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Clinical Trial
. 2015 Aug 6;126(6):790-7.
doi: 10.1182/blood-2015-03-633404. Epub 2015 Jun 29.

Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib

Keyur P Patel  1 , Kate J Newberry  2 , Rajyalakshmi Luthra  1 , Elias Jabbour  2 , Sherry Pierce  2 , Jorge Cortes  2 , Rajesh Singh  1 , Meenakshi Mehrotra  1 , Mark J Routbort  1 , Madan Luthra  1 , Taghi Manshouri  2 , Fabio P Santos  3 , Hagop Kantarjian  2 , Srdan Verstovsek  2
Affiliations
Clinical Trial

Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib

Keyur P Patel et al. Blood. .

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.

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Figures

Figure 1
Figure 1
Frequency and distribution of mutations. (A) Circos plot showing the frequency of co-occurring mutations. Length of the arc corresponds to the frequency of mutations, whereas the width of the ribbons between 2 genes shows the frequency of co-occurrence. (B) Frequency of mutations by disease subtype. (C) Plot of mutations by case.
Figure 2
Figure 2
Kaplan-Meier analysis of time to event outcomes. Time to treatment failure stratified by (A) molecular risk group and (B) number of mutations.
See this image and copyright information in PMC

References

    1. Guglielmelli P, Biamonte F, Rotunno G, et al. COMFORT-II Investigators; Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative (AGIMM) Investigators. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood. 2014;123(14):2157–2160. - PubMed
    1. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–798. - PubMed
    1. Tenedini E, Bernardis I, Artusi V, et al. AGIMM investigators. Targeted cancer exome sequencing reveals recurrent mutations in myeloproliferative neoplasms. Leukemia. 2014;28(5):1052–1059. - PMC - PubMed
    1. Engle EK, Fisher DAC, Miller CA, et al. Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia. Leukemia. 2015;29(4):869-876. - PMC - PubMed
    1. Cazzola M, Kralovics R. From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood. 2014;123(24):3714-3719. - PubMed

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