Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study.
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.
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
Paola
P
Guglielmelli
Flavia
F
Biamonte
Giada
G
Rotunno
Valentina
V
Artusi
Lucia
L
Artuso
Isabella
I
Bernardis
Elena
E
Tenedini
Lisa
L
Pieri
Chiara
C
Paoli
Carmela
C
Mannarelli
Rajmonda
R
Fjerza
Elisa
E
Rumi
Viktoriya
V
Stalbovskaya
Matthew
M
Squires
Mario
M
Cazzola
Rossella
R
Manfredini
Claire
C
Harrison
Enrico
E
Tagliafico
Alessandro M
AM
Vannucchi
D004252:DNA Mutational Analysis; D000071221:Enhancer of Zeste Homolog 2 Protein; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053613:Janus Kinase 1 / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics; D009154:Mutation; D009570:Nitriles; D009687:Nuclear Proteins / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines; D012097:Repressor Proteins / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D016896:Treatment Outcome
C473949:ASXL1 protein, human; D009570:Nitriles; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012097:Repressor Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; C540383:ruxolitinib; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2