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Myelodysplastic syndrome

Leukemia evolving from paroxysmal nocturnal hemoglobinuria

Leukemia volume 34, pages 327–330 (2020)Cite this article

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It is well known that myeloid malignancies can evolve from antecedent hematologic disorders, most commonly acute myeloid leukemia (AML) evolving from myelodysplastic syndromes (MDS). Although aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are not intrinsically malignant conditions, they, too, can evolve to myeloid malignancies, albeit at a lower frequency than other bone marrow disorders, like MDS. While AA has been shown to be associated with somatic mutations prior to evolution to, e.g., MDS, PNH has not [1, 2]. We revisited the issue of malignant transformation of PNH to myeloid conditions in the setting of the current availability of somatic mutational testing (Table 1). Previous reports of PNH transformation contain grouped data and lack many details including time to malignant progression and associated molecular characterization [3,4,5,6] (Table S1). Our series of PNH cases evolving to MDS/AML was derived from 243 adult patients evaluated for hemolytic PNH including primary (pPNH: patients without antecedent AA) and secondary (sPNH: patients evolving from AA with PNH clone >20%) (n = 83), AA, and AA/PNH (n = 160; Table S2). Among those with hemolytic PNH, 7 patients progressed to AML (n = 1), MDS (n = 5), or myelofibrosis (n = 1) (Table 1). These cases had a median PNH clone size of 71% (range, 29–99) and carried various somatic mutations (ASXL1, BCOR, NPM1, TET2, U2AF1, WT1). The incidence rate of myeloid disorders in all cohorts was 3% (7/243) ranging from 4% to 10% in a meta-analysis (Table S1). Time to MDS/AML diagnosis was <1–22 years in our cohort while ranging from 0 to 3.4 years in one study [3] and had a cumulative incidence of 2 years (1.2% [0.9]) for MDS and (4.0% [1.4]) for AML in another [4] (Table S1). These results help to approximate the risk of clonal evolution in PNH.

Table 1 Characteristics of hemolytic PNH patients who progressed to myeloid disorders
Full size table

While PNH has been classically considered a molecularly monogenic disease due to somatic PIGA mutations (PIGAMT) (most of the cases) or microdeletions of the PIGA locus (Xp22.2; a few cases) [7], our recent sequencing studies of PNH and non-PNH cells have identified, besides PIGAMT, accessory somatic hits—a finding consistent with a more complex clonal architecture present in some PNH patients. While early studies by our group examined the spectrum of somatic lesions of PNH patients, the current study aims to explore the potentiality of clonal evolution due to somatic hits [8,9,10].

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Acknowledgements

We thank Edward P. Evans Foundation for the grants R01HL118281, R01HL123904, R01HL132071, R35HL135795 (to J.P.M), AA&MDSIF, VeloSano Pilot Award, and Vera and Joseph Dresner Foundation–MDS (to V.V.).

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Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Hassan Awada, Shafia Rahman, Jibran Durrani, Mohammad F. Asad, Cassandra M. Kerr, Vera Adema, Ashwin Kishtagari, Amy Graham, Christina A. Snider, Sunisa Kongkiatkamon, Yasunobu Nagata, Mikkael A. Sekeres, Jaroslaw P. Maciejewski & Valeria Visconte

  2. Leukemia Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Bhumika J. Patel, Hetty E. Carraway, Mikkael A. Sekeres & Jaroslaw P. Maciejewski

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Contributions

H.A. collected clinical information, analyzed the data, and wrote the manuscript; S.R. and M.F.A. collected clinical information, C.M.K. performed sequencing and edited the manuscript; V.A., J.D., A.G., C.A.S., Y.N., A.K., S.K. and B.J.P. participated in the study and edited the manuscript; H.E.C. and M.A.S. helped in recruitment of patients, edited the manuscript, and added important insights into the manuscript; J.P.M. followed the patients, led the collection of the clinical chart review, sponsored the sequencing study, and wrote the manuscript; V.V. analyzed the data, interpreted the results, and wrote the manuscript.

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Correspondence to Valeria Visconte.

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Awada, H., Rahman, S., Durrani, J. et al. Leukemia evolving from paroxysmal nocturnal hemoglobinuria. Leukemia 34, 327–330 (2020). https://doi.org/10.1038/s41375-019-0555-0

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