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Chronic myelogenous leukemia

Activity of venetoclax-based therapy in chronic myelomonocytic leukemia

Leukemia volume 35, pages 1494–1499 (2021)Cite this article

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Chronic myelomonocytic leukemia (CMML) is a hematological disorder [1, 2] with limited therapeutic options, high risk of transformation to acute myeloid leukemia (AML) and poor prognosis [3, 4]. Hypomethylating agents (HMAs) are the standard of care for these patients, but only up to 40% of patients respond to therapy, and HMA treatment failure precedes reduction in survival time [5]. To date, the cellular and biological mechanisms of resistance to HMA therapy are not fully understood. The B-cell Leukemia/Lymphoma-2 (BCL2) protein is overexpressed in hematological malignancies as a mechanism of enhanced cell survival, and represents a mechanism of HMA resistance and progression in MDS [6]. Preliminary results from a phase 1b study of azacitidine and venetoclax in frontline or relapsed higher-risk MDS reported complete remission (CR) rates of up to 32% and 13%, respectively [7, 8]. RAS/MAPK activating mutations, which are observed in up to 30% of patients with CMML, have been associated with Myeloid leukemia Cell differentiation protein 1 (MCL1) upregulation and resistance to BCL2 inhibition [9]. Moreover, both the molecular and metabolic properties of monocytic clones in AML have been linked to venetoclax resistance [10]. The efficacy of venetoclax in combination with azacitidine in CMML has not yet been explicitly reported. In addition, despite the activity and survival benefit of the combination of azacitidine and venetoclax in AML, specific data on AML with myelodysplasia-related changes (AML-MRC) evolving from previously-treated CMML is lacking.

In this study, we evaluated all patients who received venetoclax-based regimens as any line of therapy for CMML and as frontline therapy for AML-MRC after CMML at the University of Texas MD Anderson Cancer Center (MDACC) from 2016 to 2020. Informed consent was obtained according to protocols approved by the MDACC institutional review board in accordance with the Declaration of Helsinki. Whole bone marrow (BM) DNA was subjected to 81 gene targeted next-generation sequencing (NGS) analysis (Supplementary Table S1) prior to venetoclax therapy. Responses were evaluated per the MDS/MPN International Working Group response criteria [11] for CMML and per European LeukemiaNet 2017 criteria for AML-MRC [12]. On selected cases, immunohistochemical staining was performed on 4 μm thick formalin-fixed paraffin-embedded BM sections using standard procedures, as described elsewhere, using a mouse monoclonal antibody for BCL2 oncoprotein (Bcl-2/100/D5; 1:50, Leica [13]).

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Fig. 1: Mutation landscape and dynamics, and clinical outcomes of study population.

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported in part by the University of Texas MD Anderson Cancer Center Support Grant CA016672.

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  1. These authors contributed equally: Guillermo Montalban-Bravo, Danielle Hammond

Authors and Affiliations

  1. Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Guillermo Montalban-Bravo, Danielle Hammond, Courtney D. DiNardo, Marina Konopleva, Gautam Borthakur, Nicholas J. Short, Jorge Ramos-Perez, Veronica Guerra, Kiran Naqvi, Koji Sasaki, Elias Jabbour, Naveen Pemmaraju, Tapan M. Kadia, Farhad Ravandi, Naval Daver, Zeev Estrov, Sherry Pierce, Hagop Kantarjian & Guillermo Garcia-Manero

  2. Departments of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Rashmi Kanagal-Shamanna

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Correspondence to Guillermo Montalban-Bravo.

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Conflict of interest

KS: This author declares an advisory role with Pfizer Japan. EJ: This author declares research support and an advisory role with Adaptive, AbbVie, Amgen, Pfizer, Cyclacel LTD, Takeda, and Bristol Myers Squibb. CD: This author declares research support and an advisory role with Abbvie/Genentech, Agios, Celgene/BMS, ImmuneOnc, Novartis and Notable Labs, and honoraria from Takeda and Foghorn Therapeutics. MK: This author declares research support and an advisory role with Eli Lilly, AbbVie, Cellectis, Amgen, F. Hoffman La-Roche, Genentech, Ascentage, Kisoji, Reata Pharmaceuticals, Ablynx, Astra Zeneca, Agios, Forty-Seven, Stemline Therapeutics, and Calithera. T.K.: This author declares research support and an advisory role with Amgen, Bioline RX, Pfizer, Jazz, Bristol Myers Squibb, Celgene, Genentech, Pharmacyclics, Takeda, and AbbVie. FR: This author declares research support and an advisory role with Macrogeni, Selvita, Cyclacel LTD, Menarini Ricerche, and Xencor. HK: This author declares research support and an advisory role with Actinium, and research support from AbbVie, Agio, Amgen, Ariad, Astex, Bristol Myers Squibb, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, and Pfizer. GG-M: This author declares research support and an advisory role with Bristol Myers Squibb, Astex, and Helsinn, and research support from Amphivena, Novartis, AbbVie, H3 Biomedicine, Onconova, and Merck. The remaining authors declare no conflicts of interest.

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Montalban-Bravo, G., Hammond, D., DiNardo, C.D. et al. Activity of venetoclax-based therapy in chronic myelomonocytic leukemia. Leukemia 35, 1494–1499 (2021). https://doi.org/10.1038/s41375-021-01240-2

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