Dóra Aczél1, Richárd Kiss1, Zoltán Mátrai2, András Masszi3, Péter Farkas3, Szabolcs Benedek3, Alexandra Balogh3, Judit Demeter4, Ilona Tárkányi4, Hussain Alizadeh5, Róbert Szász6, Tímea Gurbity7, Miklós Egyed8, Csaba Bödör1, Donát Alpár1
1 MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; 2 Department of Haematology and Stem Cell Transplantation, St. István and St László Hospital, Budapest, Hungary; 3 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary; 4 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary; 5 1st Department of Internal Medicine, University of Pécs, Pécs, Hungary; 6 2nd Department of Internal Medicine, University of Debrecen, Debrecen, Hungary; 7 2nd Department of Internal Medicine and Cardiology Center, University of Szeged, Szeged, Hungary; 8 Somogy County Kaposi Mór Teaching Hospital, Kaposvár, Hungary
Introduction: Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has dramatically changed the therapeutic landscape of chronic lymphocytic leukemia (CLL) with remarkable response rates among patients with relapsed/refractory disease. However, 20% of CLL patients receiving ibrutinib treatment experience disease progression, with the majority of them harboring resistance mutations in the BTK gene at the time of relapse. Although longitudinal studies have shed some light on the significance and early detection of these genetic aberrations, a guideline for resistance mutation screening has not been established to date.
Aims: To scrutinize the correlation between disease progression and the emergence of the most common BTK resistance mutation C481S, as well as to assess the real-life clinical value of ultra-sensitive screening for this alteration during ibrutinib therapy.
Methods: Serial blood samples from 40 previously relapsed/refractory CLL patients were collected during ibrutinib treatment. Genomic DNA was extracted from peripheral blood mononuclear cells after assessment of the leukemic cell purity by flow cytometry. Fractional abundance of the BTK C481S variant was quantified using a QX200 droplet digital PCR system (BioRad) with specifically designed custom assays.
Results: With a median follow-up time of 30 months on ibrutinib treatment, BTK C481S mutation was detected in 14/40 (35%) patients, with 9/14 (64%) of them already showing disease progression during the examined period. The aberration was identified in 9/12 (75%) patients experiencing relapse. In these cases, the emergence of the BTK mutation predated the symptoms of clinical progression with an average of 6 (range: 3-12) months.
Conclusions: In three-quarters of treatment-resistant CLL patients, ultra-sensitive time-resolved screening for BTK C481S, a mutation located at the ibrutinib binding site of the BTK protein, allows for the prediction of an impending relapse months before the first clinical signs of disease progression.
Supporting grants: NKFIH K16-119950, KH17-126718 and NVKP_16-1-2016-0004; ÚNKP-17-4-III-SE-62; HAS LP95021 and János Bolyai Scholarship Program.
Doctoral School: Pathology
Supervisor: Donát Alpár
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