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Chronic myeloproliferative neoplasms

Insights on mechanisms of clonal evolution in chronic neutrophilic leukemia on ruxolitinib therapy

Leukemia volume 34, pages 1684–1688 (2020)Cite this article

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Chronic neutrophilic leukemia (CNL) is a rare BCR-ABL negative myeloproliferative neoplasm (MPN) characterized by neutrophilic leukocytosis. Colony stimulating factor 3 receptor membrane-proximal mutation (CSF3R-T618I) is an oncogenic driver in the vast majority of patients. The identification of this mutation has therapeutic implications as the CSF3R-T618I mutation constitutively activates JAK/STAT signaling [1]. Recurrent disease-modifying mutations (e.g., ASXL1, SETBP1, spliceosome genes) confer a poor prognosis [2]. Understanding changes in clonal evolution of CNL during the course of treatment may reveal disease biology, identify potential markers of disease progression, and help optimize treatment strategies.

A phase II clinical trial is evaluating safety and efficacy of ruxolitinib (JAK 1/2 inhibitor) monotherapy in patients with CNL or atypical chronic myeloid leukemia. We assessed the mutation profile of patients during therapy using peripheral blood samples. A custom next generation sequencing library kit (QIAseq, Qiagen Inc.) evaluated 76 genes recurrently mutated in leukemia (details provided in Supplementary methods). The average coverage was 2000× with a 2% lower detection limit. Patients provided written consent for the use of samples and collected data. Complete study design is described at clinicaltrials.gov/NCT02092324. Patients were included in this analysis if they had a CNL diagnosis, completed ≥12 4-week treatment cycles, and displayed evidence of disease progression (molecular or clinical). Molecular evidence was indicated by subclonal evolution (i.e., gain of new disease-modifying mutations). Clinical evidence included increased leukocytosis, spleen volume, or peripheral or marrow blasts, or progressive granulocytic dysplasia.

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Fig. 1: Clonal evolution of chronic neutrophilic leukemia in patients on ruxolitinib.

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Acknowledgements

This work was supported in part by Incyte, Inc. KHD served on advisory board meetings and received compensation from Incyte. JWT received grants from the National Cancer Institute (1U01CA217862, 1U54CA224019, and 1R01CA183947), the V Foundation for Cancer Research, and the Gabrielle’s Angel Foundation for Cancer Research. JWT has received research support from Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Seattle Genetics, Syros, and Takeda; JWT is a co-founder of Vivid Biosciences.

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Authors and Affiliations

  1. School of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, mailcode KR-HEM, Portland, OR, 97239, USA

    Ryan C. Stoner & Julia E. Maxson

  2. Department of Pathology, Oregon Health & Science University, Portland, OR, 97239, USA

    Richard D. Press

  3. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA

    Richard D. Press, Julia E. Maxson, Jeffrey W. Tyner & Kim-Hien T. Dao

  4. Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR, 97239, USA

    Jeffrey W. Tyner & Kim-Hien T. Dao

  5. Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, 97239, USA

    Jeffrey W. Tyner

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Correspondence to Kim-Hien T. Dao.

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Stoner, R.C., Press, R.D., Maxson, J.E. et al. Insights on mechanisms of clonal evolution in chronic neutrophilic leukemia on ruxolitinib therapy. Leukemia 34, 1684–1688 (2020). https://doi.org/10.1038/s41375-019-0688-1

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