Skip to main content

Advertisement

SpringerLink
Log in

Management of Myelofibrosis-Associated Anemia: Focus on Standard Agents and Novel Therapeutics in Phase 3 Clinical Trials

  • Myeloproliferative Neoplasms (BL Stein, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The management of myelofibrosis is risk-adapted when considering transplant eligibility and symptom-directed, prioritizing the most burdensome symptoms for the patient. Unfortunately, myelofibrosis-anemia is common, multifactorial in its origin, and impactful regarding prognosis. While clinical trials are advised, not all patients have convenient access, and therefore, hematologists should be aware of the data supporting the use of conventional agents such as erythropoietin-stimulating agents, steroid treatments (danazol and prednisone), and immunomodulatory drugs (thalidomide and lenalidomide). This review summarizes the conventional approach to treating myelofibrosis-anemia and highlights recent data from 3 novel agents that are under phase 3 evaluation.

Recent Findings

Momelotonib is a JAK1/2 and ACVR1 inhibitor that has demonstrated not only improvements in splenomegaly and symptoms, but also amelioration of anemia on the SIMPLIFY 1 and 2 clinical trial program. This may occur through suppression of hepcidin production. Luspatercept promotes late-stage hematopoiesis, and the phase 2 study has shown promise in ameliorating anemia as a monotherapy, and especially in combination with ruxolitinib. Finally, CP-0160, a BET inhibitor, has shown efficacy as an anemia-directed agent, when used as monotherapy and in combination. This agent reduces cytokine production and promotes erythroid differentiation. Results have been presented for patients previously treated with JAK inhibitors, as well as those who were naïve to JAK inhibitor therapy.

Summary

Safety and effectiveness are reviewed for both conventional and selected novel agents used in the treatment of MF-anemia. A practical approach to treatment is presented, and data from ASH 2020 are presented.

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

Access this article

Log in via an institution

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

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6(4):372–5.

    Article  CAS  Google Scholar 

  2. Marneth AE, Mullally A. The molecular genetics of myeloproliferative neoplasms. Cold Spring Harb Perspect Med. 2020;10(2):a034876. https://doi.org/10.1101/cshperspect.a034876.

  3. Verstovsek S, et al. 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. 2017;10(1):55.

    Article  CAS  Google Scholar 

  4. Harrison CN, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701–7.

    Article  CAS  Google Scholar 

  5. Vannucchi AM. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(17):1670–1.

    Article  Google Scholar 

  6. Pardanani A, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643–51.

    Article  Google Scholar 

  7. Harrison CN, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317–24.

    Article  Google Scholar 

  8. Guglielmelli P, et al. MIPSS70: mutation-enhanced international prognostic score system for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018;36(4):310–8.

    Article  CAS  Google Scholar 

  9. Myeloproliferative neoplasms. NCCN Guidelines 2021 [cited 2021 2/22/21].

  10. Cervantes F. How I treat myelofibrosis. Blood. 2014;124(17):2635–42.

    Article  CAS  Google Scholar 

  11. • Elli EM, et al. Deferasirox in the management of iron-overload in patients with myelofibrosis: a multicentre study from the Rete Ematologica Lombarda (IRON-M study). Br J Haematol. 2019;186(5):e123–6. The role of iron chelation is unclear in Myelofibrosis. This is a multicenter study showed that 43% had an erythroid response to iron chelation.

    Article  Google Scholar 

  12. Hernandez-Boluda JC, et al. Predictive factors for anemia response to erythropoiesis-stimulating agents in myelofibrosis. Eur J Haematol. 2017;98(4):407–14.

    Article  CAS  Google Scholar 

  13. Crisa E, et al. The use of erythropoiesis-stimulating agents is safe and effective in the management of anaemia in myelofibrosis patients treated with ruxolitinib. Br J Haematol. 2018;182(5):701–4.

    Article  CAS  Google Scholar 

  14. Hernandez-Boluda JC, et al. Long-term results of prednisone treatment for the anemia of myelofibrosis. Leuk Lymphoma. 2016;57(1):120–4.

    Article  CAS  Google Scholar 

  15. Cervantes F, et al. Danazol therapy for the anemia of myelofibrosis: assessment of efficacy with current criteria of response and long-term results. Ann Hematol. 2015;94(11):1791–6.

    Article  CAS  Google Scholar 

  16. Gowin K, et al. Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis. Leuk Res. 2017;60:31–5.

    Article  CAS  Google Scholar 

  17. Luo X, et al. Thalidomide plus prednisone with or without danazol therapy in myelofibrosis: a retrospective analysis of incidence and durability of anemia response. Blood Cancer J. 2018;8(1):9.

    Article  Google Scholar 

  18. Tefferi A, et al. A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence. Leukemia. 2017;31(4):896–902.

    Article  CAS  Google Scholar 

  19. Thapaliya P, et al. International working group for myelofibrosis research and treatment response assessment and long-term follow-up of 50 myelofibrosis patients treated with thalidomide-prednisone based regimens. Am J Hematol. 2011;86(1):96–8.

    Article  CAS  Google Scholar 

  20. Mesa RA, et al. Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903. Blood. 2010;116(22):4436–8.

    Article  CAS  Google Scholar 

  21. • Castillo-Tokumori F, et al. Retrospective analysis of the clinical use and benefit of lenalidomide and thalidomide in myelofibrosis. Clin Lymphoma Myeloma Leuk. 2020;20(12):e956–60. This is a more contemporary retrospective study demonstrating response rates for immunomodulatory drugs when used to treat MF anemia.

    Article  Google Scholar 

  22. • Oh ST, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020;4(18):4282–91. This study provides some proof of principle regarding the ability of momelotonib to suppress hepcidin and offer anemia responses in some patients with MF and transfusion-dependent anemia.

    Article  CAS  Google Scholar 

  23. Asshoff M, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood. 2017;129(13):1823–30.

    Article  CAS  Google Scholar 

  24. Mesa RA, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naive patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844–50.

    Article  CAS  Google Scholar 

  25. Harrison CN, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5(2):e73–81.

    Article  Google Scholar 

  26. Gerds AT, et al. A phase 2 study of luspatercept in patients with myelofibrosis-associated anemia. Blood. 2019;134(Supplement_1):557–557.

    Article  Google Scholar 

  27. Gerds AT, et al. Duration of response to luspatercept in patients (Pts) requiring red blood cell (RBC) transfusions with myelofibrosis (MF) - updated data from the phase 2 ACE-536-MF-001 Study. Blood. 2020;134(Supplement_1):557 ((557)).

    Article  Google Scholar 

  28. Kleppe M, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(1):29-43 e7.

    Article  CAS  Google Scholar 

  29. Talpaz Mea. CPI-0610, a bromodomain and extraterminal domain protein (BET) inhibitor, as monotherapy in advanced myelofibrosis patients refractory/intolerant to JAK inhibitor: update from phase 2 MANIFEST Study. Blood. 2020. 134(Paper 2163).

  30. Verstovsek S et al. CPI-0610, bromodomain and extraterminal domain protein (BET) inhibitor, as “add-on” to ruxolitinib, in advanced myelofibrosis patients with suboptimal response: update of MANIFEST Phase 2 Study. Blood. 2020(Supplement_1): p. Abstract 56.

  31. Mascarenhas J et al. CPI-0610, a bromodomain and extraterminal domain protein (BET) inhibitor, in combination with ruxolitinib, in JAK-inhibitor-naïve myelofibrosis patients: update of MANIFEST Phase 2 Study. Blood. 2020(Supplement_1): p. Abstract 55.

Download references

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology and Department of Medicine, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, 645 N Michigan Avenue, Suite 1020, Chicago, IL, 60611, USA

    Brady L. Stein

Authors
  1. Brady L. Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brady L. Stein.

Ethics declarations

Conflict of Interest

The author declares no competing interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the author.

Additional information

Publisher's Note

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

This article is part of the Topical Collection on Myeloproliferative Neoplasms

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stein, B.L. Management of Myelofibrosis-Associated Anemia: Focus on Standard Agents and Novel Therapeutics in Phase 3 Clinical Trials. Curr Hematol Malig Rep 16, 483–489 (2021). https://doi.org/10.1007/s11899-021-00651-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-021-00651-3

Keywords

Search

Navigation