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Molecular determinants of therapy response of venetoclax-based combinations in acute myeloid leukemia

  • Philipp Makowka

    Philipp Makowka received his MD and Physician’s License at the University of Bonn, Germany. He is currently working as assistant physician and clinician scientist at the Department of medicine 2 at the University hospital Frankfurt, Germany. His research project investigates resistance mechanisms of AML cells to venetoclax-based therapies.

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    , Verena Stolp

    Verena Stolp received her Master of Science in Molecular Medicine at the Goethe University Frankfurt, Germany. She is now a PhD student in the Department of Medicine 2 at the University Hospital Frankfurt, aiming to complete her PhD project about sensitizing AML cells to venetoclax-based therapies.

    , Karoline Stoschek

    Karoline Stoschek started her medical degree in 2016 at Goethe University Frankfurt, Germany. In 2019, she began her MD project in the research group of Prof. Dr. Hubert Serve at the Department of Medicine 2 at the University Hospital Frankfurt. She is currently working on resistance mechanisms of AML to venetoclax-based therapies.

    and Hubert Serve

    Hubert Serve received his MD at the University of Heidelberg, Germany and was trained in Hematology/Oncology and Molecular Cancer Biology at the Universities of Munich, Ulm, Berlin, and Münster and at the Memorial Sloan-Kettering Cancer Center in New York. He is currently full professor and director of the Department of Medicine at the Goethe-University Frankfurt, Speaker of the University Cancer Center (UCT) Frankfurt and Coordinator of the local site of the German Cancer Consortium (DKTK). His scientific work focusses on the exploration of the Acute Myeloid Leukemia, oncogenic signaling in leukemias and on the development of molecular targeted therapies. He was a member of the IZKF Münster, where he worked as an Attending physician and where he was Associate Professor from 2002-2007.

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Published/Copyright: October 27, 2021

Abstract

Acute myeloid leukemia (AML) is a heterogeneous, highly malignant disease of the bone marrow. After decades of slow progress, recent years saw a surge of novel agents for its treatment. The most recent advancement is the registration of the Bcl-2 inhibitor ventoclax in combination with a hypomethylating agent (HMA) in the US and Europe for AML patients not eligible for intensive chemotherapy. Treatment of newly diagnosed AML patients with this combination results in remission rates that so far could only be achieved with intensive treatment. However, not all AML patients respond equally well, and some patients relapse early, while other patients experience longer periods of complete remission. A hallmark of AML is its remarkable genetic, molecular and clinical heterogeneity. Here, we review the current knowledge about molecular features of AML that help estimate the probability of response to venetoclax-containing therapies. In contrast to other newly developed AML therapies that target specific recurrent molecular alterations, it seems so far that responses are not specific for a certain subgroup. One exception is spliceosome mutations, where good response has been observed in clinical trials with venetoclax/azacitidine. These mutations are rather associated with a more unfavorable outcome with chemotherapy. In summary, venetoclax in combination with hypomethylating agents represents a significant novel option for AML patients with various molecular aberrations. Mechanisms of primary and secondary resistance seem to overlap with those towards chemotherapy.


Corresponding authors: Philipp Makowka, Department of Medicine 2, Hematology, Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany; and Frankfurt Cancer Institute (FCI), D-60590 Frankfurt am Main, Germany, E-mail: ; and Hubert Serve, Department of Medicine 2, Hematology, Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany; University Hospital Frankfurt, Frankfurt am Main, German Cancer Consortium (DKTK), partner site Frankfurt and DKFZ, D-69120 Heidelberg, Germany; and Frankfurt Cancer Institute (FCI), D-60590 Frankfurt am Main, Germany, E-mail:
This article is a contribution to the issue highlighting the 25th Anniversary of the Interdisciplinary Centre for Clinical Research (IZKF) Münster.

Funding source: Deutsche ForschungsgemeinschaftElse Kröner-Fresenius-StiftungJosé Carreras Leukämie-Stiftung

About the authors

Philipp Makowka

Philipp Makowka received his MD and Physician’s License at the University of Bonn, Germany. He is currently working as assistant physician and clinician scientist at the Department of medicine 2 at the University hospital Frankfurt, Germany. His research project investigates resistance mechanisms of AML cells to venetoclax-based therapies.

Verena Stolp

Verena Stolp received her Master of Science in Molecular Medicine at the Goethe University Frankfurt, Germany. She is now a PhD student in the Department of Medicine 2 at the University Hospital Frankfurt, aiming to complete her PhD project about sensitizing AML cells to venetoclax-based therapies.

Karoline Stoschek

Karoline Stoschek started her medical degree in 2016 at Goethe University Frankfurt, Germany. In 2019, she began her MD project in the research group of Prof. Dr. Hubert Serve at the Department of Medicine 2 at the University Hospital Frankfurt. She is currently working on resistance mechanisms of AML to venetoclax-based therapies.

Hubert Serve

Hubert Serve received his MD at the University of Heidelberg, Germany and was trained in Hematology/Oncology and Molecular Cancer Biology at the Universities of Munich, Ulm, Berlin, and Münster and at the Memorial Sloan-Kettering Cancer Center in New York. He is currently full professor and director of the Department of Medicine at the Goethe-University Frankfurt, Speaker of the University Cancer Center (UCT) Frankfurt and Coordinator of the local site of the German Cancer Consortium (DKTK). His scientific work focusses on the exploration of the Acute Myeloid Leukemia, oncogenic signaling in leukemias and on the development of molecular targeted therapies. He was a member of the IZKF Münster, where he worked as an Attending physician and where he was Associate Professor from 2002-2007.

  1. Author contribution: Conceptualization: H.S., investigation, draft preparation, writing and editing: P.M., V.S., K.S. and H.S., supervision: P.M. and H.S.

  2. Research funding: This work was supported by the Deutsche Forschungsgemeinschaft (SFB815, project A10 [H.S.]; SFB1177, project C06 [H.S.]), HMWK LOEWE Main Research Focus DynaMem IllL6-519/03/03.001-(0006) (H.S.), EU H2020-MSCA-ITN-2015 Deciphering the Metabolism of Haematological Cancers — HaemMetabolome’ Grant Agreement Number: 675790, LOEWE Center Frankfurt Cancer Institute (FCI) funded by the Hessen State Ministry for Higher Education, Research and the Arts [III L 5–519/03/03.001 – (0015)], furthermore this work was supported by grants from the Else Kröner-Fresenius-Stiftung (to P.M.), from the Deutsche José Carreras Leukämie-Stiftung (DGHO MD Scholarship to K.S.).

  3. Conflict of interest statement: The authors declare no conflict of interest.

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Received: 2021-06-09
Accepted: 2021-10-08
Published Online: 2021-10-27
Published in Print: 2021-11-25

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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