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: Keyur P Patel, Kate J Newberry, Rajyalakshmi Luthra, Elias Jabbour, Sherry Pierce, Jorge Cortes, Rajesh Singh, Meenakshi Mehrotra, Mark J Routbort, Madan Luthra, Taghi Manshouri, Fabio P Santos, Hagop Kantarjian, Srdan Verstovsek
• Journal: Blood (Blood) Vol. 126 Issue 6 Pg. 790-7 (Aug 06 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 26124496 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• ASXL1 protein, human
• Antineoplastic Agents
• Calreticulin
• DNA-Binding Proteins
• Neoplasm Proteins
• Nitriles
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Pyrazoles
• Pyrimidines
• Receptors, Thrombopoietin
• Repressor Proteins
• MPL protein, human
• ruxolitinib
• Dioxygenases
• TET2 protein, human
• JAK2 protein, human
• Janus Kinase 2

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Calreticulin (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Dioxygenases
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• High-Throughput Nucleotide Sequencing
• Humans
• Janus Kinase 2 (genetics, metabolism)
• Male
• Middle Aged
• Mutation
• Neoplasm Proteins (genetics, metabolism)
• Nitriles
• Odds Ratio
• Primary Myelofibrosis (drug therapy, genetics, mortality, pathology)
• Prognosis
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins (genetics, metabolism)
• Pyrazoles (therapeutic use)
• Pyrimidines
• Receptors, Thrombopoietin (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Spleen (drug effects, metabolism, pathology)
• Survival Analysis