Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial

Srdan Verstovsek, Ruben A. Mesa, Jason Gotlib, Vikas Gupta, John F. DiPersio, John V. Catalano, Michael W N Deininger, Carole B. Miller, Richard T. Silver, Moshe Talpaz, Elliott F. Winton, Jimmie H. Harvey, Murat O. Arcasoy, Elizabeth O. Hexner, Roger M. Lyons, Ronald Paquette, Azra Raza, Mark Jones, Deanna Kornacki, Kang SunHagop Kantarjian

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalJournal of Hematology and Oncology
Volume10
Issue number1
DOIs
StatePublished - Feb 22 2017

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Primary Myelofibrosis
Placebos
Therapeutics
Spleen
Survival
INCB018424
Safety
Splenomegaly
Platelet Count
Canada
Fatigue
Disease Progression
Anemia
Diarrhea
Sepsis
Pneumonia

Keywords

  • JAK
  • Janus kinase
  • Myelofibrosis

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Long-term treatment with ruxolitinib for patients with myelofibrosis : 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. / Verstovsek, Srdan; Mesa, Ruben A.; Gotlib, Jason; Gupta, Vikas; DiPersio, John F.; Catalano, John V.; Deininger, Michael W N; Miller, Carole B.; Silver, Richard T.; Talpaz, Moshe; Winton, Elliott F.; Harvey, Jimmie H.; Arcasoy, Murat O.; Hexner, Elizabeth O.; Lyons, Roger M.; Paquette, Ronald; Raza, Azra; Jones, Mark; Kornacki, Deanna; Sun, Kang; Kantarjian, Hagop.

In: Journal of Hematology and Oncology, Vol. 10, No. 1, 22.02.2017, p. 1-14.

Research output: Contribution to journalArticle

Verstovsek, S, Mesa, RA, Gotlib, J, Gupta, V, DiPersio, JF, Catalano, JV, Deininger, MWN, Miller, CB, Silver, RT, Talpaz, M, Winton, EF, Harvey, JH, Arcasoy, MO, Hexner, EO, Lyons, RM, Paquette, R, Raza, A, Jones, M, Kornacki, D, Sun, K & Kantarjian, H 2017, 'Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial', Journal of Hematology and Oncology, vol. 10, no. 1, pp. 1-14. https://doi.org/10.1186/s13045-017-0417-z
Verstovsek, Srdan ; Mesa, Ruben A. ; Gotlib, Jason ; Gupta, Vikas ; DiPersio, John F. ; Catalano, John V. ; Deininger, Michael W N ; Miller, Carole B. ; Silver, Richard T. ; Talpaz, Moshe ; Winton, Elliott F. ; Harvey, Jimmie H. ; Arcasoy, Murat O. ; Hexner, Elizabeth O. ; Lyons, Roger M. ; Paquette, Ronald ; Raza, Azra ; Jones, Mark ; Kornacki, Deanna ; Sun, Kang ; Kantarjian, Hagop. / Long-term treatment with ruxolitinib for patients with myelofibrosis : 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. In: Journal of Hematology and Oncology. 2017 ; Vol. 10, No. 1. pp. 1-14.
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abstract = "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",
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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

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

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