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Symposium | The treatment landscape for patients with myelofibrosis and anemia
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Francesco PassamontiDo you know... Which of the following is true of new/worsening anemia in patients with myelofibrosis?
During the European School of Haematalogy (ESH) 4th How to Diagnose and Treat CML/MPN conference, the MPN Hub held a symposium on March 9, 2025, titled Anemia in myelofibrosis: Sequencing therapies to optimize patient outcomes. Here, we share a presentation by Francesco Passamonti, Università degli Studi di Milano, Milan, IT, discussing the treatment landscape for patients with myelofibrosis and anemia.
The treatment landscape for patients with myelofibrosis and anemia
The treatment landscape for patients with myelofibrosis and anemia
Firstly, Passamonti provided an overview of current treatment strategies for patients with myelofibrosis (MF)-related anemia, including red blood cell transfusion, erythropoiesis-stimulating agents, androgens, splenectomy, immunomodulatory drug agents, and Janus kinase inhibitors (JAKis).1 He then discussed key efficacy and safety data from phase III trials of ruxolitinib, fedratinib, pacritinib, and momelotinib, with a focus on anemia.
Ruxolitinib
The phase III COMFORT-I (NCT00952289) and COMFORT-II (NCT00952289) trials demonstrated the spleen response benefit of ruxolitinib vs placebo and best available therapy (BAT), respectively (Figure 1).2,3
Figure 1. SVR35 response rates in the COMFORT-I and COMFORT-II trials*
The majority of patients treated with ruxolitinib in the COMFORT-I (96%) and COMFORT-II (97%) trials were anemic, and almost 50% of patients in both trials became transfusion dependent.2–4
The efficacy of ruxolitinib is dose-dependent, as shown in the phase IIIb JUMP (NCT01493414) trial, which included patients with low platelet (PLT) counts (50 to <100 × 109/L); lower ≥50% spleen volume reduction (SVR) rates were observed in patients with low PLT counts who received lower doses of ruxolitnib.5
Results from the JUMP trial and a real-world study of adult patients with MF who were treated with ruxolitinib in the US Flatiron database demonstrated that new or worsening anemia was associated with worse overall survival in patients who were nonanemic at baseline.6,7
The response to ruxolitinib after 6 months (RR6) model includes anemia as a risk factor for worse survival among patients treated with ruxolitinib.8
Fedratinib
Results from the phase III JAKARTA (NCT01437787),9,10JAKARTA-2 (NCT01523171),9,11FREEDOM (NCT03755518),12 and FREEDOM-2 (NCT03952039)13 trials showed that fedratinib has similar efficacy to ruxolitinib in terms of spleen response; however, anemia was a common adverse event.
Pacritinib
Results from the phase III PERSIST-1 (NCT01773187) and PERSIST-2 (NCT02055781) trials demonstrated the benefit of pacritinib vs BAT in patients with MF, with no exclusions for baseline anemia or thrombocytopenia in PERSIST-1, and patients with PLT count ≤100 × 109/L in PERSIST-2 (Figure 2).14,15
A subanalysis from PERSIST-2 showed that patients treated with pacritinib had improved transfusion independence (TI) rates vs BAT when assessed using the Gale criteria (37% vs 7%; p = 0.001) and the SIMPLIFY criteria (24% vs 4.5%; p = 0.013).16
Figure 2. Response rates in the PERSIST-1 and PERSIST-2 trials*
A pooled analysis from the PERSIST-1 and PERSIST-2 trials found that pacritinib improved SVR35 (23% vs 2%; p = 0.0007) and 50% reduction in total symptom score (TSS; 25% vs 8%; p = 0.0441) vs BAT in patients with PLT count <50 × 109/L (n = 189).17
Momelotinib
In the SIMPLIFY-1 (NCT01969838) trial, momelotinib demonstrated similar SVR35 response rates to ruxolitinib (26.5% vs 29.0%; noninferiority p = 0.011), and improved TI rates (66.5% vs 49.3%; p <0.001) in JAKi-naïve patients (Figure 3).18
Mean hemoglobin levels increased in patients who crossed over from ruxolitinib to momelotinib.19
Figure 3. Response rates in the SIMPLIFY-1 trial*
Results from SIMPLIFY-2 showed similar rates of SVR35 response between momelotinib and BAT (7% vs 6%; p = 0.90), while momelotinib was associated with improved TSS50 (26% vs 6%; p = 0.0006) and TI rates (43% vs 21%; p = 0.0012) in JAKi-experienced patients.20
Patients who crossed over from BAT to momelotinib had increased mean hemoglobin levels.21
In the phase III MOMENTUM trial (NCT04173494) trial, the TSS50, TI, and SVR35 rates at Week 48 among patients treated with momelotinib were 45%, 57%, and 43%, respectively, and among patients who crossed over from the danazol to momelotinib, the response rates were 50%, 60%, and 13%, respectively.22
Conclusions
Passamonti concludes by highlighting the following:
Ruxolitinib and fedratinib can effectively improve splenomegaly; however, they may exacerbate anemia in patients with MF.
Results from the PERSIST trials suggest that pacritinib is effective in patients with MF and severe thrombocytopenia.
Data from the SIMPLIFY and MOMENTUM trials indicate that momelotinib can improve TI in patients with MF and anemia while also reducing splenomegaly.
A tailored approach may be necessary when choosing a JAKi for patients with MF, particularly if the patient presents with or develops anemia or severe thrombocytopenia.
This independent educational activity is supported by GSK. All content is developed independently by the faculty; the funder is allowed no influence on the content.
Your opinion matters
What do you consider to be the highest unmet need for patients with myelofibrosis?
References
Passamonti F, Harrison CN, Mesa RA, et al. Anemia in myelofibrosis: Current and emerging treatment options. Crit Rev Oncol Hematol. 2022;180:103862. DOI: 10.1016/j.critrevonc.2022.103862
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. DOI: 10.1056/NEJMoa1110557
Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-98. DOI: 10.1056/NEJMoa1110556
Verstovsek S, Mesa RA, Livingston RA, et al. Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. J Hematol Oncol. 2023;16(1):82. DOI: 10.1186/s13045-023-01471-z
Al-Ali HK, Griesshammer M, Foltz L, et al. Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. Br J Haematol. 2020;189(5):888-903. DOI: 10.1111/bjh.16462
Gupta V. Effect of new or worsening anemia on clinical outcomes in 2233 patients with myelofibrosis treated with ruxolitinib in the expanded-access Jump study. Poster abstract #5174. 65th American Society of Hematology (ASH) Annual Meeting and Exposition; Dec 9–12, 2023; San Diego, US.
Kuykendall A. Retrospective real-world analysis of survival outcomes in patients with myelofibrosis and new or worsening anemia treated with ruxolitinib in the United States. Poster abstract #3804. 66th American Society of Hematology (ASH) Annual Meeting and Exposition; Dec 7–10, 2024; San Diego, US.
Maffioli M, Mora B, Ball S, et al. A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis. Blood Adv. 2022;6(6):1855-1864. DOI: 10.1182/bloodadvances.2021006889
Mullally A, Hood J, Harrison C, et al. Fedratinib in myelofibrosis. Blood Adv. 2020;4(8):1792-1800. DOI: 10.1182/bloodadvances.2019000954
Pardanani A, Harrison C, Cortes JE, 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. DOI: 10.1001/jamaoncol.2015.1590
Harrison CN, Schaap N, Vannucchi AM, 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-e324. DOI: 10.1016/S2352-3026(17)30088-1
Gupta V, Yacoub A, Mesa RA, et al. Safety and efficacy of fedratinib in patients with myelofibrosis previously treated with ruxolitinib: primary analysis of FREEDOM trial. Leuk Lymphoma. 2024;65(9):1314-1324. DOI: 10.1080/10428194.2024.2346733
Harrison CN, Mesa R, Talpaz M, et al. Efficacy and safety of fedratinib in patients with myelofibrosis previously treated with ruxolitinib (FREEDOM2): results from a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Haematol. 2024;11(10):e729-e740. DOI: 10.1016/S2352-3026(24)00212-6
Mesa RA, Vannucchi AM, Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017;4(5):e225-e236. DOI: 10.1016/S2352-3026(17)30027-3
Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: A randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. DOI: 10.1001/jamaoncol.2017.5818
Oh ST, Mesa RA, Harrison CN, et al. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood Adv. 2023;7(19):5835-5842. DOI: 10.1182/bloodadvances.2023010151
Verstovsek S, Mesa R, Talpaz M, et al. Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia. Haematologica. 2022;107(7):1599-1607. DOI: 10.3324/haematol.2021.279415
Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A phase iii randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850. DOI: 10.1200/JCO.2017.73.4418
Mesa R, Oh ST, Gerds AT, et al. Momelotinib reduces transfusion requirements in patients with myelofibrosis. Leuk Lymphoma. 2022;63(7):1718-1722. DOI: 10.1080/10428194.2022.2043304
Harrison CN, Vannucchi AM, Platzbecker U, 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-e81. DOI: 10.1016/S2352-3026(17)30237-5
Harrison CN, Vannucchi AM, Recher C, et al. Momelotinib versus continued ruxolitinib or best available therapy in JAK inhibitor-experienced patients with myelofibrosis and anemia: Subgroup analysis of SIMPLIFY-2. Adv Ther. 2024;41(9):3722-3735. DOI: 10.1007/s12325-024-02928-4
Gerds AT, Verstovsek S, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study. Lancet Haematol. 2023;10(9):e735-e746. DOI: 10.1016/S2352-3026(23)00174-6
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