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.

  • Correspondence
  • Published:

Molecular alterations monitoring in myelodysplastic patients receiving an allogeneic hematopoietic stem cell transplantation after a reduced-intensity conditioning regimen

Bone Marrow Transplantation volume 59, pages 1309–1312 (2024)Cite this article

Subjects

Access through your institution
Buy or subscribe

Somatic mutations in myelodysplastic syndrome (MDS) are increasingly considered to assess patients’ prognosis. IPSS-M, a recently developed and validated (including after allogeneic hematopoietic stem cell transplantation (HSCT)) molecular international score system with genetic alteration, stratifies six prognostic groups [1, 2]. IPSS-M, like non-molecular IPSS, may help to estimate post-HSCT outcome and to guide transplantation indication [3,4,5]. Somatic mutations screening and monitoring may also be crucial markers of minimal measurable residual disease (MRD), especially after HSCT when the aim is complete remission and cure. Gene detection by next generation sequencing (NGS) after transplantation was reported by Duncavage and colleagues in 90 MDS patients transplanted after myeloablative or reduced-intensity conditioning regimen (RIC), confirming the feasibility of NGS MRD monitoring in MDS patients: [6] Post-transplantation NGS-MRD positivity predicted relapse, especially after RIC. Another multicenter study reported MRD monitoring by digital droplet PCR (ddPCR) targeting pre-transplantation mutations in 266 MDS patients, mainly receiving a treosulfan-based conditioning regimen [7]: MRD was positive 70 days (median) before morphological relapse and significantly associated with relapse-free survival and overall survival (OS). However, standard MRD detection in MDS is still under investigation; screening a MDS-gene panel may be an option if the detection sensibility is high enough [8].

The present study analyzed the potential impact on the outcomes of somatic mutations detected before and after transplantation by NGS and highly-sensitive ddPCR in a cohort of 106 MDS patients transplanted after a RIC. Methods are available in Supplementary data. This is a single-center retrospective study conducted according to the declaration of Helsinki. All patients signed an informed consent form about sharing their clinical and biological data on a local database and for molecular analysis. The study was approved by the Ethical committee Île-de-France (2015/69NICB). This is a single-center retrospective study conducted according to the declaration of Helsinki. All patients signed an informed consent form about sharing their clinical and biological data on a local database and for molecular analysis. The study was approved by the Ethical committee Île-de-France (2015/69NICB). We only included patients who received a RIC, where MRD+ has been reported as predictive of relapse mainly after RIC [9]. In our cohort, most patients had MDS with (n = 63) or without (n = 15) excess blast; 10 had chronic myelomonocytic leukemia and 18 MDS transformed into AML before transplantation. Patient characteristics are available in Table 1S. Eighty-eight (83%) patients had at least one somatic mutation detectable before transplantation using a 36-genes panel. IPSS-M strongly correlated with IPSS (linear correlation, r = 0.6063, p < 0.0001), IPSS-R (r = 0.7422, p < 0.0001), and IPSS-R cytogenetics (r = 0.6017, p < 0.0001). Pre-graft, none of the 36 patients tested had mutation clearance, regardless of the treatment received. Eleven patients had a stable genetic profile (including no detected mutation), 10 patients enriched their profile by at least one additional mutation, and 15 patients had a different mutational profile (initial mutations not all found, new molecular alterations), Fig. 1S. This confirms that chemotherapy or demethylating agents not often eradicate malignant clones, and that genetic profile changes over time in these patients [10].

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Overall survival probability curves and relapse incidence curves.

Data availability

Data available on request.

References

  1. Bernard E, Tuechler H, Greenberg PL, Hasserjian RP, Arango Ossa JE, Nannya Y, et al. Molecular international prognostic scoring system for myelodysplastic syndromes. NEJM Evid. 2022;1:EVIDoa2200008.

    Article  PubMed  Google Scholar 

  2. Sauta E, Robin M, Bersanelli M, Travaglino E, Meggendorfer M, Zhao L-P, et al. Real-world validation of molecular international prognostic scoring system for myelodysplastic syndromes. J Clin Oncol. 2023;41:2827–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Robin M, Porcher R, Adès L, Raffoux E, Michallet M, François S, et al. HLA-matched allogeneic stem cell transplantation improves outcome of higher risk myelodysplastic syndrome A prospective study on behalf of SFGM-TC and GFM. Leukemia. 2015;29:1496–501.

    Article  CAS  PubMed  Google Scholar 

  4. Kröger N, Sockel K, Wolschke C, Bethge W, Schlenk RF, Wolf D, et al. Comparison between 5-azacytidine treatment and allogeneic stem-cell transplantation in elderly patients with advanced MDS according to donor availability (VidazaAllo Study). J Clin Oncol. 2021;39:3318–27.

  5. Nakamura R, Saber W, Martens MJ, Ramirez A, Scott B, Oran B, et al. Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50–75 years of age with advanced myelodysplastic syndrome. J Clin Oncol. 2021;39:3328–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Duncavage EJ, Jacoby MA, Chang GS, Miller CA, Edwin N, Shao J, et al. Mutation clearance after transplantation for myelodysplastic syndrome. N Engl J Med. 2018;379:1028–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tobiasson M, Pandzic T, Illman J, Nilsson L, Weström S, Ejerblad E, et al. Patient-specific measurable residual disease markers predict outcome in patients with myelodysplastic syndrome and related diseases after hematopoietic stem-cell transplantation. J Clin Oncol. 2024:42:1378–90.

  8. Schulz E, Aplan PD, Freeman SD, Pavletic SZ. Moving toward a conceptualization of measurable residual disease in myelodysplastic syndromes. Blood Adv. 2023;7:4381–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Festuccia M, Deeg HJ, Gooley TA, Baker K, Wood BL, Fang M, et al. Minimal identifiable disease and the role of conditioning intensity in hematopoietic cell transplantation for myelodysplastic syndrome and acute myelogenous leukemia evolving from myelodysplastic syndrome. Biol Blood Marrow Transpl. 2016;22:1227–33.

    Article  Google Scholar 

  10. Hong S, Rybicki L, Gurnari C, Pagliuca S, Zhang A, Thomas D, et al. Pattern of somatic mutation changes after allogeneic hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. Bone Marrow Transpl. 2022;57:1615–9.

    Article  Google Scholar 

  11. Hou C, Zhou L, Yang M, Jiang S, Shen H, Zhu M, et al. The prognostic value of early detection of minimal residual disease as defined by flow cytometry and gene mutation clearance for myelodysplastic syndrome patients after myeloablative allogeneic hematopoietic stem-cell transplantation. Front Oncol. 2021;11:700234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee J-M, Kim Y-J, Park S-S, Han E, Kim M, Kim Y. Simultaneous monitoring of mutation and chimerism using next-generation sequencing in myelodysplastic syndrome. J Clin Med. 2019;8:2077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cilloni D, Gottardi E, De Micheli D, Serra A, Volpe G, Messa F, et al. Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia. 2002;16:2115–21.

    Article  CAS  PubMed  Google Scholar 

  14. Woo J, Howard NP, Storer BE, Fang M, Yeung CC, Scott BL, et al. Mutational analysis in serial marrow samples during azacitidine treatment in patients with post-transplant relapse of acute myeloid leukemia or myelodysplastic syndromes. Haematologica. 2017;102:e216–8.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Heuser M, Heida B, Büttner K, Wienecke CP, Teich K, Funke C, et al. Posttransplantation MRD monitoring in patients with AML by next-generation sequencing using DTA and non-DTA mutations. Blood Adv. 2021;5:2294–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank patients and their family.

Author information

Authors and Affiliations

  1. Hématologie-greffe, hôpital Saint-Louis, Université de Paris Cité, Paris, France

    Marie Robin, David Michonneau, Aliénor Xhaard, Flore Sicre de Fontbrune, Gérard Socié & Régis Peffault de Latour

  2. Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 -CANTHER -Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France

    Olivier Nibourel & Claude Preudhomme

  3. UR 7537 BioSTM, faculté de pharmacie de Paris, université Paris Cité, 4, avenue de l’Observatoire, F-75014, Paris, France

    Martin Tournaire, Marie Verbanck & Emmanuel Curis

  4. Hématologie-senior, hôpital Saint-Louis, Université, Paris, France

    Lionel Adès, Marie Sébert & Pierre Fenaux

  5. Laboratoire d’hématologie, hôpital Lariboisière, Assistance publique-hôpitaux de Paris, 2, rue Ambroise Paré, F-75010, Paris, France

    Emmanuel Curis

Authors
  1. Marie Robin
    View author publications

    Search author on:PubMed Google Scholar

  2. Olivier Nibourel
    View author publications

    Search author on:PubMed Google Scholar

  3. Martin Tournaire
    View author publications

    Search author on:PubMed Google Scholar

  4. David Michonneau
    View author publications

    Search author on:PubMed Google Scholar

  5. Claude Preudhomme
    View author publications

    Search author on:PubMed Google Scholar

  6. Marie Verbanck
    View author publications

    Search author on:PubMed Google Scholar

  7. Aliénor Xhaard
    View author publications

    Search author on:PubMed Google Scholar

  8. Lionel Adès
    View author publications

    Search author on:PubMed Google Scholar

  9. Flore Sicre de Fontbrune
    View author publications

    Search author on:PubMed Google Scholar

  10. Marie Sébert
    View author publications

    Search author on:PubMed Google Scholar

  11. Pierre Fenaux
    View author publications

    Search author on:PubMed Google Scholar

  12. Gérard Socié
    View author publications

    Search author on:PubMed Google Scholar

  13. Régis Peffault de Latour
    View author publications

    Search author on:PubMed Google Scholar

  14. Emmanuel Curis
    View author publications

    Search author on:PubMed Google Scholar

Contributions

MR designed the study, recruited patients & collected the data; ON & CP made NGS & ddPCR, interpreted the results; MT, MV and EC made statistics and analyzed the data; DM, AX, LA, MS, FSF,GS & RPL provided patient data; all co-authors interpreted the results, wrote the paper and approved the final version of the paper. MR designed the study, MT, MV and EC made the statistical analysis, ON and CP made the biological analysis, MR, DM, FS, RPD, GS, PF, LA, MR and PF provide the patients, all authors wrote and approved the paper.

Corresponding author

Correspondence to Marie Robin.

Ethics declarations

Competing interests

The 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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Robin, M., Nibourel, O., Tournaire, M. et al. Molecular alterations monitoring in myelodysplastic patients receiving an allogeneic hematopoietic stem cell transplantation after a reduced-intensity conditioning regimen. Bone Marrow Transplant 59, 1309–1312 (2024). https://doi.org/10.1038/s41409-024-02314-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41409-024-02314-2

Search

Advanced search

Quick links