Skip to main content

Advertisement

Springer Nature Link
Log in

Phase II study of single-agent nivolumab in patients with myelofibrosis

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Dysregulated JAK-STAT signaling in myelofibrosis induces pro-inflammatory cytokines, which suppresses T cell proliferation and differentiation, likely responsible for disease progression. The PD-1 pathway, found to be overexpressed in myeloid malignancies, has gained great interest as a therapeutic target, where a significant unmet need exists for novel therapeutic strategies. Preclinical models showed JAK2 mutant cells had higher expression of PD-L1; furthermore, JAK2 mutant xenografts treated with PD-1 inhibition had prolonged survival and reduction in JAK2 allele burden. We evaluated the efficacy and safety of single-agent nivolumab in 8 adult patients with myelofibrosis. Nivolumab was given at 3 mg/kg every 2 weeks for 8 doses, then every 12 weeks for up to 4 years, or until disease progression or toxicity. The median number of nivolumab doses received was 6 [range, 5–16 doses]. Five patients had stable disease including spleen size, total symptom score, and blood requirements for a median of 3.3 months [range, 2.3–15.2 months]. After a median follow-up of 57 months, two patients were still alive. The median overall survival was 6.1 months [range, 3.2–57.4 months]. Due to failure to meet the predetermined efficacy endpoint, the study was terminated early. Trial registration: Clinical trials.gov NCT: 02,421,354

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Arber DA, Orazi A, Hasserjian R et al (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127(20):2391–2405

    Article  CAS  Google Scholar 

  2. Levine RL, Wadleigh M, Cools J et al (2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7(4):387–397

    Article  CAS  Google Scholar 

  3. Baxter EJ, Scott LM, Campbell PJ et al (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365(9464):1054–1061

    Article  CAS  Google Scholar 

  4. Verstovsek S, Mesa RA, Gotlib J et al (2017) Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol 10(1):55

    Article  Google Scholar 

  5. Pardanani A, Tefferi A (2018) How I treat myelofibrosis after failure of JAK inhibitors. Blood 132(5):492–500

    Article  CAS  Google Scholar 

  6. Newberry KJ, Patel K, Masarova L et al (2017) Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood 130(9):1125–1131

    Article  CAS  Google Scholar 

  7. Tefferi A (2005) Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol 23(33):8520–8530

    Article  CAS  Google Scholar 

  8. Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A (2011) Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol 29(10):1356–1363

    Article  CAS  Google Scholar 

  9. Bellucci R, Martin A, Bommarito D et al (2015) Interferon-gamma-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression. Oncoimmunology. 4(6):e1008824

    Article  Google Scholar 

  10. Koschmieder S, Mughal TI, Hasselbalch HC et al (2016) Myeloproliferative neoplasms and inflammation: whether to target the malignant clone or the inflammatory process or both. Leukemia 30(5):1018–1024

    Article  CAS  Google Scholar 

  11. Masarova L, Verstovsek S, Kantarjian H, Daver N (2017) Immunotherapy based approaches in myelofibrosis. Expert Rev Hematol 10(10):903–914

    Article  CAS  Google Scholar 

  12. Quintas-Cardama A, Kantarjian HM, Manshouri T et al (2009) Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis. J Clin Oncol 27(28):4760–4766

    Article  CAS  Google Scholar 

  13. Mesa RA, Yao X, Cripe LD et al (2010) Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903. Blood 116(22):4436–4438

    Article  CAS  Google Scholar 

  14. Silver RT, Kiladjian JJ, Hasselbalch HC (2013) Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibrosis. Expert Rev Hematol 6(1):49–58

    Article  CAS  Google Scholar 

  15. Jabbour E, Kantarjian H, Cortes J et al (2007) PEG-IFN-alpha-2b therapy in BCR-ABL-negative myeloproliferative disorders: final result of a phase 2 study. Cancer 110(9):2012–2018

    Article  CAS  Google Scholar 

  16. Yang H, Bueso-Ramos C, DiNardo C et al (2014) Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 28(6):1280–1288

    Article  CAS  Google Scholar 

  17. Daver N, Garcia-Manero G, Basu S et al (2018) Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a non-randomized, open-label, phase 2 study. Cancer Discov

  18. Prestipino A, Emhardt AJ, Aumann K et al (2018) Oncogenic JAK2(V617F) causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci Transl Med 10(429)

  19. Choi DC, Tremblay D, Iancu-Rubin C, Mascarenhas J (2017) Programmed cell death-1 pathway inhibition in myeloid malignancies: implications for myeloproliferative neoplasms. Ann Hematol 96(6):919–927

    Article  CAS  Google Scholar 

  20. Tefferi A, Cervantes F, Mesa R et al (2013) Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood 122(8):1395–1398

    Article  CAS  Google Scholar 

  21. Cimen Bozkus C, Finnigan JP, Mascarenhas J, Hoffman R, Bhardwaj N, Iancu-Rubin C (2017) Immune checkpoint blockade enhances mutated calreticulin-induced T cell immunity in myeloproliferative neoplasms. Blood 130(Suppl 1):384–384

    Google Scholar 

  22. Debureaux PE, Arrondeau J, Bouscary D, Goldwasser F (2018) Nivolumab combined with ruxolitinib: antagonism or synergy? Ann Oncol 29(5):1334–1335

    Article  CAS  Google Scholar 

  23. Mikkelsen SU, Kjaer L, Bjorn ME et al (2018) Safety and efficacy of combination therapy of interferon-alpha2 and ruxolitinib in polycythemia vera and myelofibrosis. Cancer Med 7(8):3571–3581

    Article  CAS  Google Scholar 

  24. Daver N, Cortes J, Newberry K et al (2015) Ruxolitinib in combination with lenalidomide as therapy for patients with myelofibrosis. Haematologica 100(8):1058–1063

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Bose P, Alfayez M, Verstovsek S (2019) New concepts of treatment for patients with myelofibrosis. Curr Treat Options Oncol 20(1):5

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0428, Houston, TX, 77030, USA

    Iman Abou Dalle, Hagop Kantarjian, Naval Daver, Lucia Masarova, Naveen Pemmaraju, Prithivaj Bose, Guillermo Garcia-Manero & Srdan Verstovsek

Authors
  1. Iman Abou Dalle
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Hagop Kantarjian
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Naval Daver
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Lucia Masarova
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Naveen Pemmaraju
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Prithivaj Bose
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Guillermo Garcia-Manero
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Srdan Verstovsek
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

IA and SV wrote the manuscript; SV designed and coordinated the study, treated patients, directed the clinical trial; HK, LM, ND, PB, NP, and GGM enrolled the patients and conducted the research; IA analyzed the data. All of the authors participated in the discussion, and have reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Srdan Verstovsek.

Ethics declarations

Conflict of interest

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.

Key points

• Nivolumab demonstrates no clinical activity in patients with advanced myelofibrosis, after failure of ruxolitinib therapy.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abou Dalle, I., Kantarjian, H., Daver, N. et al. Phase II study of single-agent nivolumab in patients with myelofibrosis. Ann Hematol 100, 2957–2960 (2021). https://doi.org/10.1007/s00277-021-04618-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-021-04618-5

Keywords