Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

MYELODYSPLASTIC NEOPLASM

A Phase II prospective trial of azacitidine in steroid-dependent or refractory systemic autoimmune/inflammatory disorders and VEXAS syndrome associated with MDS and CMML

Leukemia volume 36, pages 2739–2742 (2022)Cite this article

Subjects

Systemic autoimmune and inflammatory disorders (SAID) are underestimated, and potentially life-threatening complications observed in 15–25% of myelodysplastic neoplasms (MDS) and chronic myelomonocytic leukemia (CMML), although pathophysiological links between both types of disorders remain uncertain [1, 2]. In 2020, Beck et al. described Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome (OMIM #301054) [3], defined by the presence of UBA1 mutations, in patients with severe systemic inflammation, chronic fever, 30% of whom had concurrent MDS [4]. VEXAS is typically associated with refractoriness to conventional immunosuppressive therapies (IST) and dismal prognosis, and prospectively evaluated effective treatment strategies remain to be established [5]. In MDS/CMML patients with concomitant SAID, but no UBA1 mutation, we and others observed a high incidence of mutations of the epigenetic regulators TET2 and IDH1/2, whose presence correlated with defects in adaptive T lymphocyte homeostasis [2].

Azacitidine (AZA) is a reference treatment for higher-risk MDS, also approved for lower-risk MDS treatment in various countries [6]. After the publication of several case reports, we found in a retrospective series of patients with MDS/CMML and SAID that AZA had efficacy on SAID features, allowing steroid-sparing effects in 19 of 22 patients [7]. This led us to launch a prospective phase II trial of AZA in patients with MDS/CMML and steroid-dependent/refractory SAID.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Data availability

Details about the data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Mekinian A, Grignano E, Braun T, Decaux O, Liozon E, Costedoat-Chalumeau N, et al. Systemic inflammatory and autoimmune manifestations associated with myelodysplastic syndromes and chronic myelomonocytic leukaemia: a French multicentre retrospective study. Rheumatology. 2016;55:291–300.

    Article  CAS  PubMed  Google Scholar 

  2. Zhao L-P, Boy M, Azoulay C, Clappier E, Sébert M, Amable L, et al. Genomic landscape of MDS/CMML associated with systemic inflammatory and autoimmune disease. Leukemia. 2021;35:2720–4.

    Article  PubMed  Google Scholar 

  3. Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med. 2020;383:2628–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhao L-P, Schell B, Sébert M, Kim R, Lemaire P, Boy M, et al. Prevalence of UBA1 mutations in MDS/CMML patients with systemic inflammatory and auto-immune disease. Leukemia. 2021;35:2731–3.

    Article  CAS  PubMed  Google Scholar 

  5. Grayson PC, Patel BA, Young NS. VEXAS syndrome. Blood. 2021;137:3591–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Fenaux P, Platzbecker U, Ades L. How we manage adults with myelodysplastic syndrome. Br J Haematol. 2020;189:1016–27.

    Article  CAS  PubMed  Google Scholar 

  7. Fraison J-B, Mekinian A, Grignano E, Kahn J-E, Arlet J-B, Decaux O, et al. Efficacy of Azacitidine in autoimmune and inflammatory disorders associated with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Res. 2016;43:13–17.

    Article  CAS  PubMed  Google Scholar 

  8. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–25.

    Article  CAS  PubMed  Google Scholar 

  9. Merkel D, Filanovsky K, Gafter-Gvili A, Vidal L, Aviv A, Gatt ME, et al. Predicting infections in high-risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: a retrospective multicenter study. Am J Hematol. 2013;88:130–4.

    Article  CAS  PubMed  Google Scholar 

  10. Comont T, Heiblig M, Rivière E, Terriou L, Rossignol J, Bouscary D, et al. Azacitidine for patients with Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome (VEXAS) and myelodysplastic syndrome: data from the French VEXAS registry. Br J Haematol. 2022;196:969–74.

    Article  CAS  PubMed  Google Scholar 

  11. Raaijmakers MHGP, Hermans M, Aalbers A, Rijken M, Dalm VASH, van Daele P, et al. Azacytidine treatment for VEXAS syndrome. Hemasphere. 2021;5:e661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ricard L, Hirsch P, Largeaud L, Deswarte C, Jachiet V, Mohty M, et al. Clonal haematopoiesis is increased in early onset in systemic sclerosis. Rheumatology. 2020;59:3499–504.

    Article  CAS  PubMed  Google Scholar 

  13. Hecker JS, Hartmann L, Rivière J, Buck MC, van der Garde M, Rothenberg-Thurley M, et al. CHIP & HIPs: clonal hematopoiesis is common in hip arthroplasty patients and associates with autoimmune disease. Blood. 2021;138:1727–32.

    Article  CAS  PubMed  Google Scholar 

  14. Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25:1147–52.

    Article  CAS  PubMed  Google Scholar 

  15. Costantini B, Kordasti SY, Kulasekararaj AG, Jiang J, Seidl T, Abellan PP, et al. The effects of 5-azacytidine on the function and number of regulatory T cells and T-effectors in myelodysplastic syndrome. Haematologica. 2013;98:1196–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the French consortium MINHEMON, GFM, and French VEXAS groups.

Author information

Author notes

  1. These authors contributed equally: Arsene Mekinian, Lin Pierre Zhao.

Authors and Affiliations

  1. Service de médecine interne et Inflammation-Immunopathology-Biotherapy Department (DMU i3), Sorbonne Université, AP-HP, Hôpital Saint Antoine, F-75012, Paris, France

    Arsene Mekinian, Vincent Jachiet & Olivier Fain

  2. Service d’hématologie, Université de Paris Cité, AP-HP, Hôpital Saint Louis, F-75010, Paris, France

    Lin Pierre Zhao, Fatiha Chermat, Karine Lemaire, Lionel Ades & Pierre Fenaux

  3. APHP, Department of Biostatistics and Medical Information, APHP, Saint-Louis Hospital, Paris, INSERM, UMR-1153, ECSTRA Team, Paris, France

    Sylvie Chevret & Kristell Desseaux

  4. Service d’hématologie, Hôpital Saint Vincent de Paul, Lille, France

    Laurent Pascal

  5. Service d’hématologie, CHU Toulouse, Toulouse, France

    Thibaut Comont & Odile Beyne Rauzy

  6. Service de médecine interne CHU Montpellier, Montpellier, France

    Alexandre Maria

  7. Service d’hématologie, CHU Nantes, Nantes, France

    Pierre Peterlin

  8. Service d’hématologie, CHU Lille, Lille, France

    Louis Terriou

  9. Service d’hématologie, CHU Nancy, Nancy, France

    Maud D’Aveni Piney

  10. Service d’hématologie, CHU Limoges, Limoges, France

    Marie-Pierre Gourin & Laurent Voillat

  11. Service d’hématologie, CHU Marseille, Marseille, France

    Norbert Vey

  12. Internal Medicine Department, Clermont-Ferrand University Hospital, 1 Rue Lucie et Raymond Aubrac, 63003, Clermont Ferrand, France

    Vincent Grobost

  13. Service de médecine interne CHU Dupuytren 2, 87000, Limoges, France

    Holy Bezanahary

  14. Service d’hématologie, CHU Bordeaux, Bordeaux, France

    Sophie Dimicoli-Salazar

  15. Service d’hématologie, Centre Hospitalier de Biarritz, Biarritz, France

    Anne Banos

  16. Service d’hématologie, CHU Nimes, Nimes, France

    Stefan Wickenhauser

  17. Service d’hématologie, CHU Clermont Ferrand, Clermont Ferrand, France

    Benoit De Renzis

  18. Service d’hématologie, CHU Reims, Reims, France

    Eric Durot & Chantal Himberlin

  19. Service d’hématologie, Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France

    Shanti Natarajan-Amé

  20. Service d’hématologie, CHU d’Angers, Angers, France

    Sylvain Thépot

  21. Service d’hématologie, CHU de Poitiers, Poitiers, France

    Jose Miguel Torregrosa Diaz

  22. AP-HP, Hôpital Necker, Paris, France

    Laurent Frenzel

  23. Service d’hématologie, CHRU de Tours – Bretonneau, Tours, France

    Emmanuel Gyan

  24. Service d’hématologie, CH de Rochefort, Rochefort, France

    Guillaume Denis

  25. Service d’hématologie biologique, Sorbonne Université, INSERM UMR938, Centre de Recherche Saint-Antoine (CRSA), AP-HP, Hôpital Saint Antoine, Paris, France

    Pierre Hirsch

  26. Service d’hématologie biologique, APHP, Hôpital Cochin, Paris, France

    Olivier Kosmider

Authors
  1. Arsene Mekinian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin Pierre Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sylvie Chevret
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kristell Desseaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laurent Pascal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thibaut Comont
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexandre Maria
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pierre Peterlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Louis Terriou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maud D’Aveni Piney
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marie-Pierre Gourin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Norbert Vey
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Odile Beyne Rauzy
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Vincent Grobost
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Holy Bezanahary
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Sophie Dimicoli-Salazar
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Anne Banos
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Stefan Wickenhauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Benoit De Renzis
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Eric Durot
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Shanti Natarajan-Amé
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Laurent Voillat
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Fatiha Chermat
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Karine Lemaire
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Vincent Jachiet
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Chantal Himberlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Sylvain Thépot
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Jose Miguel Torregrosa Diaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Laurent Frenzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Emmanuel Gyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Guillaume Denis
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Pierre Hirsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Olivier Kosmider
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Lionel Ades
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Olivier Fain
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Pierre Fenaux
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A Mekinian, PF, and LPZ designed the study and wrote the manuscript. FC and KL collected the data. SC and KD performed the analysis. A Mekinian, LPZ, LP, TC, A Maria, PP, LT, MAP, M-PG, NV, OBR, VG, HB, SD-Z, AB, SW, BDR, ED, SN-A, LV, VJ, CH, ST, JMTD, LF, EG, GD, PH, OK, LA, OF, and PF took care of the patients. All the authors critically reviewed the manuscript.

Corresponding author

Correspondence to Arsene Mekinian.

Ethics declarations

Competing interests

A Mekinian is an investigator of Celgene, Roche, Chugai founded trials with APHP and Hôpital 15–20 promotion; and received several fees for advisory boards from LFB, Sanofi, Shire, and Celgene. The other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mekinian, A., Zhao, L.P., Chevret, S. et al. A Phase II prospective trial of azacitidine in steroid-dependent or refractory systemic autoimmune/inflammatory disorders and VEXAS syndrome associated with MDS and CMML. Leukemia 36, 2739–2742 (2022). https://doi.org/10.1038/s41375-022-01698-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-022-01698-8

This article is cited by

Search

Advanced search

Quick links