| FICAN-Mid | |
| Helsinki Institute of Life Science, Helsingin Yliopisto | |
| Helsinki University Central Hospital, Comprehensive Cancer Center | |
| Helsingin yliopisto | |
| Saara Vaalas | |
| Syöpäsäätiö | |
| Suomen Lääketieteen Säätiö | |
| Biocenter Finland |
Publication forum classification
- Publication forum level 3
ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology