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Myelodysplastic Syndrome

Genomic stratification of myelodysplastic/myeloproliferative neoplasms, unclassifiable: Sorting through the unsorted

Leukemia volume 35, pages 3329–3333 (2021)Cite this article

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As per the latest World Health Organization (WHO) classification, the category of MDS/MPN overlap syndromes includes chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), juvenile myelomonocytic leukemia, and MDS/MPN-unclassifiable (MDS/MPN-U) [1, 2]. Several groups have described the genomic landscape of MDS/MPN-U with consistent findings such as a lower frequency of TET2 somatic pathogenic variants (mt) compared to CMML and higher frequency of JAK2mt compared to aCML and CMML [3,4,5]. Palomo et al. recently proposed a genomic classification of patients with myelodysplastic/myeloproliferative (MDS/MPN) overlap neoplasms [6]. In 2019, we reported a combined Mayo Clinic-H. Lee Moffitt Cancer Center cohort of 135 patients with MDS/MPN-U, and found that the Revised International Prognostic Scoring System (IPSS-R) and Global MD Anderson Prognostic Model (MDA) were the best at predicting outcomes, with the highest concordance, or area under the curve (C) statistical values [5]. Importantly, we also established that MDS/MPN-U with >15% RS (not otherwise meeting criteria for MDS/MPN-RS-T) is a distinct subset of MDS/MPN-U with favorable outcomes, and that TP53mt and CBLmt are associated with an independent adverse prognostic impact in MDS/MPN-U [5]. Based on the aforementioned studies and their own work, Palomo et al. divided MDS/MPN-U into distinct molecular subtypes namely MDS/MPN-RS-T-like (JAK2 mt and/or SF3B1mt), CMML-like (ASXL1 mt, SRSF2 mt, RUNX1mt, and/or NRAS mt), aCML-like (ASXL1 mt and/or SETBP1 mt), TP53-mutant, and others, and found differential survival outcomes, with the MDS/MPN-RS-T-like category being associated with the highest median OS [median not reached (NR)], followed by CMML-like [median not reached (NR)], others (median 80.3 months), aCML (median 18.8 months), and TP53 mutant (median 5.2 months) subtypes, respectively [6]. However, the performance of this genomic stratification in comparison to contemporary prognostic classifications systems such as IPSS-R [7] and global MDA model [8] in MDS/MPN-U was not assessed.

We retrospectively abstracted our combined cohort of 140 patients (five patients added since the original published cohort [5]) with WHO-defined MDS/MPN-U from Mayo Clinic (n = 93) and H. Lee Moffitt Cancer Center (n = 47) as reported before with interim updates. Of note, cases that were deemed to be therapy-related were excluded from this cohort. Distribution of continuous variables was statistically compared using nonparametric (Mann–Whitney or Kruskal–Wallis) tests, while nominal variables were compared using the Chi-Square test. Time to event analyses used the method of Kaplan–Meier, and overall survival (OS) was calculated from the date of diagnosis to date of death or last follow-up. Cut-off points for continuous variables were derived through a Receiver Operating Characteristic (ROC) analysis. Harrell’s Concordance (C) statistic or area under curve (AUC) of ROC curve was used to statistically compare performance of prognostic models in predicting OS. The nonparametric method by DeLong was used to test for differences in ROC curves.

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Fig. 1: This figure shows the spectrum of molecular abnormalities and clinical outcomes of the genomically defined subtypes of myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U).

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Acknowledgements

This publication was supported by Grant#UL1 TR002377 from the National Center for Advancing Translational Sciences (NCATS), however findings do not necessarily represent official views of NIH.

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Authors and Affiliations

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

    Abhishek A. Mangaonkar, Terra L. Lasho, Christy Finke & Mrinal M. Patnaik

  2. Division of Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    David M. Swoboda, Eric Padron & Chetasi Talati

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

    Rhett P. Ketterling & Kaaren K. Reichard

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  1. Abhishek A. Mangaonkar
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Contributions

AM compiled the clinical and genomics data, performed data analysis, and wrote the first draft of the manuscript. DS, RK, KR, EP, and CT contributed patients and data. TL and CF performed the genomics analysis. MP conceptualized the study and approved the final draft. All authors contributed in the writing of the manuscript.

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Correspondence to Chetasi Talati.

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Mangaonkar, A.A., Swoboda, D.M., Lasho, T.L. et al. Genomic stratification of myelodysplastic/myeloproliferative neoplasms, unclassifiable: Sorting through the unsorted. Leukemia 35, 3329–3333 (2021). https://doi.org/10.1038/s41375-021-01258-6

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