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Cited by 2,103Myeloproliferative Neoplasms: Diagnosis and TreatmentAcute Myeloid Leukemia ResearchChronic Lymphocytic Leukemia Research

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

Open access
Verstovsek, Srdan, Mesa, Ruben A., Gotlib, Jason, Levy, Richard S., Gupta, Vikas, DiPersio, John F., Catalano, John V., Deininger, Michael +16 more·2012·New England Journal of Medicine
DOI 10.1056/nejmoa1110557PMC PMC4822164
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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 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.).

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  • Ruxolitinib has promising activity in PMF patients, showing reduction in splenomegaly, improvement in disease-related symptoms, and increased overall survival compared with placebo or best available therapy.

    “Ruxolitinib, a JAK1/JAK2 inhibitor, has demonstrated promising activity in PMF patients, showing increased benefit across several end points, e.g., reduction in splenomegaly, improvement in disease-related symptoms, and increased overall survival, when compared with placebo or best available therapy”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Verstovsek et al., 2012

    The Results (Efficacy, page unavailable) report reduced spleen volume and improved symptoms in the PMF subgroup versus placebo. The Abstract (Results, page unavailable) reports better overall survival for the combined myelofibrosis population, not specifically for PMF. This trial compared ruxolitinib with placebo, not best available therapy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • A twice-daily dosing regimen has been successfully applied in treatment of myelofibrosis patients.

    “A twice-daily dosing regimen was furthermore successfully applied in the treatment of myelofibrosis patients (Verstovsek et al., 2012).”

    From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Verstovsek et al., 2012

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Research works printed but not linked: 16

  1. [1]Tefferi A Vaidya R Caramazza D Finke C Lasho T Pardanani A Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study J Clin Oncol 2011 29 1356 63 21300928
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Authors
Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M., Miller, C., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E., Lyons, R. M., Paquette, R., Raza, A., Vaddi, K., Erickson-Viitanen, S., Koumenis, I. L., Sun, W., Sandor, V., & Kantarjian, H. M.
Affiliations
  • Mayo Clinic (US)
  • Stanford Cancer Institute (US)
  • Incyte (United States) (US)
  • University of Toronto (CA)
  • Washington University in St. Louis (US)
  • Frankston Hospital (AU)
  • Oregon Health & Science University (US)
  • Saint Agnes Hospital (US)
  • Weill Cornell Medical Center (US)
  • University of Michigan (US)
  • Emory University (US)
  • Duke University Health System (US)
  • Abramson Cancer Center (US)
  • University of California, Los Angeles (US)
  • The University of Texas MD Anderson Cancer Center (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2012-03
Volume
366
Issue
9
Pages
799-807
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1110557
PMC
PMC4822164
OpenAlex
W2121743767
Cited by
2,103
References
0
Citations by year
2026: 120 · 2025: 104 · 2024: 138 · 2023: 137 · 2022: 140 · 2021: 166 · 2020: 160 · 2019: 122 · 2018: 142 · 2017: 146 · 2016: 171 · 2015: 166 · 2014: 147 · 2013: 166 · 2012: 75
FWCI
84.76
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Funders
National Cancer Institute (P30CA016672)
Topics
  • Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
Keywords
ruxolitinib, myelofibrosis, JAK inhibitors, spleen volume reduction, symptom burden, overall survival, anemia, thrombocytopenia, acute myeloid leukemia transformation, adverse events, treatment durability
MeSH terms
Adult, Aged, Aged, 80 and over, Cell Transformation, Neoplastic, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Nitriles, Organ Size, Pyrazoles, Pyrimidines, Quality of Life, Spleen, Splenomegaly, Leukemia, Myeloid, Acute, Protein Kinase Inhibitors, Kaplan-Meier Estimate, Janus Kinase 1, Janus Kinase 2, Primary Myelofibrosis, Intention to Treat Analysis

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