title: Acquired mutations associated with ibrutinib resistance in Waldenström macroglobulinemia.
abstract: Ibrutinib produces high response rates and durable remissions in Waldenström macroglobulinemia (WM) that are impacted by MYD88 and CXCR4WHIMmutations. 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 otherBTKmutations, and other targets in B-cell receptor and MYD88 signaling. Among the 6 progressing patients, 3 hadBTKCys481variants that includedBTKCys481Ser(c.1635G>Candc.1634T>A)andBTKCys481Arg(c.1634T>C)Two of these patients had multipleBTKmutations. Screening of 38 additional patients on ibrutinib without clinical progression identifiedBTKCys481mutations in 2 (5.1%) individuals, both of whom subsequently progressed.BTKCys481mutations were not detected in baseline samples or in 100 ibrutinib-naive WM patients. Using mutatedMYD88as a tumor marker,BTKCys481mutations were subclonal, with a highly variable clonal distribution. Targeted deep-sequencing confirmed AS-PCR findings, and identified an additionalBTKCys481Tyr(c.1634G>A)mutation in the 2 patients with multiple otherBTKCys481mutations, as well asCARD11Leu878Phe(c.2632C>T)andPLCγ2Tyr495His(c.1483T>C)mutations. Four of the 5 patients withBTKC481variants were CXCR4 mutated.BTKCys481mutations are common in WM patients with clinical progression on ibrutinib, and are associated with mutatedCXCR4.
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.
authors.forename: Lian
authors.initials: L
authors.lastname: Xu
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Tsakmaklis
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.
authors.forename: Jiaji G
authors.initials: JG
authors.lastname: Chen
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.
authors.forename: Maria
authors.initials: M
authors.lastname: Demos
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.
authors.forename: Amanda
authors.initials: A
authors.lastname: Kofides
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Patterson
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Meid
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.
authors.forename: Joshua
authors.initials: J
authors.lastname: Gustine
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.
authors.forename: Toni
authors.initials: T
authors.lastname: Dubeau
authors.affiliation: Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: M Lia
authors.initials: ML
authors.lastname: Palomba
authors.affiliation: Division of Oncology, Stanford University Medical Center, Stanford, CA; and.
authors.forename: Ranjana
authors.initials: R
authors.lastname: Advani
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: Castillo
authors.affiliation: Division of Hematology and Oncology, Weill Cornell Medical School, New York, NY.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Furman
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Hunter
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, and.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000368:Aged; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010880:Piperidines; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine