Acquired mutations associated with ibrutinib resistance in Waldenström macroglobulinemia. Academic Article uri icon

Overview

abstract

  • Ibrutinib produces high response rates and durable remissions in Waldenström macroglobulinemia (WM) that are impacted by MYD88 and CXCR4(WHIM) mutations. Disease progression can develop on ibrutinib, although the molecular basis remains to be clarified. We sequenced sorted CD19(+) lymphoplasmacytic cells from 6 WM patients who progressed after achieving major responses on ibrutinib using Sanger, TA cloning and sequencing, and highly sensitive and allele-specific polymerase chain reaction (AS-PCR) assays that we developed for Bruton tyrosine kinase (BTK) mutations. AS-PCR assays were used to screen patients with and without progressive disease on ibrutinib, and ibrutinib-naïve disease. Targeted next-generation sequencing was used to validate AS-PCR findings, assess for other BTK mutations, and other targets in B-cell receptor and MYD88 signaling. Among the 6 progressing patients, 3 had BTK(Cys481) variants that included BTK(Cys481Ser(c.1635G>C and c.1634T>A)) and BTK(Cys481Arg(c.1634T>C)) Two of these patients had multiple BTK mutations. Screening of 38 additional patients on ibrutinib without clinical progression identified BTK(Cys481) mutations in 2 (5.1%) individuals, both of whom subsequently progressed. BTK(Cys481) mutations were not detected in baseline samples or in 100 ibrutinib-naive WM patients. Using mutated MYD88 as a tumor marker, BTK(Cys481) mutations were subclonal, with a highly variable clonal distribution. Targeted deep-sequencing confirmed AS-PCR findings, and identified an additional BTK(Cys481Tyr(c.1634G>A)) mutation in the 2 patients with multiple other BTK(Cys481) mutations, as well as CARD11(Leu878Phe(c.2632C>T)) and PLCγ2(Tyr495His(c.1483T>C)) mutations. Four of the 5 patients with BTK(C481) variants were CXCR4 mutated. BTK(Cys481) mutations are common in WM patients with clinical progression on ibrutinib, and are associated with mutated CXCR4. © 2017 by The American Society of Hematology.

publication date

  • May 4, 2017

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1182/blood-2017-01-761726

PubMed ID

  • 28235842

Additional Document Info

start page

  • 2519

end page

  • 2525

volume

  • 129

number

  • 18