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 trial of ipilimumab, nivolumab, or ipilimumab and nivolumab with or without azacitidine in relapsed or refractory myelodysplastic neoplasms

Leukemia volume 39, pages 524–528 (2025)Cite this article

Subjects

Access through your institution
Buy or subscribe

Patients with myelodysplastic neoplasms (MDS) who progress on hypomethylating agents have poor outcomes [1,2,3]. There are no standard treatment approaches in this setting; while high-dose chemotherapy followed by allogeneic stem cell transplant remains a curative option for higher-risk MDS, advanced age and significant comorbidities preclude this approach for many patients [4]. In these cases, novel therapies are urgently needed.

Programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) are upregulated in hypomethylating agent failure MDS [5]. PD-L1 on the surface of MDS cells binds to PD-1 on T cells, facilitating immune evasion [6]. Similarly, CTLA4 on T cells binds to B7 on MDS cells, stifling T-cell receptor activation and contributing to immune escape [7]. These findings provide a rationale for assessing PD-1 and CTLA4 blockade in MDS following hypomethylating agent exposure [7]. Ipilimumab and nivolumab are fully human IgG1k monoclonal antibodies that target CTLA4 and PD-1, respectively [8, 9]. Both monotherapy and combination immunotherapy approaches are safe and effective in solid tumors and lymphomas; however, their safety and efficacy in relapsed or refractory MDS remains unclear.

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: Time-to-event analyses of patients w1ho received ipilimumab, nivolumab, or ipilimumab-nivolumab.

Data availability

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

References

  1. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jabbour E, Garcia-Manero G, Batty N, Shan J, O’Brien S, Cortes J, et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010;116:3830–4.

    Article  CAS  PubMed  Google Scholar 

  3. Jabbour EJ, Garcia-Manero G, Strati P, Mishra A, Al Ali NH, Padron E, et al. Outcome of patients with low-risk and intermediate-1-risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS Clinical Research Consortium. Cancer. 2015;121:876–82.

    Article  PubMed  Google Scholar 

  4. Kadia TM, Jabbour E, Kantarjian H. Failure of hypomethylating agent-based therapy in myelodysplastic syndromes. Semin Oncol. 2011;38:682–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28:1280–8.

    Article  CAS  PubMed  Google Scholar 

  6. Yang X, Ma L, Zhang X, Huang L, Wei J. Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia. Exp Hematol Oncol. 2022;11:11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Boddu P, Kantarjian H, Garcia-Manero G, Allison J, Sharma P, Daver N. The emerging role of immune checkpoint based approaches in AML and MDS. Leuk Lymphoma. 2018;59:790–802.

    Article  CAS  PubMed  Google Scholar 

  8. Graziani G, Tentori L, Navarra P. Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharm Res. 2012;65:9–22.

    Article  CAS  Google Scholar 

  9. Guo L, Zhang H, Chen B. Nivolumab as Programmed Death-1 (PD-1) Inhibitor for Targeted Immunotherapy in Tumor. J Cancer. 2017;8:410–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zeidan AM, Platzbecker U, Bewersdorf JP, Stahl M, Ades L, Borate U, et al. Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes. Blood. 2023;141:2047–61.

    CAS  PubMed  Google Scholar 

  11. Thall PF, Sung HG. Some extensions and applications of a Bayesian strategy for monitoring multiple outcomes in clinical trials. Stat Med. 1998;17:1563–80.

    Article  CAS  PubMed  Google Scholar 

  12. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42:377–81.

    Article  Google Scholar 

  13. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al. The REDCap consortium: Building an international community of software platform partners. J Biomed Inf. 2019;95:103208.

    Article  Google Scholar 

  14. Chen M, Linstra R, van Vugt M. Genomic instability, inflammatory signaling and response to cancer immunotherapy. Biochim Biophys Acta Rev Cancer. 2022;1877:188661.

    Article  CAS  PubMed  Google Scholar 

  15. Aggarwal C, Ben-Shachar R, Gao Y, Hyun SW, Rivers Z, Epstein C, et al. Assessment of Tumor Mutational Burden and Outcomes in Patients With Diverse Advanced Cancers Treated With Immunotherapy. JAMA Netw Open. 2023;6:e2311181.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Ashli Nguyen-Villarreal, Associate Scientific Editor, in the Research Medical Library at The University of Texas MD Anderson Cancer Center, for editing this article. Study data were collected and managed using REDCap electronic data capture tools hosted at MD Anderson (Project ERIS MDS, version 4.5). We thank Ashli Nguyen-Villarreal, Associate Scientific Editor, in the Research Medical Library at The University of Texas MD Anderson Cancer Center for editing this article. We thank the patients and their caregivers for their participation in our clinical trials.

Funding

This research was funded by the Bristol Myers Squibb Alliance and supported, in part, by the NIH/NCI under award number CA016672 and The University of Texas MD Anderson Cancer Center MDS/AML Moon Shot Program.

Author information

Authors and Affiliations

  1. The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Ian M. Bouligny, Guillermo Montalban-Bravo, Koji Sasaki, Naval Daver, Elias Jabbour, Yesid Alvarado, Courtney D. DiNardo, Farhad Ravandi, Gautam Borthakur, Naveen Pemmaraju, Tapan Kadia, Lucia Masarova, Koichi Takahashi, Michael Andreeff, Alexandre Bazinet, Hui Yang, Sherry Pierce, Meghan Meyer & Guillermo Garcia-Manero

  2. The University of Texas MD Anderson Cancer Center, Department of Hematopathology, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Rashmi Kanagal

  3. The University of Texas MD Anderson Cancer Center, Department of Biostatistics, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Xuelin Huang

Authors
  1. Ian M. Bouligny
    View author publications

    Search author on:PubMed Google Scholar

  2. Guillermo Montalban-Bravo
    View author publications

    Search author on:PubMed Google Scholar

  3. Koji Sasaki
    View author publications

    Search author on:PubMed Google Scholar

  4. Naval Daver
    View author publications

    Search author on:PubMed Google Scholar

  5. Elias Jabbour
    View author publications

    Search author on:PubMed Google Scholar

  6. Yesid Alvarado
    View author publications

    Search author on:PubMed Google Scholar

  7. Courtney D. DiNardo
    View author publications

    Search author on:PubMed Google Scholar

  8. Farhad Ravandi
    View author publications

    Search author on:PubMed Google Scholar

  9. Gautam Borthakur
    View author publications

    Search author on:PubMed Google Scholar

  10. Naveen Pemmaraju
    View author publications

    Search author on:PubMed Google Scholar

  11. Tapan Kadia
    View author publications

    Search author on:PubMed Google Scholar

  12. Lucia Masarova
    View author publications

    Search author on:PubMed Google Scholar

  13. Koichi Takahashi
    View author publications

    Search author on:PubMed Google Scholar

  14. Michael Andreeff
    View author publications

    Search author on:PubMed Google Scholar

  15. Alexandre Bazinet
    View author publications

    Search author on:PubMed Google Scholar

  16. Hui Yang
    View author publications

    Search author on:PubMed Google Scholar

  17. Rashmi Kanagal
    View author publications

    Search author on:PubMed Google Scholar

  18. Sherry Pierce
    View author publications

    Search author on:PubMed Google Scholar

  19. Meghan Meyer
    View author publications

    Search author on:PubMed Google Scholar

  20. Xuelin Huang
    View author publications

    Search author on:PubMed Google Scholar

  21. Guillermo Garcia-Manero
    View author publications

    Search author on:PubMed Google Scholar

Contributions

IM Bouligny designed the study database, analyzed the data, created the figures, and prepared the manuscript. G Montalban-Bravo enrolled patients and revised the manuscript. K Sasaki enrolled patients and revised the manuscript. N Daver enrolled patients and revised the manuscript. E Jabbour enrolled patients and revised the manuscript. Y Alvarado enrolled patients and revised the manuscript. CD DiNardo revised the manuscript. F Ravandi enrolled patients and revised the manuscript. G Borthakur enrolled patients and revised the manuscript. N Pemmaraju enrolled patients and revised the manuscript. T Kadia enrolled patients and revised the manuscript. L Masarova enrolled patients and revised the manuscript. K Takahashi enrolled patients and revised the manuscript. M Andreeff enrolled patients and revised the manuscript. A Bazinet revised the manuscript. H Yang revised the manuscript. R Kanagal interpreted pathology samples and revised the manuscript. S Pierce collected data and revised the manuscript. M Meyer obtained patient consent, organized the trial, and revised the manuscript. X Haung assisted with data analysis and revised the manuscript. G Garcia-Manero oversaw the study, enrolled patients, and revised the manuscript.

Corresponding author

Correspondence to Guillermo Garcia-Manero.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The MD Anderson Institutional Review Board approved this study. All patients provided written informed consent according to the Declaration of Helsinki.

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 (e.g. a society or other partner) 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

Bouligny, I.M., Montalban-Bravo, G., Sasaki, K. et al. A phase II trial of ipilimumab, nivolumab, or ipilimumab and nivolumab with or without azacitidine in relapsed or refractory myelodysplastic neoplasms. Leukemia 39, 524–528 (2025). https://doi.org/10.1038/s41375-024-02457-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41375-024-02457-7

Search

Advanced search

Quick links