A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis
Srdan Verstovsek, Ruben A 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 Jr, Murat O Arcasoy, Elizabeth Hexner, Roger M Lyons, Ronald Paquette, Azra Raza, Kris Vaddi, Susan Erickson-Viitanen, Iphigenia L Koumenis, William Sun, Victor Sandor, Hagop M Kantarjian, Srdan Verstovsek, Ruben A 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 Jr, Murat O Arcasoy, Elizabeth Hexner, Roger M Lyons, Ronald Paquette, Azra Raza, Kris Vaddi, Susan Erickson-Viitanen, Iphigenia L Koumenis, William Sun, Victor Sandor, Hagop M Kantarjian
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 high-risk 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.).
Figures
![Figure 1. Assessment of Spleen Volume Reduction](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4822164/bin/nihms772841f1a.jpg)
![Figure 1. Assessment of Spleen Volume Reduction](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4822164/bin/nihms772841f1b.jpg)
![Figure 1. Assessment of Spleen Volume Reduction](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4822164/bin/nihms772841f1c.jpg)
![Figure 2. Assessment of Symptom Improvement](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4822164/bin/nihms772841f2a.jpg)
Figure 2. Assessment of Symptom Improvement
Figure…
Figure 2. Assessment of Symptom Improvement
Figure 2A shows the intent-to-treat analysis of the proportion…
Figure 2. Assessment of Symptom Improvement
Figure…
Figure 2. Assessment of Symptom Improvement
Figure 2A shows the intent-to-treat analysis of the proportion…
Figure 3. Overall Survival
Figure 3 shows…
Figure 3. Overall Survival
Figure 3 shows the Kaplan-Meier plot of overall survival, including 4…
- Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms.Tefferi A. Tefferi A. N Engl J Med. 2012 Mar 1;366(9):844-6. doi: 10.1056/NEJMe1115119. N Engl J Med. 2012. PMID: 22375977 No abstract available.
- Ruxolitinib for myelofibrosis.Haznedaroglu IC. Haznedaroglu IC. N Engl J Med. 2012 May 24;366(21):2032; author reply 2032-5. doi: 10.1056/NEJMc1203704. N Engl J Med. 2012. PMID: 22621635 No abstract available.
- JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, Cervantes F, Vannucchi AM, Barbui T, Barosi G. Harrison C, et al. N Engl J Med. 2012 Mar 1;366(9):787-98. doi: 10.1056/NEJMoa1110556. N Engl J Med. 2012. PMID: 22375970 Clinical Trial.
- Janus kinase-1 and Janus kinase-2 inhibitors for treating myelofibrosis.Martí-Carvajal AJ, Anand V, Solà I. Martí-Carvajal AJ, et al. Cochrane Database Syst Rev. 2015 Apr 10;(4):CD010298. doi: 10.1002/14651858.CD010298.pub2. Cochrane Database Syst Rev. 2015. PMID: 25860512 Review.
- Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial.Mascarenhas J, Hoffman R, Talpaz M, Gerds AT, Stein B, Gupta V, Szoke A, Drummond M, Pristupa A, Granston T, Daly R, Al-Fayoumi S, Callahan JA, Singer JW, Gotlib J, Jamieson C, Harrison C, Mesa R, Verstovsek S. Mascarenhas J, et al. JAMA Oncol. 2018 May 1;4(5):652-659. doi: 10.1001/jamaoncol.2017.5818. JAMA Oncol. 2018. PMID: 29522138 Free PMC article. Clinical Trial.
- 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 S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Paquette R, Raza A, Jones M, Kornacki D, Sun K, Kantarjian H; COMFORT-I investigators. Verstovsek S, et al. J Hematol Oncol. 2017 Feb 22;10(1):55. doi: 10.1186/s13045-017-0417-z. J Hematol Oncol. 2017. PMID: 28228106 Free PMC article. Clinical Trial.
- Ruxolitinib.Becker H, Engelhardt M, von Bubnoff N, Wäsch R. Becker H, et al. Recent Results Cancer Res. 2014;201:249-57. doi: 10.1007/978-3-642-54490-3_16. Recent Results Cancer Res. 2014. PMID: 24756798 Review.
- Myelofibrosis and Survival Prognostic Models: A Journey between Past and Future.Duminuco A, Nardo A, Giuffrida G, Leotta S, Markovic U, Giallongo C, Tibullo D, Romano A, Di Raimondo F, Palumbo GA. Duminuco A, et al. J Clin Med. 2023 Mar 11;12(6):2188. doi: 10.3390/jcm12062188. J Clin Med. 2023. PMID: 36983189 Free PMC article. Review.
- Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer.Viganò M, La Milia M, Grassini MV, Pugliese N, De Giorgio M, Fagiuoli S. Viganò M, et al. Cancers (Basel). 2023 Mar 14;15(6):1766. doi: 10.3390/cancers15061766. Cancers (Basel). 2023. PMID: 36980652 Free PMC article. Review.
- Impaired inflammation resolution in murine bone marrow failure is rescued by Resolvin E1 treatment.Grazda R, Seyfried AN, Maddipatti KR, Fredman G, MacNamara KC. Grazda R, et al. bioRxiv. 2023 Feb 15:2023.02.15.528688. doi: 10.1101/2023.02.15.528688. Preprint. bioRxiv. 2023. PMID: 36909559 Free PMC article.
- Exploration and identification of anoikis-related genes in polycythemia vera.Aini W, Xie L, Hu W, Tang Y, Peng H, Zhang G, Deng T. Aini W, et al. Front Genet. 2023 Feb 17;14:1139351. doi: 10.3389/fgene.2023.1139351. eCollection 2023. Front Genet. 2023. PMID: 36873934 Free PMC article.
- How I manage anemia related to myelofibrosis and its treatment regimens.Verstovsek S. Verstovsek S. Ann Hematol. 2023 Apr;102(4):689-698. doi: 10.1007/s00277-023-05126-4. Epub 2023 Feb 14. Ann Hematol. 2023. PMID: 36786879 Free PMC article. Review.
- Clinical Trial, Phase III
- Comparative Study
- Multicenter Study
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- Adult
- Aged
- Aged, 80 and over
- Cell Transformation, Neoplastic
- Double-Blind Method
- Female
- Follow-Up Studies
- Humans
- Intention to Treat Analysis
- Janus Kinase 1 / antagonists & inhibitors*
- Janus Kinase 2 / antagonists & inhibitors*
- Kaplan-Meier Estimate
- Leukemia, Myeloid, Acute / mortality
- Male
- Middle Aged
- Nitriles
- Organ Size
- Primary Myelofibrosis / drug therapy*
- Primary Myelofibrosis / mortality
- Primary Myelofibrosis / pathology
- Protein Kinase Inhibitors / adverse effects
- Protein Kinase Inhibitors / therapeutic use*
- Pyrazoles / adverse effects
- Pyrazoles / therapeutic use*
- Pyrimidines
- Quality of Life
- Spleen / drug effects
- Spleen / pathology
- Splenomegaly / drug therapy*
- Nitriles
- Protein Kinase Inhibitors
- Pyrazoles
- Pyrimidines
- ruxolitinib
- Janus Kinase 1
- Janus Kinase 2
- ClinicalTrials.gov/NCT00952289
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
NCBI Literature Resources
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![Figure 2. Assessment of Symptom Improvement](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4822164/bin/nihms772841f2b.jpg)
Figure 2. Assessment of Symptom Improvement
Figure…
Figure 2. Assessment of Symptom Improvement
Figure 2A shows the intent-to-treat analysis of the proportion…
Figure 3. Overall Survival
Figure 3 shows…
Figure 3. Overall Survival
Figure 3 shows the Kaplan-Meier plot of overall survival, including 4…
- Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms.Tefferi A. Tefferi A. N Engl J Med. 2012 Mar 1;366(9):844-6. doi: 10.1056/NEJMe1115119. N Engl J Med. 2012. PMID: 22375977 No abstract available.
- Ruxolitinib for myelofibrosis.Haznedaroglu IC. Haznedaroglu IC. N Engl J Med. 2012 May 24;366(21):2032; author reply 2032-5. doi: 10.1056/NEJMc1203704. N Engl J Med. 2012. PMID: 22621635 No abstract available.
- JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, Cervantes F, Vannucchi AM, Barbui T, Barosi G. Harrison C, et al. N Engl J Med. 2012 Mar 1;366(9):787-98. doi: 10.1056/NEJMoa1110556. N Engl J Med. 2012. PMID: 22375970 Clinical Trial.
- Janus kinase-1 and Janus kinase-2 inhibitors for treating myelofibrosis.Martí-Carvajal AJ, Anand V, Solà I. Martí-Carvajal AJ, et al. Cochrane Database Syst Rev. 2015 Apr 10;(4):CD010298. doi: 10.1002/14651858.CD010298.pub2. Cochrane Database Syst Rev. 2015. PMID: 25860512 Review.
- Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial.Mascarenhas J, Hoffman R, Talpaz M, Gerds AT, Stein B, Gupta V, Szoke A, Drummond M, Pristupa A, Granston T, Daly R, Al-Fayoumi S, Callahan JA, Singer JW, Gotlib J, Jamieson C, Harrison C, Mesa R, Verstovsek S. Mascarenhas J, et al. JAMA Oncol. 2018 May 1;4(5):652-659. doi: 10.1001/jamaoncol.2017.5818. JAMA Oncol. 2018. PMID: 29522138 Free PMC article. Clinical Trial.
- 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 S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Paquette R, Raza A, Jones M, Kornacki D, Sun K, Kantarjian H; COMFORT-I investigators. Verstovsek S, et al. J Hematol Oncol. 2017 Feb 22;10(1):55. doi: 10.1186/s13045-017-0417-z. J Hematol Oncol. 2017. PMID: 28228106 Free PMC article. Clinical Trial.
- Ruxolitinib.Becker H, Engelhardt M, von Bubnoff N, Wäsch R. Becker H, et al. Recent Results Cancer Res. 2014;201:249-57. doi: 10.1007/978-3-642-54490-3_16. Recent Results Cancer Res. 2014. PMID: 24756798 Review.
- Myelofibrosis and Survival Prognostic Models: A Journey between Past and Future.Duminuco A, Nardo A, Giuffrida G, Leotta S, Markovic U, Giallongo C, Tibullo D, Romano A, Di Raimondo F, Palumbo GA. Duminuco A, et al. J Clin Med. 2023 Mar 11;12(6):2188. doi: 10.3390/jcm12062188. J Clin Med. 2023. PMID: 36983189 Free PMC article. Review.
- Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer.Viganò M, La Milia M, Grassini MV, Pugliese N, De Giorgio M, Fagiuoli S. Viganò M, et al. Cancers (Basel). 2023 Mar 14;15(6):1766. doi: 10.3390/cancers15061766. Cancers (Basel). 2023. PMID: 36980652 Free PMC article. Review.
- Impaired inflammation resolution in murine bone marrow failure is rescued by Resolvin E1 treatment.Grazda R, Seyfried AN, Maddipatti KR, Fredman G, MacNamara KC. Grazda R, et al. bioRxiv. 2023 Feb 15:2023.02.15.528688. doi: 10.1101/2023.02.15.528688. Preprint. bioRxiv. 2023. PMID: 36909559 Free PMC article.
- Exploration and identification of anoikis-related genes in polycythemia vera.Aini W, Xie L, Hu W, Tang Y, Peng H, Zhang G, Deng T. Aini W, et al. Front Genet. 2023 Feb 17;14:1139351. doi: 10.3389/fgene.2023.1139351. eCollection 2023. Front Genet. 2023. PMID: 36873934 Free PMC article.
- How I manage anemia related to myelofibrosis and its treatment regimens.Verstovsek S. Verstovsek S. Ann Hematol. 2023 Apr;102(4):689-698. doi: 10.1007/s00277-023-05126-4. Epub 2023 Feb 14. Ann Hematol. 2023. PMID: 36786879 Free PMC article. Review.
- Clinical Trial, Phase III
- Comparative Study
- Multicenter Study
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- Adult
- Aged
- Aged, 80 and over
- Cell Transformation, Neoplastic
- Double-Blind Method
- Female
- Follow-Up Studies
- Humans
- Intention to Treat Analysis
- Janus Kinase 1 / antagonists & inhibitors*
- Janus Kinase 2 / antagonists & inhibitors*
- Kaplan-Meier Estimate
- Leukemia, Myeloid, Acute / mortality
- Male
- Middle Aged
- Nitriles
- Organ Size
- Primary Myelofibrosis / drug therapy*
- Primary Myelofibrosis / mortality
- Primary Myelofibrosis / pathology
- Protein Kinase Inhibitors / adverse effects
- Protein Kinase Inhibitors / therapeutic use*
- Pyrazoles / adverse effects
- Pyrazoles / therapeutic use*
- Pyrimidines
- Quality of Life
- Spleen / drug effects
- Spleen / pathology
- Splenomegaly / drug therapy*
- Nitriles
- Protein Kinase Inhibitors
- Pyrazoles
- Pyrimidines
- ruxolitinib
- Janus Kinase 1
- Janus Kinase 2
- ClinicalTrials.gov/NCT00952289
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
![Figure 2. Assessment of Symptom Improvement](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4822164/bin/nihms772841f2c.jpg)
Figure 3. Overall Survival
Figure 3 shows…
Figure 3. Overall Survival
Figure 3 shows the Kaplan-Meier plot of overall survival, including 4…
![Figure 3. Overall Survival](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4822164/bin/nihms772841f3.jpg)
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