VINCENT: A randomized-controlled trial evaluating venetoclax plus azacitidine versus intensive chemotherapy in patients with newly diagnosed, NPM1-mutated AML

Lydia Kretschmer^#¹, Leo Ruhnke^#², Christoph Schliemann³, Lars Fransecky⁴, Björn Steffen⁵, Martin Kaufmann⁶, Andreas Burchert⁷, Christoph Schmid⁸, Maher Hanoun⁹, Tim Sauer¹⁰, Klaus H Metzeler¹¹, Kerstin Schäfer-Eckart¹², Mathias Hänel¹³, Martina Crysandt¹⁴, Paul Jäger¹⁵, Stefan W Krause¹⁶, Christine Dierks¹⁷, Stefan Klein¹⁸, Nadia Maguire¹⁹, Lukas P Frenzel²⁰, Veit L Bücklein²¹, Wolfgang Blau²², Ulrich Kaiser²³, Kai Wegehenkel²⁴, Alexander Höllein²⁵, Ruth Seggewiss-Bernhardt^{26

27}, Wenke Markgraf², Frank Fiebig², Anna Harig², Katharina Schmidt-Brücken², Christian Thiede^{2

28}, Jan Moritz Middeke², Richard Dillon²⁹, Claudia D Baldus⁴, Hubert Serve⁵, Karsten Spiekermann²¹, Wolfgang Hiddemann²¹, Richard F Schlenk¹⁰, Carsten Müller-Tidow¹⁰, Martin Bornhäuser², Christoph Röllig²

Affiliations

¹ Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Fetscherstraße 74, Dresden, 01307, Germany. lydia.kretschmer@ukdd.de.
² Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Fetscherstraße 74, Dresden, 01307, Germany.
³ Department of Medicine A, University Hospital Münster, Münster, Germany.
⁴ Department of Hematology and Oncology, University Hospital Schleswig- Holstein, Campus Kiel, Kiel, Germany.
⁵ Department of Internal Medicine II, University Hospital Frankfurt, Frankfurt, Germany.
⁶ Robert Bosch Hospital, Stuttgart, Germany.
⁷ Department of Internal Medicine, Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany.
⁸ Department of Internal Medicine II, Hematology and Oncology, University Hospital Augsburg, Augsburg, Germany.
⁹ Department of Hematology and Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹⁰ Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
¹¹ Department of Internal Medicine I, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.
¹² Department of Internal Medicine V, Klinikum Nürnberg, Paracelsus Medical University, Nuremberg, Germany.
¹³ Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany.
¹⁴ Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, Center for Integrated Oncology Aachen, Bonn Cologne Duesseldorf, Aachen, Germany.
¹⁵ University Hospital of Düsseldorf, Düsseldorf, Germany.
¹⁶ Department of Internal Medicine V, University Hospital Erlangen, Erlangen, Germany.
¹⁷ University Hospital Halle, Halle, Germany.
¹⁸ University Medical Centre Mannheim, Mannheim, Germany.
¹⁹ Barmherzige Brüder Hospital, Regensburg, Germany.
²⁰ Department I of Internal Medicine, Faculty of Medicine and Cologne University Hospital, Center for Integrated Oncology Aachen, University of Cologne, Bonn, Cologne, Düsseldorf, Cologne, Germany.
²¹ LMU Hospital, Munich, Germany.
²² Department of Internal Medicine III, Hematology, Oncology and Palliative Care, Helios Dr. Horst Schmidt Hospital Wiesbaden, Wiesbaden, Germany.
²³ Department of Hematology, Oncology and Immunology, St. Bernward Hospital, Hildesheim, Germany.
²⁴ University Hospital OWL/Bielefeld Hospital, Bielefeld, Germany.
²⁵ Department of Internal Medicine III, Hematology and Oncology, Rotkreuzklinikum München, Munich, Germany.
²⁶ Department of Internal Medicine V, Sozialstiftung Bamberg, Bamberg, Germany.
²⁷ Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
²⁸ AgenDix GmbH, Dresden, Germany.
²⁹ King's College, London, UK.

^# Contributed equally.

PMID: 40629154
PMCID: PMC12334493
DOI: 10.1007/s00277-025-06496-7

VINCENT: A randomized-controlled trial evaluating venetoclax plus azacitidine versus intensive chemotherapy in patients with newly diagnosed, NPM1-mutated AML

Lydia Kretschmer et al. Ann Hematol. 2025 Jul.

. 2025 Jul;104(7):3647-3654.

doi: 10.1007/s00277-025-06496-7. Epub 2025 Jul 9.

Authors

Affiliations

¹ Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Fetscherstraße 74, Dresden, 01307, Germany. lydia.kretschmer@ukdd.de.
² Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Fetscherstraße 74, Dresden, 01307, Germany.
³ Department of Medicine A, University Hospital Münster, Münster, Germany.
⁴ Department of Hematology and Oncology, University Hospital Schleswig- Holstein, Campus Kiel, Kiel, Germany.
⁵ Department of Internal Medicine II, University Hospital Frankfurt, Frankfurt, Germany.
⁶ Robert Bosch Hospital, Stuttgart, Germany.
⁷ Department of Internal Medicine, Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany.
⁸ Department of Internal Medicine II, Hematology and Oncology, University Hospital Augsburg, Augsburg, Germany.
⁹ Department of Hematology and Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹⁰ Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
¹¹ Department of Internal Medicine I, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.
¹² Department of Internal Medicine V, Klinikum Nürnberg, Paracelsus Medical University, Nuremberg, Germany.
¹³ Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany.
¹⁴ Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, Center for Integrated Oncology Aachen, Bonn Cologne Duesseldorf, Aachen, Germany.
¹⁵ University Hospital of Düsseldorf, Düsseldorf, Germany.
¹⁶ Department of Internal Medicine V, University Hospital Erlangen, Erlangen, Germany.
¹⁷ University Hospital Halle, Halle, Germany.
¹⁸ University Medical Centre Mannheim, Mannheim, Germany.
¹⁹ Barmherzige Brüder Hospital, Regensburg, Germany.
²⁰ Department I of Internal Medicine, Faculty of Medicine and Cologne University Hospital, Center for Integrated Oncology Aachen, University of Cologne, Bonn, Cologne, Düsseldorf, Cologne, Germany.
²¹ LMU Hospital, Munich, Germany.
²² Department of Internal Medicine III, Hematology, Oncology and Palliative Care, Helios Dr. Horst Schmidt Hospital Wiesbaden, Wiesbaden, Germany.
²³ Department of Hematology, Oncology and Immunology, St. Bernward Hospital, Hildesheim, Germany.
²⁴ University Hospital OWL/Bielefeld Hospital, Bielefeld, Germany.
²⁵ Department of Internal Medicine III, Hematology and Oncology, Rotkreuzklinikum München, Munich, Germany.
²⁶ Department of Internal Medicine V, Sozialstiftung Bamberg, Bamberg, Germany.
²⁷ Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
²⁸ AgenDix GmbH, Dresden, Germany.
²⁹ King's College, London, UK.

^# Contributed equally.

PMID: 40629154
PMCID: PMC12334493
DOI: 10.1007/s00277-025-06496-7

Abstract

For younger, medically fit patients with NPM1-mutated, FLT3-wildtype acute myeloid leukemia (AML) intensive chemotherapy represents standard of care (SOC), with complete remission (CR) rates observed in up to 85% of patients and 5-year overall survival (OS) rates of 40-50%. However, significant toxicity and need for hospitalization pose challenges on patients' outcome and quality of life (QoL). Venetoclax (VEN) combined with azacitidine (AZA) has demonstrated encouraging efficacy in older, unfit AML patients, achieving high CR/CRi rates and promising OS with lower toxicity. Prospective, randomized data comparing VEN/AZA to SOC in younger, fit patients are currently missing. VINCENT is a randomized-controlled, multicenter, non-inferiority, phase 2 trial (NCT05904106) evaluating VEN/AZA versus SOC in adults aged 18-70 years with newly diagnosed, NPM1-mutated, FLT3-wildtype AML. Patients medically fit for intensive chemotherapy (ECOG ≤ 2) with adequate organ function are eligible, while patients with relapsed/refractory AML or prior cytotoxic treatment are excluded. A total of 146 patients will be randomized 1:1 to receive either VEN/AZA or SOC. Hematologic remission is evaluated according to ELN 2022 guidelines. The primary endpoint is the modified event-free survival, defined as either primary induction failure, hematologic relapse, molecular failure or death. Secondary endpoints include safety, tolerability, CR/CRi/CRh/CR_MRD- rates, MRD kinetics (using NPM1 RT-qPCR and MFC), relapse-free survival, OS, early mortality, health-related QoL and cumulative health-care-resource use. Patients will be followed up for at least two years post enrollment. The VINCENT trial will be the first study to provide comprehensive prospective data comparing VEN/AZA to SOC, addressing both efficacy and patient-centered outcomes.

Keywords: NPM1; AML; Azacitidine; Fit patients; Intensive chemotherapy; Venetoclax.

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Conflict of interest statement

Declarations. Ethics approval: The study (NCT05904106) is conducted in accordance with the Declaration of Helsinki and approved by the institutional bioethics review committee of the Technische Universität (TU) Dresden (EK13012023). Competing interests: LK: Travel grants: AbbVie Inc., Beigene, Jazz Pharmaceuticals, Johnson & Johnson. LR: Travel grants: BeiGene, Inc., AbbVie Inc., Jazz Pharmaceuticals, Johnson & Johnson, Neovii Pharmaceuticals; Consultancy und Honoraria: Actitrexx GmbH, AbbVie Inc.; Research Funding: AbbVie Inc. CR: Consultancy und Honoraria: AbbVie Inc., Amgen, Astellas, Bristol-Meyer-Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, J&J, Novartis, Otsuka, Pfizer, Roche, Servier; Research Funding: AbbVie Inc., Astellas, Novartis, Pfizer. CS: Honoraria/Advisory Boards: AbbVie Inc., Astellas, AstraZeneca, Bristol-Meyer-Squibb, Laboratories Delbert, Jazz Pharmaceuticals, Novartis, Otsuka, Pfizer, Roche; Research support (institutional): Jazz Pharmaceuticals; Travel grants: AbbVie Inc., Bristol-Meyer-Squibb, Jazz Pharmaceuticals, Pfizer. LF: Consultancy und Honoraria: AbbVie Inc.; Research Funding: AbbVie Inc. RSB: Honoraria: AbbVie Inc., Amgen, Astra Zeneca, Beigene, Bristol-Meyer-Squibb, Celgene, Eusa Pharma, IPSEN, Merck, MSD, Novartis, Pfizer, Roche; Membership on an entity’s Board of Directors or advisory committees: AbbVie Inc., Beigene, MSD, Novartis, Roche.

Figures

**Fig. 1**
VINCENT trial design. VINCENT is a randomized-controlled, open-label, multicenter, phase 2 trial evaluating efficacy and safety of VEN in combination with AZA compared to SOC intensive chemotherapy in adult treatment-naïve patients with *NPM1*-mutated AML. Patients will be randomized in a 1:1 fashion stratified by age to receive either VEN/AZA or SOC. AML, acute myeloid leukemia; AZA, azacitidine; CNS, central nervous system; CR, complete remission; DA, daunorubicin; EOS, end of study; *FLT3*, FMS-like tyrosine kinase 3; GO, gemtuzumab-ozogamicin; HRQoL, health-related quality of life; IDAC, intermediate-dose cytarabine; *NPM1*, Nucleophosmin 1; RFS, relapse-free survival; OS, overall survival

See this image and copyright information in PMC

References

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VINCENT: A randomized-controlled trial evaluating venetoclax plus azacitidine versus intensive chemotherapy in patients with newly diagnosed, NPM1-mutated AML

Affiliations

VINCENT: A randomized-controlled trial evaluating venetoclax plus azacitidine versus intensive chemotherapy in patients with newly diagnosed, NPM1-mutated AML

Authors

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Abstract

Conflict of interest statement

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