TY - JOUR
T1 - Long-term treatment with ruxolitinib for patients with myelofibrosis
T2 - 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial
AU - Verstovsek, Srdan
AU - Mesa, Ruben A.
AU - Gotlib, Jason
AU - Gupta, Vikas
AU - DiPersio, John F.
AU - Catalano, John V.
AU - Deininger, Michael W.N.
AU - Miller, Carole B.
AU - Silver, Richard T.
AU - Talpaz, Moshe
AU - Winton, Elliott F.
AU - Harvey, Jimmie H.
AU - Arcasoy, Murat O.
AU - Hexner, Elizabeth O.
AU - Lyons, Roger M.
AU - Paquette, Ronald
AU - Raza, Azra
AU - Jones, Mark
AU - Kornacki, Deanna
AU - Sun, Kang
AU - Kantarjian, Hagop
N1 - Funding Information:
Conduct of this study and editorial assistance were funded by Incyte Corporation. Incyte Corporation employees worked with external investigators in designing the study, analyzing data, and confirming accuracy of this report. The authors had full access to all the data in the study and had final responsibility for the decision to submit.
Funding Information:
SV participated in advisory boards for Incyte Corporation and received research support for the conduct of clinical studies from Incyte Corporation, Roche, AstraZeneca, Lilly Oncology, Geron, NS Pharma, Bristol-Myers Squibb, Celgene, Gilead, Seattle Genetics, Promedior, CTI BioPharma Corp, Galena BioPharma, Pfizer, and Genentech. RAM received research funding from Incyte Corporation, CTI, Gilead Sciences, Genentech, Eli Lilly, Promedior, NS Pharma, Sanofi, and Celgene and has served as a consultant for Novartis and ARIAD. JG received research funding from Incyte Corporation, Gilead Sciences, Novartis, Promedior, and CTI Biopharma. VG received honoraria and research funding from Incyte Corporation. JFD, JHH, EOH, and AR received research funding from Incyte Corporation. JVC received research funding from Incyte Corporation and served as a consultant for and received honoraria from Roche, Gilead Sciences, and Celgene Corporation. MWND served as a consultant for and received honoraria and research funding from Incyte Corporation. CBM received research funding and honoraria and served on a speakers bureau and as a consultant for Incyte Corporation, and received research funding and served as a consultant and on a speakers bureau for Novartis. RTS received research funding from Promedior and Incyte Corporation and served as a consultant to Incyte Corporation, Sanofi, PharmaEssentia, AOP Orphan, and Gilead Sciences. MT has received research funding from ARIAD, Bristol-Myers Squibb, Sanofi, Incyte Corporation, and Pfizer. EFW has received research funding from Gilead Sciences, Incyte Corporation, Pfizer, and Sanofi and has served on advisory boards for Incyte Corporation. MOA received research funding from Incyte Corporation and Gilead Sciences. RML received research funding from Galena Biopharma Incorporated and Incyte Corporation and served as a consultant for Amgen. RP received research funding from Incyte Corporation and received honoraria from ARIAD, Bristol-Myers Squibb, and Novartis. MJ, DK, and KS are employees and stockholders of Incyte Corporation. HK received research funding from ASTEX and Incyte Corporation.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/2/22
Y1 - 2017/2/22
N2 - Background: The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that ruxolitinib - the first myelofibrosis-approved therapy - reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results. Methods: Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo. Investigators and patients were blinded to treatment. The secondary endpoints evaluated in this analysis were durability of a ≥35% reduction from baseline in spleen volume (spleen response) and overall survival, evaluated in the intent-to-treat population. Safety was evaluated in patients who received study treatment. Results: Patients were randomized (September 2009-April 2010) to ruxolitinib (n = 155) or placebo (n = 154). At termination, 27.7% of ruxolitinib-randomized patients and 25.2% (28/111) who crossed over from placebo were on treatment; no patients remained on placebo. Patients randomized to ruxolitinib had a median spleen response duration of 168.3 weeks and prolonged median overall survival versus placebo (ruxolitinib group, not reached; placebo group, 200 weeks; HR, 0.69; 95% CI, 0.50-0.96; P = 0.025) despite the crossover to ruxolitinib. The ruxolitinib safety profile remained consistent with previous analyses. The most common new-onset all-grade nonhematologic adverse events starting <12 versus ≥48 months after ruxolitinib initiation were fatigue (29.0 vs 33.3%) and diarrhea (27.8 vs 14.6%). New-onset grade 3 or 4 anemia and thrombocytopenia both primarily occurred within the first 6 months, with no cases after 42 months. The most common treatment-emergent adverse event-related deaths in the ruxolitinib-randomized group were sepsis (2.6%), disease progression (1.9%), and pneumonia (1.9%). Conclusion: The final COMFORT-I results continue to support ruxolitinib as an effective treatment for patients with intermediate-2/high-risk MF. Trial registration: ClinicalTrials.gov, NCT00952289
AB - Background: The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that ruxolitinib - the first myelofibrosis-approved therapy - reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results. Methods: Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo. Investigators and patients were blinded to treatment. The secondary endpoints evaluated in this analysis were durability of a ≥35% reduction from baseline in spleen volume (spleen response) and overall survival, evaluated in the intent-to-treat population. Safety was evaluated in patients who received study treatment. Results: Patients were randomized (September 2009-April 2010) to ruxolitinib (n = 155) or placebo (n = 154). At termination, 27.7% of ruxolitinib-randomized patients and 25.2% (28/111) who crossed over from placebo were on treatment; no patients remained on placebo. Patients randomized to ruxolitinib had a median spleen response duration of 168.3 weeks and prolonged median overall survival versus placebo (ruxolitinib group, not reached; placebo group, 200 weeks; HR, 0.69; 95% CI, 0.50-0.96; P = 0.025) despite the crossover to ruxolitinib. The ruxolitinib safety profile remained consistent with previous analyses. The most common new-onset all-grade nonhematologic adverse events starting <12 versus ≥48 months after ruxolitinib initiation were fatigue (29.0 vs 33.3%) and diarrhea (27.8 vs 14.6%). New-onset grade 3 or 4 anemia and thrombocytopenia both primarily occurred within the first 6 months, with no cases after 42 months. The most common treatment-emergent adverse event-related deaths in the ruxolitinib-randomized group were sepsis (2.6%), disease progression (1.9%), and pneumonia (1.9%). Conclusion: The final COMFORT-I results continue to support ruxolitinib as an effective treatment for patients with intermediate-2/high-risk MF. Trial registration: ClinicalTrials.gov, NCT00952289
KW - JAK
KW - Janus kinase
KW - Myelofibrosis
UR - http://www.scopus.com/inward/record.url?scp=85013472843&partnerID=8YFLogxK
U2 - 10.1186/s13045-017-0417-z
DO - 10.1186/s13045-017-0417-z
M3 - Article
C2 - 28228106
AN - SCOPUS:85013472843
VL - 10
SP - 1
EP - 14
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
SN - 1756-8722
IS - 1
ER -