title: Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib.
abstract: Although most patients with myelofibrosis (MF) derive benefit from ruxolitinib, some are refractory, have a suboptimal response, or quickly lose their response. To identify genes that may predict response to ruxolitinib, we performed targeted next-generation sequencing (NGS) of a panel of 28 genes recurrently mutated in hematologic malignancies in a cohort of patients with MF who were treated with ruxolitinib in a phase 1/2 study. We also tested for CALR deletions by standard polymerase chain reaction methods. Ninety-eight percent of patients had a mutation in ≥1 gene. Seventy-nine (82.1%) patients had the JAK2(V617F) mutation, 9 (9.5%) had CALR mutations (7 type 1, 2 type 2), 3 (3.1%) had MPL mutations, and 4 (4.2%) were negative for all 3. ASXL1/JAK2 and TET2/JAK2 were the most frequently comutated genes. Mutations in NRAS, KRAS, PTPN11, GATA2, TP53, and RUNX1 were found in <5% of patients. Spleen response (≥50% reduction in palpable spleen size) was inversely correlated with the number of mutations; patients with ≤2 mutations had ninefold higher odds of a spleen response than those with ≥3 mutations (odds ratio = 9.37; 95% confidence interval, 1.86-47.2). Patients with ≥3 mutations also had a shorter time to treatment discontinuation and shorter overall survival than those with fewer mutations. In multivariable analysis, only number of mutations and spleen response remained associated with time to treatment discontinuation. Patients with ≥3 mutations had the worst outcomes, suggesting that multigene profiling may be useful for therapeutic planning for MF.
authors.affiliation: Departments of Hematopathology and.
authors.forename: Keyur P
authors.initials: KP
authors.lastname: Patel
authors.affiliation: Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Kate J
authors.initials: KJ
authors.lastname: Newberry
authors.affiliation: Departments of Hematopathology and.
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.affiliation: Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.affiliation: Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Sherry
authors.initials: S
authors.lastname: Pierce
authors.affiliation: Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Departments of Hematopathology and.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Singh
authors.affiliation: Departments of Hematopathology and.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Mehrotra
authors.affiliation: Departments of Hematopathology and.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Routbort
authors.affiliation: Departments of Hematopathology and.
authors.forename: Madan
authors.initials: M
authors.lastname: Luthra
authors.affiliation: Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Taghi
authors.initials: T
authors.lastname: Manshouri
authors.affiliation: Hematology and Oncology Center, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.
authors.forename: Fabio P
authors.initials: FP
authors.lastname: Santos
authors.affiliation: Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009570:Nitriles; D016017:Odds Ratio; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis
chemical_list: C473949:ASXL1 protein, human; D000970:Antineoplastic Agents; D037282:Calreticulin; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin; D012097:Repressor Proteins; C082218:MPL protein, human; C540383:ruxolitinib; D049308:Dioxygenases; C541081:TET2 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2