Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax.

Autor: Kotmayer L; HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary., László T; HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary., Mikala G; South-Pest Central Hospital, National Institute of Hematology and Infectology, 1097 Budapest, Hungary., Kiss R; HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary., Lévay L; HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary., Hegyi LL; HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary., Gróf S; HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary., Nagy T; HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary.; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary., Barna G; HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary., Farkas P; Department of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, Hungary., Weisinger J; Department of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, Hungary., Nagy Z; Department of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, Hungary., Balogh A; Department of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, Hungary., Masszi T; Department of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, Hungary., Demeter J; Department of Internal Medicine and Oncology, Semmelweis University, 1085 Budapest, Hungary., Sulák A; 2nd Department of Internal Medicine and Cardiology Center, University of Szeged, 6725 Szeged, Hungary., Kohl Z; 1st Department of Internal Medicine, Clinical Centre, University of Pécs, 7622 Pécs, Hungary., Alizadeh H; 1st Department of Internal Medicine, Clinical Centre, University of Pécs, 7622 Pécs, Hungary., Egyed M; Kaposi Mór University Teaching Hospital of County Somogy, 7400 Kaposvár, Hungary., Pettendi P; Hetényi Géza Hospital, Clinic of County Jász-Nagykun-Szolnok, 5000 Szolnok, Hungary., Gergely L; Division of Hematology, Department of Internal Medicine, University of Debrecen, 4032 Debrecen, Hungary., Plander M; Markusovszky University Teaching Hospital, 9700 Szombathely, Hungary., Pauker Z; Borsod-Abaúj-Zemplén County Hospital and University Teaching Hospital, 3515 Miskolc, Hungary., Masszi A; National Institute of Oncology, 1122 Budapest, Hungary., Matolcsy A; HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary.; Department of Laboratory Medicine, Karolinska Institute, 171 77 Solna, Sweden., Szász R; Division of Hematology, Department of Internal Medicine, University of Debrecen, 4032 Debrecen, Hungary., Bödör C; HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary., Alpár D; HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 Mar 18; Vol. 24 (6). Date of Electronic Publication: 2023 Mar 18.
DOI: 10.3390/ijms24065802
Abstrakt: The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10 -4 ) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax-rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.
Databáze: MEDLINE
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