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The clinical relevance of minor paroxysmal nocturnal hemoglobinuria clones in refractory cytopenia of childhood: a prospective study by EWOG-MDS

Leukemia volume 28, pages 189–192 (2014)Cite this article

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Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, resulting in peripheral blood cytopenias, myeloid dysplasia and risk of leukemic transformation. MDS in childhood are rare with an estimated annual incidence of 0.8–1.8 per million children aged 0–14 years.1 Refractory cytopenia of childhood (RCC), defined as myelodysplasia without an increased blast count, is the most common subtype of childhood MDS. Karyotype is normal in the majority of patients with RCC, and, in contrast to adults with MDS-refractory anemia (RA), about 80% of children have a hypocellular bone marrow (BM).1 Although the exact pathophysiology of MDS remains unclear, immunosuppressive therapy (IST), consisting of antithymocytic globulin (ATG) and/or cyclosporine A (CsA), is effective in some adults with MDS, suggesting a T-cell mediated immune response directed against hematopoietic progenitor cells in a proportion of the patients.2 ATG and CsA might also be effective in RCC,3 but predictors of response to IST in RCC are yet unknown. In some,4, 5, 6 but not all,2 studies conducted in adult MDS patients, a predictor of good response to IST is the presence of a minor paroxysmal nocturnal hemoglobinuria (PNH) clone.

Minor PNH or glycosylphosphatidylinositol (GPI)-deficient clones are present in 20–57% of adult and pediatric patients with the immune-mediated BM failure syndrome aplastic anemia4, 7, 8, 9 and in 13–23% of adults with low-grade MDS.4, 6, 8, 10 The mechanisms by which PNH clones arise in immune-mediated BM failure syndromes are incompletely understood, but it is hypothesized that GPI-deficient cells have a conditional growth advantage by evading an immune attack directed against normal hematopoietic progenitor cells. Another recent hypothesis is that GPI-deficient cells, which can be detected at very low numbers in healthy individuals, can expand without a conditional advantage, especially in conditions with reduced stem cell numbers.11

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Acknowledgements

AMA and this research were supported by the KiKa Foundation, Amstelveen, The Netherlands. In the Czech Republic RCC diagnosis and treatment were supported by a grant of the Ministry of Health for conceptual development of research organization 00064203 (University Hospital Motol, Prague, Czech Republic).

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Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, Sophia Children’s Hospital—Erasmus University Medical Center, Rotterdam, The Netherlands

    A M Aalbers, C M Zwaan, R Pieters & M M van den Heuvel-Eibrink

  2. Department of Immunology, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands

    A M Aalbers, V H J van der Velden, A W Langerak & J J M van Dongen

  3. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University of Freiburg, Freiburg, Germany

    A Yoshimi, A Fischer, P Noellke & C M Niemeyer

  4. Department of Pathology, Clinical Centre South West, Böblingen Clinics, Böblingen, Germany

    I Baumann

  5. Department of Clinical Genetics, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands

    H B Beverloo

  6. Department of Pediatrics, St. Anna Children’s Hospital and Children’s Cancer Research Institute, Medical University of Vienna, Vienna, Austria

    M Dworzak

  7. Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark

    H Hasle

  8. Department of Pediatric Hematology-Oncology, IRCCS Ospedale Bambino Gesù, Rome, University of Pavia, Rome, Italy

    F Locatelli

  9. Department of Pediatric Hematology/Oncology, Ghent University Hospital, Ghent, Belgium

    B De Moerloose

  10. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    G Göhring

  11. Department of Hematology, University Children’s Hospital, Zurich, Switzerland

    M Schmugge

  12. Department of Pediatric Hematology/Oncology, Charles University and University Hospital Motol, Prague, Czech Republic

    J Stary

  13. Pediatric Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    M Zecca

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  1. A M Aalbers
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  2. V H J van der Velden
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  18. J J M van Dongen
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  19. R Pieters
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  20. C M Niemeyer
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  21. M M van den Heuvel-Eibrink
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Corresponding author

Correspondence to M M van den Heuvel-Eibrink.

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The authors declare no conflict of interest.

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Author Contributions

VHJV, AWL, CMN, MHE conceived and designed the study; AMA, AY, AF, PN analyzed the data; AMA, VHJV, AY, JJMD, RP, CMN, MHE interpreted the data; MD, HH, FL, BDM, MSL, JS, MZ, CMN, MHE treated patients and contributed patient samples; IB performed central review of bone marrow morphology; GG, BB performed central review of cytogenetics; AMA, VHJV, MHE wrote the paper; all authors approved the final version of the paper.

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Aalbers, A., van der Velden, V., Yoshimi, A. et al. The clinical relevance of minor paroxysmal nocturnal hemoglobinuria clones in refractory cytopenia of childhood: a prospective study by EWOG-MDS. Leukemia 28, 189–192 (2014). https://doi.org/10.1038/leu.2013.195

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