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  • Bonfiglio, SilviaIRCCS Osped San Raffaele, Ctr Omics Sci, Milan, Italy.;IRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy. (author)

BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2023-01-25
  • American Society of Hematology,2023
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-511624
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-511624URI
  • https://doi.org/10.1182/bloodadvances.2022008821DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-336055URI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:153591476URI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • QC 20230911
  • Patients with chronic lymphocytic leukemia (CLL) progressing on ibrutinib constitute an unmet need. Though Bruton tyrosine kinase (BTK) and PLCG2 mutations are associated with ibrutinib resistance, their frequency and relevance to progression are not fully understood. In this multicenter retrospective observational study, we analyzed 98 patients with CLL on ibrutinib (49 relapsing after an initial response and 49 still responding after ≥1 year of continuous treatment) using a next-generation sequencing (NGS) panel (1% sensitivity) comprising 13 CLL-relevant genes including BTK and PLCG2. BTK hotspot mutations were validated by droplet digital polymerase chain reaction (ddPCR) (0.1% sensitivity). By integrating NGS and ddPCR results, 32 of 49 relapsing cases (65%) carried at least 1 hotspot BTK and/or PLCG2 mutation(s); in 6 of 32, BTK mutations were only detected by ddPCR (variant allele frequency [VAF] 0.1% to 1.2%). BTK/PLCG2 mutations were also identified in 6 of 49 responding patients (12%; 5/6 VAF <10%), of whom 2 progressed later. Among the relapsing patients, the BTK-mutated (BTKmut) group was enriched for EGR2 mutations, whereas BTK-wildtype (BTKwt) cases more frequently displayed BIRC3 and NFKBIE mutations. Using an extended capture-based panel, only BRAF and IKZF3 mutations showed a predominance in relapsing cases, who were enriched for del(8p) (n = 11; 3 BTKwt). Finally, no difference in TP53 mutation burden was observed between BTKmut and BTKwt relapsing cases, and ibrutinib treatment did not favor selection of TP53-aberrant clones. In conclusion, we show that BTK/PLCG2 mutations were absent in a substantial fraction (35%) of a real-world cohort failing ibrutinib, and propose additional mechanisms contributing to resistance.

Subject headings and genre

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  • Sutton, Lesley-AnnKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (author)
  • Ljungström, Viktor,1986-Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin,Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden(Swepub:uu)viklj600 (author)
  • Capasso, AntonellaIRCCS Osped San Raffaele, Strateg Res Program CLL, Milan, Italy. (author)
  • Pandzic, TatjanaUppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin(Swepub:uu)tatdj291 (author)
  • Weström, SimoneUppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin(Swepub:uu)simku408 (author)
  • Foroughi-Asl, HassanKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (author)
  • Skaftason, AronKarolinska Institutet,Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (author)
  • Gellerbring, AnnaSci Life Lab, Clin Genom Stockholm, Solna, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. (author)
  • Lyander, AnnaKTH,Genteknologi,Science for Life Laboratory, SciLifeLab,Sci Life Lab, Clin Genom Stockholm, Solna, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.;KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden.(Swepub:kth)u1l0oby5 (author)
  • Gandini, FrancescaIRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy. (author)
  • Gaidano, GianlucaUniv Piemonte Orientale, Dept Translat Med, Div Hematol, Novara, Italy. (author)
  • Trentin, LivioUniv Padua, Dept Med Hematol & Clin Immunol, Padua, Italy. (author)
  • Bonello, LisaAOU Citta Salute & Sci, Mol Pathol Unit, Turin, Italy.;Univ Torino, Dept Mol Biotechnol & Hlth Sci, Turin, TO, Italy. (author)
  • Reda, GianluigiFdn IRCCS Ca Granda Osped Maggiore Policlin, Dept Hematol, Milan, Italy. (author)
  • Bodor, CsabaHCEMM SU Mol Oncohematol Res Grp, Budapest, Hungary.;Semmelweis Univ, Dept Pathol & Expt Canc Res 1, Budapest, Hungary. (author)
  • Stavroyianni, NikiG Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece. (author)
  • Tam, Constantine S.Alfred Hlth, Dept Hematol, Melbourne, Vic, Australia.;Monash Univ, Cent Clin Sch, Melbourne, Vic, Australia. (author)
  • Marasca, RobertUniv Modena & Reggio Emilia, Dept Med & Surg Sci, Hematol Unit, Modena, Italy. (author)
  • Forconi, FrancescoUniv Southampton, Fac Med, Sch Canc Sci, Southampton, England.;Univ Hosp Natl Hlth Serv Trust, Dept Hematol, Southampton, England. (author)
  • Baliakas, Panagiotis,1977-Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin(Swepub:uu)panba345 (author)
  • Ringshausen, IngoUniv Cambridge, Dept Hematol, Cambridge, England. (author)
  • Kaksic, OzrenDubrava Univ Hosp, Zagreb, Croatia. (author)
  • Frustaci, Anna MariaASST Grande Osped Metropolitano Niguarda, Niguarda Canc Ctr, Dept Hematol, Milan, Italy. (author)
  • Iyengar, SunilRoyal Marsden Hosp, Dept Haematooncol, London, England. (author)
  • Coscia, MartaUniv Torino, Dept Mol Biotechnol & Hlth Sci, Turin, TO, Italy.;AOU Citta Salute & Sci Torino, Div Hematol, Turin, Italy. (author)
  • Mulligan, Stephen P.Univ Sydney, Royal North Shore Hosp, Dept Haematol, Sydney, Australia. (author)
  • Ysebaert, LoicInst Univ Canc Oncopole Toulouse, Dept Hematol, Toulouse, France. (author)
  • Strugov, VladimirAlmazov Natl Med Res Ctr, St Petersburg, Russia. (author)
  • Pavlovsky, CarolinaFUNDALEU, Clin Res Ctr, Buenos Aires, Argentina. (author)
  • Walewska, RenetaUniv Hosp Dorset, Dept Mol Pathol, Bournemouth, England. (author)
  • Österborg, AndersKarolinska Institutet,Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden. (author)
  • Cortese, DiegoKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (author)
  • Ranghetti, PamelaIRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy. (author)
  • Baliakas, Panagiotis,1977-Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin(Swepub:uu)panba345 (author)
  • Stamatopoulos, KostasKarolinska Institutet,Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece. (author)
  • Scarfò, LydiaIRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy.;IRCCS Osped San Raffaele, Strateg Res Program CLL, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy. (author)
  • Rosenquist, RichardKarolinska Institutet,Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Genet, Stockholm, Sweden. (author)
  • Ghia, PaoloIRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy.;IRCCS Osped San Raffaele, Strateg Res Program CLL, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy. (author)
  • IRCCS Osped San Raffaele, Ctr Omics Sci, Milan, Italy.;IRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy.Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (creator_code:org_t)

Related titles

  • In:Blood Advances: American Society of Hematology7:12, s. 2794-28062473-95292473-9537

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