: 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.

BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib / Bonfiglio, Silvia; Sutton, Lesley-Ann; Ljungström, Viktor; Capasso, Antonella; Pandzic, Tatjana; Weström, Simone; Foroughi-Asl, Hassan; Skaftason, Aron; Gellerbring, Anna; Lyander, Anna; Gandini, Francesca; Gaidano, Gianluca; Trentin, Livio; Bonello, Lisa; Reda, Gianluigi; Bödör, Csaba; Stavroyianni, Niki; Tam, Constantine S; Marasca, Roberto; Forconi, Francesco; Panayiotidis, Panayiotis; Ringshausen, Ingo; Jaksic, Ozren; Frustaci, Anna Maria; Iyengar, Sunil; Coscia, Marta; Mulligan, Stephen P; Ysebaert, Loïc; Strugov, Vladimir; Pavlovsky, Carolina; Walewska, Renata; Österborg, Anders; Cortese, Diego; Ranghetti, Pamela; Baliakas, Panagiotis; Stamatopoulos, Kostas; Scarfò, Lydia; Rosenquist, Richard; Ghia, Paolo. - In: BLOOD ADVANCES. - ISSN 2473-9529. - 7:12(2023), pp. 2794-2806. [10.1182/bloodadvances.2022008821]

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

Capasso, Antonella;Ghia, Paolo
2023-01-01

Abstract

: 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.
File in questo prodotto:
File Dimensione Formato  
blooda_adv-2022-008821-main.pdf

accesso aperto

Tipologia: PDF editoriale (versione pubblicata dall'editore)
Licenza: Creative commons
Dimensione 470.36 kB
Formato Adobe PDF
470.36 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/144076
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 13
  • ???jsp.display-item.citation.isi??? 13
social impact