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Screening and monitoring of the BTK C481S mutation in a real-world cohort of patients with relapsed/refractory chronic lymphocytic leukaemia during ibrutinib therapy

Bödör, Csaba and Kotmayer, Lili and László, Tamás and Takács, Ferenc and Barna, Gábor and Kiss, Richárd and Sebestyén, Endre and Nagy, Tibor and Hegyi, Lajos and Mikala, Gábor and Fekete, Sándor and Farkas, Péter and Balogh, Alexandra and Masszi, Tamás and Demeter, Judit and Weisinger, Júlia and Alizadeh, Hussain and Kajtár, Béla and Kohl, Zoltán and Szász, Róbert and Gergely, Lajos and Gurbity Pálfi, Tímea and Sulák, Adrienn and Kollár, Balázs and Egyed, Miklós and Plander, Márk and Rejtő, László and Szerafin, László and Ilonczai, Péter and Tamáska, Péter and Pettendi, Piroska and Lévai, Dóra and Schneider, Tamás and Sebestyén, Anna and Csermely, Péter and Matolcsy, András and Mátrai, Zoltán and Alpár, Donát (2021) Screening and monitoring of the BTK C481S mutation in a real-world cohort of patients with relapsed/refractory chronic lymphocytic leukaemia during ibrutinib therapy. BRITISH JOURNAL OF HAEMATOLOGY, 194 (2). pp. 355-364. ISSN 0007-1048 (print); 1365-2141 (online)

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Abstract

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has revolutionised the therapeutic landscape of chronic lymphocytic leukaemia (CLL). Acquired mutations emerging at position C481 in the BTK tyrosine kinase domain are the predominant genetic alterations associated with secondary ibrutinib resistance. To assess the correlation between disease progression, and the emergence and temporal dynamics of the most common resistance mutation BTKC481S , sensitive (10-4 ) time-resolved screening was performed in 83 relapsed/refractory CLL patients during single-agent ibrutinib treatment. With a median follow-up time of 40 months, BTKC481S was detected in 48·2% (40/83) of the patients, with 80·0% (32/40) of them showing disease progression during the examined period. In these 32 cases, representing 72·7% (32/44) of all patients experiencing relapse, emergence of the BTKC481S mutation preceded the symptoms of clinical relapse with a median of nine months. Subsequent Bcl-2 inhibition therapy applied in 28/32 patients harbouring BTKC481S and progressing on ibrutinib conferred clinical and molecular remission across the patients. Our study demonstrates the clinical value of sensitive BTKC481S monitoring with the largest longitudinally analysed real-world patient cohort reported to date and validates the feasibility of an early prediction of relapse in the majority of ibrutinib-treated relapsed/refractory CLL patients experiencing disease progression.

Item Type: Article
Subjects: R Medicine / orvostudomány > RB Pathology / patológia, kórtan
Depositing User: Dr Donat Alpar
Date Deposited: 17 Sep 2021 07:24
Last Modified: 17 Sep 2021 07:24
URI: http://real.mtak.hu/id/eprint/129660

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