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Myelodysplastic syndrome

A comparison of clinical and molecular characteristics of patients with systemic mastocytosis with chronic myelomonocytic leukemia to CMML alone

Leukemia volume 32, pages 1850–1856 (2018)Cite this article

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To the Editor: Systemic mastocytosis (SM) is a clonal hematological disorder characterized by the neoplastic proliferation of morphologically and immunophenotypically aberrant mast cells in one or more extracutaneous organ system [1]. A diagnosis of SM is established in the presence of multifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) detected in sections of bone marrow (BM) or extracutaneous organs. These mast cells usually have an atypical spindle-shaped morphology, are associated with activating point mutations in the KIT gene, aberrantly express CD2 and/or CD25, and result in persistently elevated serum tryptase levels (>20 ng/ml) [1, 2]. SM with an associated hematological neoplasm (AHN) fulfills the criteria for SM as well as an additional hematological malignancy, and after indolent SM (~46%), is the second most common type of SM encountered in practice (SM-AHN ~40%) [3]. Myeloid neoplasms comprise ~90% of all SM-AHN cases, with individual morphological subtypes being SM-myeloproliferative neoplasms (SM-MPNs ~45%), SM-chronic myelomonocytic leukemia (SM-CMML ~29%) and SM-myelodysplastic syndrome (SM-MDS ~23%) [4]. CMML is an aggressive hematological malignancy characterized by sustained peripheral blood monocytosis, gene mutations involving TET2 (~60%), ASXL1 (~40%), and SRSF2 (~40%), with an inherent risk for leukemic transformation (LT: 15–30%) [5, 6]. In a series of 123 patients with SM-AHN, median overall survival (OS) for individual subtypes were SM-MPN 31 months, SM-CMML 15 months, and SM-MDS 13 months, with respective LT rates of 11, 6, and 29% [4]. We carried out this study in a large molecularly annotated cohort of patients with CMML (n = 501) and SM-CMML (n = 50) to compare and contrast (i) clinical, cytogenetic, and molecular features, (ii) LT rates, and (iii) survival outcomes.

Five hundred and fifty-one patients were included in the study, of which 501 (91%) had CMML and 50 (10%) had SM-CMML; median age 72 years (range, 18–95), 66% males. In comparison to patients with CMML, SM-CMML patients were younger (p = 0.03), had a lower percentage of circulating blasts (p = 0.03), had lower lactate dehydrogenase levels (p = 0.04), were more likely to have a WHO CMML-0 morphological subtype (p = 0.003), and were more likely to have CBL (p = 0.03, 27% vs 13%) and the KIT D816V (p < 0.0001, 86% vs 1%) mutations (Table. 1). Three (1%) CMML patients had a detectable exon 17 KIT D816V mutation by NGS analysis without morphologic or immunophenotypic evidence for concomitant mast cell disease, with respective KIT D816V variant allele frequency (VAF) burdens of 12, 15, and 18%. Serum tryptase levels were not available for review in these patients. While acknowledging the fact that KIT mutations are extremely uncommon in CMML and that mast cell clones at times can be occult (<5%), or become more prominent after cytoreductive therapy, for the purposes of this study, these patients were considered to have CMML alone [8,9,10]. Importantly, there were no differences with regard to “proliferative” or “dysplastic” CMML phenotypes, cytogenetic abnormalities, CMML risk stratification by CMML-specific prognostic models, and the distribution of TET2, ASXL1, SRSF2, RUNX1, and SETBP1 mutations.

Table 1 Clinical and laboratory characteristics of 551 patients with chronic myelomonocytic leukemia stratified by the concomitant presence or absence of systemic mastocytosis
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Acknowledgements

Current publication is supported in part by grants from “The Gerstner Family Career Development Award” and the “Mayo Clinic Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.” This publication was supported by CTSA grant number KL2 TR000136 from the National Center for Advancing Translational Science (NCATS). We would like to acknowledge Dr. P. Horna for his role in obtaining the images of BM morphological changes in patients with SM-CMML.

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  1. Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Mrinal M. Patnaik,  Rangit Vallapureddy, Terra L. Lasho, Katherine P. Hoversten, Christy M. Finke, Naseema Gangat, Ayalew Tefferi & Animesh Pardanani

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Rhett P. Ketterling & Curtis A. Hanson

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  1. Mrinal M. Patnaik
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Patnaik, M.M., Rangit Vallapureddy, Lasho, T.L. et al. A comparison of clinical and molecular characteristics of patients with systemic mastocytosis with chronic myelomonocytic leukemia to CMML alone. Leukemia 32, 1850–1856 (2018). https://doi.org/10.1038/s41375-018-0121-1

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