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

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

Research output: Contribution to journalArticle

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 JAK2V617Fmutation, 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.

Original languageEnglish (US)
Pages (from-to)790-797
Number of pages8
JournalBlood
Volume126
Issue number6
DOIs
StatePublished - Aug 6 2015
Externally publishedYes

Fingerprint

Primary Myelofibrosis
Genes
Mutation
Spleen
Polymerase chain reaction
Refractory materials
Planning
INCB018424
Hematologic Neoplasms
Therapeutics
Odds Ratio
Confidence Intervals

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Patel, K. P., Newberry, K. J., Luthra, R., Jabbour, E., Pierce, S., Cortes, J., ... Verstovsek, S. (2015). Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. Blood, 126(6), 790-797. https://doi.org/10.1182/blood-2015-03-633404

Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. / Patel, Keyur P.; Newberry, Kate J.; Luthra, Rajyalakshmi; Jabbour, Elias; Pierce, Sherry; Cortes, Jorge; Singh, Rajesh; Mehrotra, Meenakshi; Routbort, Mark J.; Luthra, Madan; Manshouri, Taghi; Santos, Fabio P.; Kantarjian, Hagop; Verstovsek, Srdan.

In: Blood, Vol. 126, No. 6, 06.08.2015, p. 790-797.

Research output: Contribution to journalArticle

Patel, KP, Newberry, KJ, Luthra, R, Jabbour, E, Pierce, S, Cortes, J, Singh, R, Mehrotra, M, Routbort, MJ, Luthra, M, Manshouri, T, Santos, FP, Kantarjian, H & Verstovsek, S 2015, 'Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib', Blood, vol. 126, no. 6, pp. 790-797. https://doi.org/10.1182/blood-2015-03-633404
Patel, Keyur P. ; Newberry, Kate J. ; Luthra, Rajyalakshmi ; Jabbour, Elias ; Pierce, Sherry ; Cortes, Jorge ; Singh, Rajesh ; Mehrotra, Meenakshi ; Routbort, Mark J. ; Luthra, Madan ; Manshouri, Taghi ; Santos, Fabio P. ; Kantarjian, Hagop ; Verstovsek, Srdan. / Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. In: Blood. 2015 ; Vol. 126, No. 6. pp. 790-797.
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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 JAK2V617Fmutation, 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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AU - Singh, Rajesh

AU - Mehrotra, Meenakshi

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