Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study.

Abstract

The JAK1/JAK2 inhibitor ruxolitinib produced significant reductions in splenomegaly and symptomatic burden and improved survival in patients with myelofibrosis (MF), irrespective of their JAK2 mutation status, in 2 phase III studies against placebo (COMFORT-I) and best available therapy (COMFORT-II). We performed a comprehensive mutation analysis to evaluate the impact of 14 MF-associated mutations on clinical outcomes in 166 patients included in COMFORT-II. We found that responses in splenomegaly and symptoms, as well as the risk of developing ruxolitinib-associated anemia and thrombocytopenia, occurred at similar frequencies across different mutation profiles. Ruxolitinib improved survival independent of mutation profile and reduced the risk of death in patients harboring a set of prognostically detrimental mutations (ASXL1, EZH2, SRSF2, IDH1/2) with an hazard ratio of 0.57 (95% confidence interval: 0.30-1.08) vs best available therapy. These data indicate that clinical efficacy and survival improvement may occur across different molecular subsets of patients with MF treated with ruxolitinib.

• Authors: Paola Guglielmelli, Flavia Biamonte, Giada Rotunno, Valentina Artusi, Lucia Artuso, Isabella Bernardis, Elena Tenedini, Lisa Pieri, Chiara Paoli, Carmela Mannarelli, Rajmonda Fjerza, Elisa Rumi, Viktoriya Stalbovskaya, Matthew Squires, Mario Cazzola, Rossella Manfredini, Claire Harrison, Enrico Tagliafico, Alessandro M Vannucchi, COMFORT-II Investigators, Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative (AGIMM) Investigators
• Journal: Blood (Blood) Vol. 123 Issue 14 Pg. 2157-60 (Apr 03 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24458439 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• ASXL1 protein, human
• Nitriles
• Nuclear Proteins
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Repressor Proteins
• Ribonucleoproteins
• SRSF2 protein, human
• Serine-Arginine Splicing Factors
• ruxolitinib
• IDH2 protein, human
• Isocitrate Dehydrogenase
• IDH1 protein, human
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2
• JAK2 protein, human
• Janus Kinase 1
• Janus Kinase 2

Topics

• DNA Mutational Analysis
• Enhancer of Zeste Homolog 2 Protein
• Humans
• Isocitrate Dehydrogenase (genetics)
• Janus Kinase 1 (genetics)
• Janus Kinase 2 (genetics)
• Mutation
• Nitriles
• Nuclear Proteins (genetics)
• Polycomb Repressive Complex 2 (genetics)
• Primary Myelofibrosis (drug therapy, genetics, mortality)
• Prognosis
• Protein Kinase Inhibitors (therapeutic use)
• Pyrazoles (therapeutic use)
• Pyrimidines
• Repressor Proteins (genetics)
• Ribonucleoproteins (genetics)
• Serine-Arginine Splicing Factors
• Treatment Outcome