Emerging Treatment Options for Myelofibrosis: Focus on Anemia

References

• Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition, pathogenesis, and treatment. Annu Rev Med. 2009;60:233–245. doi:10.1146/annurev.med.60.041707.160528
   PubMed Web of Science ®Google Scholar
• Reilly JT, McMullin MF, Beer PA, et al. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol. 2012;158(4):453–471. doi:10.1111/j.1365-2141.2012.09179.x
   PubMed Web of Science ®Google Scholar
• Tefferi A, Lasho TL, Jimma T, et al. One Thousand Patients with Primary Myelofibrosis: The Mayo Clinic Experience. Elsevier; 2012.
   Google Scholar
• Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the international working group for myelofibrosis research and treatment. Blood. 2009;113(13):2895–2901. doi:10.1182/blood-2008-07-170449
   PubMed Web of Science ®Google Scholar
• Tefferi A, Hudgens S, Mesa R, et al. Use of the functional assessment of cancer therapy− anemia in persons with myeloproliferative neoplasm-associated myelofibrosis and anemia. Clin Ther. 2014;36(4):560–566. doi:10.1016/j.clinthera.2014.02.016
   PubMed Web of Science ®Google Scholar
• Guglielmelli P, Rotunno G, Pacilli A, et al. Prognostic impact of bone marrow fibrosis in primary myelofibrosis. A study of the AGIMM group on 490 patients. Am J Hematol. 2016;91(9):918–922. doi:10.1002/ajh.24442
   PubMed Web of Science ®Google Scholar
• Wang X, Cho SY, Hu CS, Chen D, Roboz J, Hoffman R. CXC motif chemokine 12 influences the development of extramedullary hematopoiesis in the spleens of myelofibrosis patients. Exp Hematol. 2015;43(2):100–109. e1. doi:10.1016/j.exphem.2014.10.013
   PubMed Web of Science ®Google Scholar
• Pardanani A, Finke C, Abdelrahman RA, Lasho TL, Tefferi A. Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis. Am J Hematol. 2013;88(4):312–316. doi:10.1002/ajh.23406
   PubMed Web of Science ®Google Scholar
• Rampal R, Al-Shahrour F, Abdel-Wahab O, et al. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood. 2014;123(22):e123–e133. doi:10.1182/blood-2014-02-554634
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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):643–651. doi:10.1001/jamaoncol.2015.1590
   PubMed Web of Science ®Google Scholar
• Oh ST, Mesa R, Harrison C, et al. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood. 2022;140(Supplement 1):1518–1521. doi:10.1182/blood-2022-156936
   Google Scholar
• Oh ST, Talpaz M, Gerds AT, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020;4(18):4282–4291. doi:10.1182/bloodadvances.2020002662
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Mesa R, Talpaz M, et al. Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia. Haematologica. 2022;107(7):1599. doi:10.3324/haematol.2021.279415
   PubMed Web of Science ®Google Scholar
• Kiladjian JJ, Platzbecker U, Mayer J, et al. Momelotinib’s spleen, symptom and anemia efficacy is maintained in intermediate/high risk myelofibrosis patients with thrombocytopenia. Blood. 2020;136:43–44. doi:10.1182/blood-2020-135880
   Web of Science ®Google Scholar
• Harrison C, Kiladjian -J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–798. doi:10.1056/NEJMoa1110556
   PubMed Web of Science ®Google Scholar
• Gupta V, Harrison C, Hexner EO, et al. The impact of anemia on overall survival in patients with myelofibrosis treated with ruxolitinib in the COMFORT studies. Haematologica. 2016;101(12):e482. doi:10.3324/haematol.2016.151449
   PubMed Web of Science ®Google Scholar
• Cervantes F, Ross DM, Radinoff A, et al. Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study. Leukemia. 2021;35(12):3455–3465. doi:10.1038/s41375-021-01261-x
   PubMed Web of Science ®Google Scholar
• Harrison CN, Vannucchi AM, Kiladjian -J-J, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701–1707. doi:10.1038/leu.2016.148
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Mesa RA, Gotlib J, 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):1–14. doi:10.1186/s13045-017-0417-z
   PubMedGoogle Scholar
• Mullally A, Hood J, Harrison C, Mesa R. Fedratinib in myelofibrosis. Blood Adv. 2020;4(8):1792–1800. doi:10.1182/bloodadvances.2019000954
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: an updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol. 2020;95(6):594–603. doi:10.1002/ajh.25777
   PubMed Web of Science ®Google Scholar
• Waksal JA, Tremblay D, Mascarenhas J. Clinical utility of fedratinib in myelofibrosis. Onco Targets Ther. 2021;14:4509. doi:10.2147/OTT.S267001
   PubMed Web of Science ®Google Scholar
• Gupta V, Yacoub A, Verstovsek S, et al. Safety and efficacy of fedratinib in patients with Primary (P), Post-Polycythemia Vera (Post-PV), and Post-Essential Thrombocythemia (Post-ET) Myelofibrosis (MF) previously treated with ruxolitinib: primary analysis of the FREEDOM trial. Blood. 2022;140(Supplement 1):3935–3937. doi:10.1182/blood-2022-156669
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Mascarenhas J, Gerds AT, Kiladjian -J-J, et al. PACIFICA: a randomized, controlled phase 3 study of pacritinib versus physician’s choice in patients with primary or secondary myelofibrosis and severe thrombocytopenia. Blood. 2022;140(Supplement 1):9592–9594. doi:10.1182/blood-2022-163456
   Google Scholar
• Yacoub A, Mesa RA, Oh ST. Long-term hematologic improvement in a patient with cytopenic myelofibrosis treated with pacritinib; 2023.
   Google Scholar
• Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006;108(9):3204–3209. doi:10.1182/blood-2006-06-027631
   PubMed Web of Science ®Google Scholar
• Pardanani A, Laborde R, Lasho T, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013;27(6):1322–1327. doi:10.1038/leu.2013.71
   PubMed Web of Science ®Google Scholar
• Pardanani A, Gotlib J, Roberts A, et al. Long-term efficacy and safety of momelotinib, a JAK1 and JAK2 inhibitor, for the treatment of myelofibrosis. Leukemia. 2018;32(4):1034–1037. doi:10.1038/leu.2017.330
   Web of Science ®Google Scholar
• Gupta V, Mesa RA, Deininger MW, et al. A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis. Haematologica. 2017;102(1):94. doi:10.3324/haematol.2016.148924
   PubMed Web of Science ®Google Scholar
• Mesa RA, Kiladjian -J-J, Catalano JV, 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):3844–3850. doi:10.1200/JCO.2017.73.4418
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Mesa RA, Jamieson C, Bhatia R, et al. NCCN guidelines insights: myeloproliferative neoplasms, version 2.2018. J Natl Compr Canc Netw. 2017;15(10):1193–1207. doi:10.6004/jnccn.2017.0157
   PubMed Web of Science ®Google Scholar
• Gwaltney C, Paty J, Kwitkowski VE, et al. Development of a harmonized patient-reported outcome questionnaire to assess myelofibrosis symptoms in clinical trials. Leuk Res. 2017;59:26–31. doi:10.1016/j.leukres.2017.05.012
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Gerds AT, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269–280. doi:10.1016/S0140-6736(22)02036-0
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and-II pooled analyses. J Hematol Oncol. 2017;10:1–6. doi:10.1186/s13045-017-0527-7
   PubMed Web of Science ®Google Scholar
• Martí‐Carvajal AJ, Anand V, Sola I. Janus kinase‐1 and Janus kinase‐2 inhibitors for treating myelofibrosis. Cochrane Database Syst Rev. 2015;(4). doi:10.1002/14651858.CD010298.pub2
   Web of Science ®Google Scholar
• Guglielmelli P, Ghirardi A, Carobbio A, et al. Impact of ruxolitinib on survival of patients with myelofibrosis in the real world: update of the ERNEST Study. Blood Adv. 2022;6(2):373–375. doi:10.1182/bloodadvances.2021006006
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Parasuraman S, Yu J, et al. Real-world survival of US patients with intermediate-to high-risk myelofibrosis: impact of ruxolitinib approval. Ann Hematol. 2022;2022:1–7.
   Google Scholar
• Harrison C, Kiladjian -J-J, Verstovsek S, et al. MPN-164: overall survival (OS) and progression-free survival (PFS) in patients treated with fedratinib as first-line myelofibrosis (MF) therapy and after prior ruxolitinib (RUX): results from the Jakarta and JAKARTA2 trials. Clin Lymphoma Myeloma Leuk. 2021;21:S356. doi:10.1016/S2152-2650(21)01822-X
   Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Mesa R, Harrison C, Oh ST, et al. Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. Leukemia. 2022;36(9):2261–2268. doi:10.1038/s41375-022-01637-7
   PubMed Web of Science ®Google Scholar
• Vachhani P, Verstovsek S, Bose P. Disease modification in myelofibrosis: an elusive goal? J Clin Oncol. 2022;40(11):1147–1154. doi:10.1200/JCO.21.02246
   PubMed Web of Science ®Google Scholar
• Pemmaraju N, Verstovsek S, Mesa R, et al. Defining disease modification in myelofibrosis in the era of targeted therapy. Cancer. 2022;128(13):2420–2432. doi:10.1002/cncr.34205
   PubMed Web of Science ®Google Scholar
• Kleppe M, Koche R, Zou L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(1):29–43. e7. doi:10.1016/j.ccell.2017.11.009
   PubMed Web of Science ®Google Scholar
• Mascarenhas J, Kremyanskaya M, Patriarca A, et al. MANIFEST: pelabresib in combination with ruxolitinib for janus kinase inhibitor treatment-naïve myelofibrosis. J Clin Oncol;2023. JCO. 22.01972. doi:10.1200/JCO.22.01972
   PubMed Web of Science ®Google Scholar
• Harrison CN, Gupta VK, Gerds AT, et al. Phase III MANIFEST-2: pelabresib+ ruxolitinib vs placebo+ ruxolitinib in JAK inhibitor treatment-naive myelofibrosis. Future Oncol. 2022;18(27):2987–2997. doi:10.2217/fon-2022-0484
   PubMed Web of Science ®Google Scholar
• Tremblay D, Mesa R, Paiva CE. New treatments for myelofibrosis. Curr Treat Options Oncol. 2023;24:1–15. doi:10.1007/s11864-022-01044-1
   PubMed Web of Science ®Google Scholar
• Waibel M, Solomon VS, Knight DA, et al. Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors. Cell Rep. 2013;5(4):1047–1059. doi:10.1016/j.celrep.2013.10.038
   PubMed Web of Science ®Google Scholar
• Lu M, Wang J, Li Y, et al. Treatment with the Bcl-xL inhibitor ABT-737 in combination with interferon α specifically targets JAK2V617F-positive polycythemia vera hematopoietic progenitor cells. Blood. 2010;116(20):4284–4287. doi:10.1182/blood-2010-04-279125
   PubMed Web of Science ®Google Scholar
• Pemmaraju N, Garcia JS, Potluri J, et al. Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study. Lancet Haematol. 2022;9(6):e434–e444. doi:10.1016/S2352-3026(22)00116-8
   PubMed Web of Science ®Google Scholar
• Pullarkat V, Cruz-Chacon A, Gangatharan S, et al. P1070: navitoclax monotherapy in patients with myelofibrosis previously treated with JAK-2 inhibitors: safety and tolerability. HemaSphere. 2022;6:960–961. doi:10.1097/01.HS9.0000847148.78233.c8
   Google Scholar
• Passamonti F, Foran JM, Tandra A, et al. The combination of navitoclax and ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis mediates responses suggestive of disease modification. Blood. 2022;140(Supplement 1):583–585. doi:10.1182/blood-2022-157949
   Google Scholar
• Suragani RN, Cadena SM, Cawley SM, et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014;20(4):408–414. doi:10.1038/nm.3512
   PubMed Web of Science ®Google Scholar
• Gerds AT, Vannucchi AM, Passamonti F, et al. A phase 2 study of luspatercept in patients with myelofibrosis-associated anemia. Blood. 2019;134:557. doi:10.1182/blood-2019-122546
   Google Scholar
• Chen Y, Stubbs MC, Pusey M, et al. Characterization of INCB00928, a potent and selective ALK2 inhibitor for the treatment of anemia. Blood. 2020;136:52. doi:10.1182/blood-2020-136138
   Web of Science ®Google Scholar
• Mohan SR, Oh ST, Ali H, et al. A phase 1/2 study of INCB000928 as monotherapy or combined with Ruxolitinib (RUX) in Patients (Pts) with anemia due to Myelofibrosis (MF). Blood. 2022;140(Supplement 1):3943–3944. doi:10.1182/blood-2022-169210
   Google Scholar
• Verstovsek S, Al-Ali HK, Mascarenhas J, et al. BOREAS: a global, phase III study of the MDM2 inhibitor navtemadlin (KRT-232) in relapsed/refractory myelofibrosis. Future Oncol. 2022;18:4059–4069. doi:10.2217/fon-2022-0901
   Web of Science ®Google Scholar
• Mascarenhas J, Harrison CN, Kiladjian -J-J, et al. Imetelstat in intermediate-2 or high-risk myelofibrosis refractory to JAK inhibitor: iMpactMF phase III study design. Future Oncol. 2022;18(22):2393–2402. doi:10.2217/fon-2022-0235
   PubMed Web of Science ®Google Scholar