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Prevalence of BTK and PLCG2 mutations in a real‑life CLL cohort still on ibrutinib after three years: a FILO group study

Anne Quinquenel, Luc-Matthieu Fornecker, Rémi Letestu, Loïc Ysebaert, Carole Fleury, Gregory Lazarian, Marie-Sarah Dilhuydy, Delphine Nollet, Romain Guieze, Pierre Feugier, Damien Roos-Weil, Lise Willems, Anne-Sophie Michallet, Alain Delmer, Katia Hormigos, Vincent Levy, Florence Cymbalista and Fanny Baran-Marszak

Key Points

  • In a real-life CLL cohort still on ibrutinib after three years, 57% of patients with residual clonal lymphocytosis had a BTKmutation

  • The presence of a BTKmutation in patients still on ibrutinib conferred a greater likelihood of subsequent CLL progression

Abstract

Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in the Bruton's tyrosine kinase (BTK) and/or phospholipase Cg2 (PLCG2) genes. However, mutational information for patients still on ibrutinib is limited. Here, we report a study aimed to provide a 'snapshot' of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least three years of treatment. Of 204 patients who initiated ibrutinib via an early access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after three years and 57 provided a fresh blood sample. Thirty patients had a CLL clone {greater than or equal to}0.5 G/L, enabling next‑generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. The presence of a BTKmutation was significantly associated with subsequent CLL progression, at a median 8.5 months from sample collection (P=0.0005 versus noBTKmutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment.

  • Submitted March 29, 2019.
  • Revision received June 24, 2019.
  • Accepted June 1, 2019.