A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis

Srdan Verstovsek, Ruben Mesa, Jason Gotlib, Richard S. Levy, Vikas Gupta, John F. DiPersio, John V. Catalano, Michael Deininger, Carole Miller, Richard T. Silver, Moshe Talpaz, Elliott F. Winton, Jimmie H. Harvey, Murat O. Arcasoy, Elizabeth Hexner, Roger M. Lyons, Ronald Paquette, Azra Raza, Kris Vaddi, Susan Erickson-Viitanen & 4 others Iphigenia L. Koumenis, William Sun, Victor Sandor, Hagop M. Kantarjian

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis. METHODS: In this double-blind trial, we randomly assigned patients with intermediate-2 or highrisk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival. RESULTS: The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P = 0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group. CONCLUSIONS: Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).

Original languageEnglish (US)
Pages (from-to)799-807
Number of pages9
JournalNew England Journal of Medicine
Volume366
Issue number9
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

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Primary Myelofibrosis
Placebos
Spleen
Thrombocytopenia
INCB018424
Anemia
Janus Kinase 1
Janus Kinase 2
Survival
Drug-Related Side Effects and Adverse Reactions
Acute Myeloid Leukemia

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Verstovsek, S., Mesa, R., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., ... Kantarjian, H. M. (2012). A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. New England Journal of Medicine, 366(9), 799-807. https://doi.org/10.1056/NEJMoa1110557

A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. / Verstovsek, Srdan; Mesa, Ruben; Gotlib, Jason; Levy, Richard S.; Gupta, Vikas; DiPersio, John F.; Catalano, John V.; Deininger, Michael; Miller, Carole; Silver, Richard T.; Talpaz, Moshe; Winton, Elliott F.; Harvey, Jimmie H.; Arcasoy, Murat O.; Hexner, Elizabeth; Lyons, Roger M.; Paquette, Ronald; Raza, Azra; Vaddi, Kris; Erickson-Viitanen, Susan; Koumenis, Iphigenia L.; Sun, William; Sandor, Victor; Kantarjian, Hagop M.

In: New England Journal of Medicine, Vol. 366, No. 9, 01.03.2012, p. 799-807.

Research output: Contribution to journalArticle

Verstovsek, S, Mesa, R, Gotlib, J, Levy, RS, Gupta, V, DiPersio, JF, Catalano, JV, Deininger, M, Miller, C, Silver, RT, Talpaz, M, Winton, EF, Harvey, JH, Arcasoy, MO, Hexner, E, Lyons, RM, Paquette, R, Raza, A, Vaddi, K, Erickson-Viitanen, S, Koumenis, IL, Sun, W, Sandor, V & Kantarjian, HM 2012, 'A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis', New England Journal of Medicine, vol. 366, no. 9, pp. 799-807. https://doi.org/10.1056/NEJMoa1110557
Verstovsek, Srdan ; Mesa, Ruben ; Gotlib, Jason ; Levy, Richard S. ; Gupta, Vikas ; DiPersio, John F. ; Catalano, John V. ; Deininger, Michael ; Miller, Carole ; Silver, Richard T. ; Talpaz, Moshe ; Winton, Elliott F. ; Harvey, Jimmie H. ; Arcasoy, Murat O. ; Hexner, Elizabeth ; Lyons, Roger M. ; Paquette, Ronald ; Raza, Azra ; Vaddi, Kris ; Erickson-Viitanen, Susan ; Koumenis, Iphigenia L. ; Sun, William ; Sandor, Victor ; Kantarjian, Hagop M. / A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. In: New England Journal of Medicine. 2012 ; Vol. 366, No. 9. pp. 799-807.
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TY - JOUR

T1 - A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis

AU - Verstovsek, Srdan

AU - Mesa, Ruben

AU - Gotlib, Jason

AU - Levy, Richard S.

AU - Gupta, Vikas

AU - DiPersio, John F.

AU - Catalano, John V.

AU - Deininger, Michael

AU - Miller, Carole

AU - Silver, Richard T.

AU - Talpaz, Moshe

AU - Winton, Elliott F.

AU - Harvey, Jimmie H.

AU - Arcasoy, Murat O.

AU - Hexner, Elizabeth

AU - Lyons, Roger M.

AU - Paquette, Ronald

AU - Raza, Azra

AU - Vaddi, Kris

AU - Erickson-Viitanen, Susan

AU - Koumenis, Iphigenia L.

AU - Sun, William

AU - Sandor, Victor

AU - Kantarjian, Hagop M.

PY - 2012/3/1

Y1 - 2012/3/1

N2 - BACKGROUND: Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis. METHODS: In this double-blind trial, we randomly assigned patients with intermediate-2 or highrisk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival. RESULTS: The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P = 0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group. CONCLUSIONS: Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).

AB - BACKGROUND: Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis. METHODS: In this double-blind trial, we randomly assigned patients with intermediate-2 or highrisk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival. RESULTS: The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P = 0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group. CONCLUSIONS: Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).

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