TREATMENT OF PRIMARY MYELOFIBROSIS, WHERE WE STAND TODAY?
Abstract
Introduction: Primary myelofibrosis (PMF) is a clonal hematopoietic neoplastic disease characterized by constitutive complaints, splenomegaly, anemia and very often thrombocytopenia.
Aim: To analyze and compare data from clinical trials, focusing on both current and emerging therapeutics.
Methods: The analysis of published clinical trials and relevant papers.
Results: Currently, the gold standard for treating primary myelofibrosis (PMF) is ruxolitinib, the first-in-class JAK inhibitor (JAKi). It has achieved a ≥35% reduction in spleen volume (SVR) in 41.9% of patients compared to placebo and has led to a >50% improvement in symptoms, as measured by the Total Symptom Score (TSS), in 49.5% of treated individuals. Ruxolitinib is not an ideal drug, as some patients experience worsening anemia, thrombocytopenia, and an increased susceptibility to various infections. Some patients are required to discontinue the treatment or reduce the dosage. Another approved JAK inhibitor, fedratinib, has shown promising results as a second-line treatment following ruxolitinib failure. As a first-line therapy, fedratinib achieved a spleen volume reduction (SVR) of ≥35% in 47% of patients, with a >50% improvement in TSS in 40% of cases.
In transfusion-dependent patients, momelotinib has demonstrated good results, showing non-inferiority to ruxolitinib, with similar spleen volume reduction (SVR≥35%) rates of 26.5% compared to 29% with ruxolitinib. Momelotinib treatment reduced transfusion independence by 17% compared to ruxolitinib (66% vs 49%). In thrombocytopenic patients (Plt 50-100 x109/L), pacritinib is the newest therapy; it reduces spleen volume compared to adjusted ruxolitinib dosing without worsening thrombocytopenia.
Drugs combined with ruxolitinib (e.g. navitoklaks, pelabresib) have the purpose to improve the outcome, especially in spleen reduction.
Conclusion: Treating PMF remains a challenge. While ruxolitinib provides effective disease control in nearly half of patients, new therapies are needed to enhance outcomes both overall and in those with refractory disease.
References
Bogdanović A. Hronična granulocitna leukemija i mijeloproliferativne neoplazme (prava policitemija, primarna mijelofibroza i esencijalna trombocitemija). In: Poremećaji i bolesti krvi i krvotvornih organa kod starih osoba. Marisavljević D, Milošević B, Nikolić-Žugić J, Čokić V, Prostran M, editors. Beograd: Zavod za udžbenike i nastavna sredstva; 2017. p. 201-15.
Passamonti F, Mora B. Myelofibrosis. Blood. 2023 Apr 20;141(16):1954-70. doi: 10.1182/blood.2022017423.
Tefferi A. Primary myelofibrosis: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2021 Jan;96(1):145-62. doi: 10.1002/ajh.26050.
Tefferi A. Primary myelofibrosis: 2023 update on diagnosis, risk-stratification and management. Am J Hematol. 2023 May;98(5):801-21. doi: 10.1002/ajh.26857.
Gangat N, Tefferi A. Myelofibrosis biology and contemporary management Br J Haematol. 2020 Oct;191(2):152-70. doi: 10.1111/bjh.16576.
Zahr AA, Salama ME, Carreau N, Tremblay D, Verstovsek S, Mesa R, et al. Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies. Haematologica. 2016 Jun;101(6):660-71. doi: 10.3324/haematol.2015.141283.
Čokić VP, Mossuz P, Han J, Socoro N, Beleslin-Čokić BB, Mitrović O, et al. Microarray and proteomic analyses of myeloproliferative neoplasms with a highlight on the mTOR signaling pathway. PLoS One. 2015 Aug 14;10(8):e0135463. doi: 10.1371/journal.pone.0135463.
Djikic D, Markovic D, Bogdanovic A, Mitrovic-Ajtic O, Suboticki T, Diklic M, et al. Oxidative and nitrosative stress in myeloproliferative neoplasms: the impact on the AKT / mTOR signaling pathway. J BUON. 2018 Sep-Oct;23(5):1481-91.
Šefer D, Bižić-Radulović S, Kraguljac-Kurtović N, Bogdanović A, Čokić V, Miljić P, et al. Proliferative characteristics of Philadelphia-negative myeloproliferative neoplasms – clinical implications. Int J Lab Hematol. 2017 Feb;39(1):21-31. doi: 10.1111/ijlh.12564.
Lekovic D, Gotic M, Skoda R, Beleslin-Cokic B, Milic N, Mitrovic-Ajtic O, et al. Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations. Ann Hematol. 2017 Mar;96(3):393-404. doi: 10.1007/s00277-016-2890-9.
Subotički T, Mitrović Ajtić O, Beleslin-Čokić BB, Nienhold R, Diklić M, Djikić D, et al. Angiogenic factors are increased in circulating granulocytes and CD34+ cells of myeloproliferative neoplasms. Mol Carcinog. 2017 Feb;56(2):567-79. doi: 10.1002/mc.22517.
Djordjevic V, Dencic-Fekete M, Jovanovic J, Bizic S, Jankovic G, Bogdanovic A, et al. Cytogenetics of agnogenic myeloid metaplasia: a study of 61 patients. Cancer Genet Cytogenet. 2007 Feb;173(1):57-62. doi: 10.1016/j.cancergencyto.2006.09.021.
Šefer D, Miljić P, Kraguljac-Kurtović N, Bižić-Radulović S, Bogdanović A, Knežević V, et al. Correlation between leukocyte-platelet aggregates and thrombosis in myeloproliferative neoplasms. Int J Lab Hematol. 2022 Apr;44(2):302-12. doi: 10.1111/ijlh.13754.
Palandri F, Sabattini E, Maffioli M. Treating early-stage myelofibrosis. Ann Hematol. 2019 Feb;98(2):241-53. doi: 10.1007/s00277-018-3526-z.
Lekovic D, Bogdanovic A, Sobas M, Arsenovic I, Smiljanic M, Ivanovic J, et al. Easily applicable predictive score for differential diagnosis of prefibrotic primary myelofibrosis from essential thrombocythemia. Cancers (Basel). 2023 Aug 20;15(16):4180. doi: 10.3390/cancers15164180.
Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011 Feb 1;29(4):392-7. doi: 10.1200/JCO.2010.32.2446.
Guglielmelli P, Lasho TL, Rotunno G, Mudireddy M, Mannarelli C, Nicolosi M, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018 Feb 1;36(4):310-8. doi: 10.1200/JCO.2017.76.4886.
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al.; COMFORT-I investigators. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015 Apr;100(4):479-88. doi: 10.3324/haematol.2014.115840.
Harrison CN, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Gisslinger H, Knoops L, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016 Aug;30(8):1701-7. doi: 10.1038/leu.2016.148.
Verstovsek S, Gotlib J, Mesa RA, Vannucchi AM, Kiladjian JJ, Cervantes F, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017 Sep 29;10(1):156. doi: 10.1186/s13045-017-0527-7.
Al-Ali HK, Griesshammer M, Foltz L, Palumbo GA, Martino B, Palandri F, 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 Jun;189(5):888-903. doi: 10.1111/bjh.16462.
Palandri F, Al-Ali HK, Guglielmelli P, Zuurman MW, Sarkar R, Gupta V. Benefit of early ruxolitinib initiation regardless of fibrosis grade in patients with primary myelofibrosis: a post hoc analysis of the single-arm phase 3b JUMP study. Cancers (Basel). 2023 May 22;15(10):2859. doi: 10.3390/cancers15102859.
Bogdanović A, Gotić M, Leković D, Ćojbašić I, Anđelković N, Perčić I, et al. Primena ruksolitiniba kod bolesnika sa mijelofibrozom: 5 godina iskustva u Srbiji. Zbornik Sažetaka 5-og Kongresa hematologa Srbije; 2022 Okt 6-9; Novi Sad, Srbija. p. 56.
Blair HA. Fedratinib: first approval. Drugs. 2019 Oct;79(15):1719-25. doi: 10.1007/s40265-019-01205-x.
Pardanani A, Tefferi A, Masszi T, Mishchenko E, Drummond M, Jourdan E, et al. Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Br J Haematol. 2021 Oct;195(2):244-8. doi: 10.1111/bjh.17727.
Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Tiu RV, Zachee P, 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 Jul;4(7):e317-24. doi: 10.1016/S2352-3026(17)30088-1.
Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Passamonti F, Zweegman S, et al. Safety and efficacy of fedratinib, a selective oral inhibitor of Janus kinase-2 (JAK2), in patients with myelofibrosis and low pretreatment platelet counts. Br J Haematol. 2022 Jul;198(2):317-27. doi: 10.1111/bjh.18207.
Keam SJ. Momelotinib: first approval. Drugs. 2023 Dec;83(18):1709-15. doi: 10.1007/s40265-023-01964-8.
Tefferi A, Pardanani A, Gangat N. Momelotinib (JAK1/JAK2/ACVR1 inhibitor): mechanism of action, clinical trial reports, and therapeutic prospects beyond myelofibrosis. Haematologica. 2023 Nov 1;108(11):2919-32. doi: 10.3324/haematol.2022.282612.
Mesa RA, Kiladjian JJ, Catalano JV, Devos T, Egyed M, Hellmann A, 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 Dec 1;35(34):3844-50. doi: 10.1200/JCO.2017.73.4418.
Verstovsek S, Mesa R, Gupta V, Lavie D, Dubruille V, Cambier N, et al. Momelotinib long-term safety and survival in myelofibrosis: integrated analysis of phase 3 randomized controlled trials. Blood Adv. 2023 Jul 25;7(14):3582-91. doi: 10.1182/bloodadvances.2022009311.
Mesa RA, Vannucchi AM, Mead A, Egyed M, Szoke A, Suvorov 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 May;4(5):e225-36. doi: 10.1016/S2352-3026(17)30027-3.
Mascarenhas J, Hoffman R, Talpaz M, Gerds AT, Stein B, Gupta V, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018 May 1;4(5):652-9. doi: 10.1001/jamaoncol.2017.5818.
Venugopal S, Mascarenhas J. Novel therapeutics in myeloproliferative neoplasms. J Hematol Oncol. 2020 Dec 2;13(1):162. doi: 10.1186/s13045-020-00995-y.
Verstovsek S, Kiladjian JJ, Vannucchi AM, Mesa RA, Squier P, Hamer-Maansson JE, et al. Early intervention in myelofibrosis and impact on outcomes: a pooled analysis of the COMFORT-I and COMFORT-II studies. Cancer. 2023 Jun 1;129(11):1681-90. doi: 10.1002/cncr.34707.
Tremblay D, Mascarenhas J. Next generation therapeutics for the treatment of myelofibrosis. Cells. 2021 Apr 27;10(5):1034. doi: 10.3390/cells10051034.
Pemmaraju N, Garcia JS, Perkins A, Harb JG, Souers AJ, Werner ME, et al. New era for myelofibrosis treatment with novel agents beyond Janus kinase-inhibitor monotherapy: focus on clinical development of BCL-X(L) /BCL-2 inhibition with navitoclax Cancer. 2023 Nov 15;129(22):3535-45. doi: 10.1002/cncr.34986.
Pemmaraju N, Garcia JS, Potluri J, Harb JG, Sun Y, Jung P, 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 Jun;9(6):e434-44. doi: 10.1016/S2352-3026(22)00116-8.
Pemmaraju N, Mead AJ, Somervaille TCP, McCloskey JK, Palandri F, Koschmieder S, et al. Transform-1: A randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Blood. 2023 Nov 2; 142 (Suppl. 1):620. doi: 10.1182/blood-2023-173509.
Mascarenhas J, Kremyanskaya M, Patriarca A, Palandri F, Devos T, Passamonti F, et al. MANIFEST: Pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naive myelofibrosis. J Clin Oncol. 2023 Nov 10;41(32):4993-5004. doi: 10.1200/JCO.22.01972.
Harrison CN, Gupta VK, Gerds AT, Rampal R, Verstovsek S, Talpaz M, et al. Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis. Future Oncol. 2022 Sep;18(27):2987-97. doi: 10.2217/fon-2022-0484.
Chifotides HT, Masarova L, Verstovsek S. SOHO state of the art updates and next questions: novel therapeutic strategies in development for myelofibrosis. Clin Lymphoma Myeloma Leuk. 2023 Apr;23(4):219-31. doi: 10.1016/j.clml.2022.12.014.
