A Double-Blind Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis
By S. Verstovsek, R. Mesa, J. Gotlib, R. Levy, Vikas Gupta, J. Dipersio, J. Catalano, M. Deininger, Carole B. Miller, R. Silver and 14 more. New England Journal of Medicine, 2012
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BACKGROUND Ruxolitinib, a selective JAK1 and JAK2 inhibitor, has clinically significant activity in myelofibrosis. METHODS In a double-blind trial, patients with intermediate-2 or high-risk myelofibrosis were randomized to twice-daily oral ruxolitinib (n=155) or placebo (n=154). The primary endpoint was the proportion of patients with ≥35% spleen volume reduction at 24 weeks assessed by magnetic resonance imaging. Secondary endpoints included durability of response, changes in symptom burden (assessed by Total Symptom Score [TSS]), and overall survival. RESULTS In the ruxolitinib group, 41.9% achieved the primary endpoint versus 0.7% in the placebo group (P<0.001). Spleen response was maintained while taking ruxolitinib: 67% of responding patients maintained response for ≥48 weeks. A ≥50% improvement in TSS at 24 weeks was achieved by 45.9% of ruxolitinib-treated versus 5.3% of placebo-treated patients (P<0.001). Thirteen deaths occurred in the ruxolitinib and 24 in the placebo group (hazard ratio, 0.50; 95% CI, 0.25–0.98; P=0.04). Discontinuations for adverse events were similar between groups (11% each). Among ruxolitinib-treated patients, anemia and thrombocytopenia were the most common adverse events, but rarely led to discontinuation (1 patient for each event). Two patients underwent transformation to acute myeloid leukemia (AML), both in the ruxolitinib group. CONCLUSIONS Ruxolitinib provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, improving debilitating myelofibrosis-related symptoms, and improving overall survival. Improvement came at a cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. The imbalance in AML transformation requires attention in further studies. (Funded by Incyte Corporation; ClinicalTrials.gov, NCT00952289)
Subfields: Genetics, Hematology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/675126eca27658190f92123aa2a65b75a1ef4946
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Citations in the corpus
- Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer (2023, background): “demonstrated the clinical benefits of ruxolitinib for patients with intermediate-2 or high-risk myelofibrosis; the ruxolitinib group showed improved manifestations, reduced spleen size, and elevated overall survival compared with the placebo group.(420) Later, the COMFORT-II trial showed that patien”
- JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age (2015, background): “Notably, in humans treated with roxolitinib for 24 wk for myelofibrosis, major infections were no more frequent than in the placebo group: only one case of clostridial infection was found in the ruxolitinib group, and one case of staphylococcal infection was found in the placebo group (33).”
- Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. (2017, background): “htm, last accessed July 6, 2016).(95,96) Recent studies have shown in vivo efficacy of ruxolitinib in JAK-activated Philadelphia chromosomeelike acute lymphoblastic leukemia.”
- JAK inhibition as a therapeutic strategy for immune and inflammatory diseases (2017, background): “1(14,18)] hexacosa‐1(24),2,4,9,14(26),15,17,20,22‐nonaene (SB1578), a potent inhibitor of Janus kinase 2/FMS‐like tyrosine kinase‐3 (JAK2/FLT3) for the treatment of rheumatoid arthritis.”