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CHRONIC MYELOPROLIFERATIVE NEOPLASMS

ASXL1 mutation is a novel risk factor for bleeding in Philadelphia-negative myeloproliferative neoplasms

Leukemia volume 38, pages 210–214 (2024)Cite this article

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Bleeding and thrombosis are prevalent across all myeloproliferative neoplasm (MPN) subtypes and have significant impact on morbidity and mortality [1, 2]. Risk factors for arterial and venous thrombosis in MPN are relatively well defined [3, 4], and validated risk stratification models that provide objective estimates of the probability of thrombotic events in newly diagnosed patients have been established [e.g., the International Prognostic Score for Essential Thrombocytopenia (IPSET) model] [5]. However, bleeding risk factors in these patients remain poorly characterized beyond extreme thrombocytosis (platelet count >1000 × 109/L) that is often associated with acquired von Willebrand disease. Indeed, identifying MPN patients at higher risk for bleeding could guide patient selection for prophylactic anticoagulation, the duration of anticoagulation therapy for those with MPN-associated thrombosis (balancing bleeding and thrombosis risks), better define the best candidates for cytoreduction in extreme thrombocytosis, and perhaps predict bleeding complications with surgical procedures. Given this unmet need, we performed a retrospective study to define novel bleeding risk factors among adult Philadelphia-negative MPN patients treated at Roswell Park Comprehensive Cancer Center.

In this study, bleeding events were classified as minor or major events as defined by the International Society of Thrombosis and Hemostasis (ISTH) [6]. The primary outcome of interest was time to initial bleeding event after MPN diagnosis. Patients’ characteristics were collected, and genomic profiling was performed at time of diagnosis using next-generation sequencing methods (FoundationOne Heme; variant allele frequency cut off >2%). Patient characteristics were summarized as range and medians (for continuous variables) and counts with percentages (for categorical variables). Chi-square and Mann Whitney U tests were used to compare categorical and continuous data, respectively. Continuous variables were dichotomized at median for the regression analyses. Cox regression was used to examine the associations between candidate risk factors and incidence of bleeding events in univariate and multivariate analyses. We considered death as a competing risk and the incidence of bleeding as an outcome. Variables with significance at p < 0.1 in univariate analyses were selected for as covariates multivariate analysis including the use of anticoagulants and anti-platelets as time-varying covariates. A time-dependent variable of thrombosis status was included, and stepwise feature selection based on Akaike Information Criterion was used for model selection.

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Fig. 1: Candidate risk factors of bleeding in Philadelphia-negative myeloproliferative neoplasms.
Fig. 2: Associations between ASXL1 mutations and clinical variables in Philadelphia-negative myeloproliferative neoplasms.

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Author notes

  1. These authors contributed equally: Hassan Awada, Manasa Bhatta.

Authors and Affiliations

  1. Benign Hematology & Leukemia Service, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Hassan Awada, Tara Cronin, Sheeba Ba Aqeel, Arya Mariam Roy, Muhammad Salman Faisal, Elizabeth A. Griffiths & Amro Elshoury

  2. Department of Medicine, The Mount Sinai Hospital, New York, NY, USA

    Manasa Bhatta

  3. Department of Biostatistics & Bioinformatic, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Han Yu & Surui Hou

  4. Virginia Polytechnic Institute and State University, Center for Biostatistics and Health Data Science, Blacksburg, VA, USA

    Wenyan Ji

  5. Department of Medicine, Rochester Regional Health, Rochester General Hospital, Rochester, NY, USA

    Peter Kouides

  6. Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    John Mascarenhas

  7. Western New York BloodCare, Buffalo, NY, USA

    Amro Elshoury

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Contributions

HA and MB collected, analyzed, and interpreted the data, and wrote the manuscript; HY, WJ, and SH studied and analyzed the data and applied biostatistical methods; TR provided patients’ data; SBA, AMR, and MSF provided important editing and wrote the manuscript; PK and JM provided important editing and wrote the manuscript; EAG provided patients and provided important editing and wrote the manuscript; AE conceptualized and designed the study and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Amro Elshoury.

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Competing interests

EAG discloses conflicts of interest including direct fees for advisory services from: AbbVie, Alexion Pharmaceuticals, Apellis, Celgene/BMS, CTI Biopharma, Genentech, Novartis, Picnic Health, Takeda Oncology, Taiho Oncology, Research Funding to Roswell Park from Astex Pharmaceuticals, AstraZeneca Rare Disease, Alexion Pharmaceuticals, Apellis Pharmaceuticals, Blueprint Medicines, Genentech Inc. and CME/Honoraria payments from Physicians Educational Resource, MediCom Worldwide, American Society of Hematology, AAMDS International Foundation, MDS International Foundation, and the Vera & Joseph Dresner Foundation.

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Awada, H., Bhatta, M., Yu, H. et al. ASXL1 mutation is a novel risk factor for bleeding in Philadelphia-negative myeloproliferative neoplasms. Leukemia 38, 210–214 (2024). https://doi.org/10.1038/s41375-023-02069-7

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