Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
08
04
2022
accepted:
23
06
2022
revised:
17
06
2022
pubmed:
23
7
2022
medline:
31
8
2022
entrez:
22
7
2022
Statut:
ppublish
Résumé
Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p < 0.0001) and multivariate (HR = 0.311; p < 0.0001) analyses. These findings underscore the importance of achieving or maintaining TI in myelofibrosis, supporting the clinical relevance of momelotinib's pro-erythropoietic mechanism of action, and potentially informing treatment decision-making.
Identifiants
pubmed: 35869266
doi: 10.1038/s41375-022-01637-7
pii: 10.1038/s41375-022-01637-7
pmc: PMC9417985
doi:
Substances chimiques
Benzamides
0
Janus Kinase Inhibitors
0
Nitriles
0
Protein Kinase Inhibitors
0
Pyrimidines
0
N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
6O01GMS00P
Janus Kinase 2
EC 2.7.10.2
Types de publication
Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2261-2268Informations de copyright
© 2022. The Author(s).
Références
Tefferi A. Primary myelofibrosis: 2021 update on diagnosis, risk‐stratification and management. Am J Hematol. 2021;96:145–62.
doi: 10.1002/ajh.26050
Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, 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;113:2895–901.
doi: 10.1182/blood-2008-07-170449
Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: A study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010;115:1703–8.
doi: 10.1182/blood-2009-09-245837
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;29:392–7.
doi: 10.1200/JCO.2010.32.2446
Nicolosi M, Mudireddy M, Lasho TL, Hanson CA, Ketterling RP, Gangat N, et al. Sex and degree of severity influence the prognostic impact of anemia in primary myelofibrosis: analysis based on 1109 consecutive patients. Leukemia. 2018;32:1254–8.
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;101:660–71.
doi: 10.3324/haematol.2015.141283
Tefferi A, Lasho TL, Jimma T, Finke CM, Gangat N, Vaidya R, et al. One thousand patients with primary myelofibrosis: The Mayo Clinic experience. Mayo Clin Proc. 2012;87:25–33.
doi: 10.1016/j.mayocp.2011.11.001
Scherber RM, Mesa RA. Management of challenging myelofibrosis after JAK inhibitor failure and/or progression. Blood Rev. 2020; https://doi.org/10.1016/j.blre.2020.100716 .
Robin M, de Wreede LC, Wolschke C, Schetelig J, Eikema D-J, van Lint MT, et al. Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis. Haematologica 2019;104:1782–8.
doi: 10.3324/haematol.2018.205211
Tiribelli M, Palandri F, Sant’Antonio E, Breccia M, Bonifacio M. The role of allogeneic stem-cell transplant in myelofibrosis in the era of JAK inhibitors: a case-based review. Bone Marrow Transplant. 2020;55:708–16.
doi: 10.1038/s41409-019-0683-1
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N. Engl J Med. 2012;366:799–807.
doi: 10.1056/NEJMoa1110557
Harrison C, Kiladjian J-J, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N. Engl J Med. 2012;366:787–98.
doi: 10.1056/NEJMoa1110556
Verstovsek S, Gotlib J, Mesa RA, Vannucchi AM, Kiladjian J-J, Cervantes F, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10; https://doi.org/10.1186/s13045-017-0527-7 .
Vannucchi AM, Kantarjian HM, Kiladjian J-J, Gotlib J, Cervantes F, Mesa RA, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica 2015;100:1139–45.
doi: 10.3324/haematol.2014.119545
Maffioli M, Mora B, Ball S, Iurlo A, Elli EM, Finazzi MC, et al. A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis. Blood Adv 2022;6:1855–64.
doi: 10.1182/bloodadvances.2021006889
Verstovsek S, Parasuraman S, Yu J, Shah A, Kumar S, Xi A, et al. Real-world survival among patients with intermediate- to high-risk myelofibrosis in the United States: Impact of ruxolitinib approval. Blood 2020;136(Suppl 1):46–7.
doi: 10.1182/blood-2020-140820
Gupta V, Harrison C, Hexner EO, Al-Ali HF, Foltz L, Montgomery M, et al. The impact of anemia on overall survival in patients with myelofibrosis treated with ruxolitinib in the COMFORT studies. Haematologica 2016;101:e482–e484.
doi: 10.3324/haematol.2016.151449
Kuykendall A, Shah S, Talati C, Al Ali N, Sweet K, Padron E, et al. Between a rux and a hard place: Evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation. Ann Hematol. 2018;97:435–41.
doi: 10.1007/s00277-017-3194-4
Mascarenhas J, Mehra M, He J, Potluri R, Loefgren C. Patient characteristics and outcomes after ruxolitinib discontinuation in patients with myelofibrosis. J Med Econ. 2020;23:721–7.
doi: 10.1080/13696998.2020.1741381
Fonseca E, Silver RT, Kazis LE, Iqbal SU, Rose M, Khan N. Ruxolitinib discontinuation in patients with myelofibrosis: An analysis from clinical practice. Blood 2013;122:2833.
doi: 10.1182/blood.V122.21.2833.2833
Mascarenhas J, Komrokji RS, Cavo M, Martino B, Niederwieser D, Reiter A, et al. Imetelstat is effective treatment for patients with intermediate-2 or high-risk myelofibrosis who have relapsed on or are refractory to janus kinase inhibitor therapy: Results of a phase 2 randomized study of two dose levels. Blood 2018;132:685.
doi: 10.1182/blood-2018-99-115163
Palandri F, Breccia M, Bonifacio M, Polverelli N, Elli EM, Benevolo G, et al. Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer 2020;126:1243–52.
doi: 10.1002/cncr.32664
Mesa RA, Kiladjian J-J, 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–naïve patients with myelofibrosis. J Clin Oncol. 2017;35:3844–50.
doi: 10.1200/JCO.2017.73.4418
Harrison CN, Vannucchi AM, Platzbecker U, Cervantes F, Gupta V, Lavie D, 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:e73–e81.
doi: 10.1016/S2352-3026(17)30237-5
Mesa R, Oh ST, Gerds AT, Gupta V, Catalano J, Cervantes F, et al. Momelotinib reduces transfusion requirements in patients with myelofibrosis. Leuk Lymphoma. 2021; https://doi.org/10.1080/10428194.2022.2043304 .
Asshoff M, Petzer V, Warr MR, Haschka D, Tymoszuk P, Demetz E, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood 2017;129:1823–30.
doi: 10.1182/blood-2016-09-740092
Oh ST, Talpaz M, Gerds AT, Gupta V, Verstovsek S, Mesa R, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020;4:4282–91.
doi: 10.1182/bloodadvances.2020002662
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;88:312–6.
doi: 10.1002/ajh.23406
Newberry KJ, Patel K, Masarova L, Luthra R, Manshouri T, Jabbour E, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood 2017;130:1125–31.
doi: 10.1182/blood-2017-05-783225
Kiladjian J-J, Platzbecker U, Mayer J, Illes A, Prejzner W, Wozny T, et al. Improved transfusion independence rates for momelotinib versus ruxolitinib in anemic JAKi naïve myelofibrosis patients independent of baseline platelet or transfusion status. J Clin Oncol 2021;39:e19039.
doi: 10.1200/JCO.2021.39.15_suppl.e19039
Verstovsek S, Chen C-C, Egyed M, Ellis M, Fox L, Goh YT, et al. MOMENTUM: Momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic. Future Oncol. 2021;17:1449–58.
doi: 10.2217/fon-2020-1048