Landscape of <i>BCL2</i> Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax
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, wi...
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MDPI AG
2023-03-01
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| author | Lili Kotmayer Tamás László Gábor Mikala Richárd Kiss Luca Lévay Lajos László Hegyi Stefánia Gróf Tibor Nagy Gábor Barna Péter Farkas Júlia Weisinger Zsolt Nagy Alexandra Balogh Tamás Masszi Judit Demeter Adrienn Sulák Zoltán Kohl Hussain Alizadeh Miklós Egyed Piroska Pettendi Lajos Gergely Márk Plander Zsolt Pauker András Masszi András Matolcsy Róbert Szász Csaba Bödör Donát Alpár |
| author_facet | Lili Kotmayer Tamás László Gábor Mikala Richárd Kiss Luca Lévay Lajos László Hegyi Stefánia Gróf Tibor Nagy Gábor Barna Péter Farkas Júlia Weisinger Zsolt Nagy Alexandra Balogh Tamás Masszi Judit Demeter Adrienn Sulák Zoltán Kohl Hussain Alizadeh Miklós Egyed Piroska Pettendi Lajos Gergely Márk Plander Zsolt Pauker András Masszi András Matolcsy Róbert Szász Csaba Bödör Donát Alpár |
| author_sort | Lili Kotmayer |
| collection | DOAJ |
| description | 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 <i>BCL2</i> mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common <i>BCL2</i> mutations G101V and D103Y, sensitive (10<sup>−4</sup>) screening for the most common <i>BCL2</i> 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, <i>BCL2</i> 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 <i>BCL2</i> 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 <i>BCL2</i> 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 <i>BCL2</i> uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of <i>BCL2</i> mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which <i>BCL2</i> resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for <i>BCL2</i> resistance mutations in R/R CLL. |
| first_indexed | 2024-03-11T06:25:30Z |
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| language | English |
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| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-dbbfd839657a43d8b87676f61dfafd572023-11-17T11:39:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01246580210.3390/ijms24065802Landscape of <i>BCL2</i> Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with VenetoclaxLili Kotmayer0Tamás László1Gábor Mikala2Richárd Kiss3Luca Lévay4Lajos László Hegyi5Stefánia Gróf6Tibor Nagy7Gábor Barna8Péter Farkas9Júlia Weisinger10Zsolt Nagy11Alexandra Balogh12Tamás Masszi13Judit Demeter14Adrienn Sulák15Zoltán Kohl16Hussain Alizadeh17Miklós Egyed18Piroska Pettendi19Lajos Gergely20Márk Plander21Zsolt Pauker22András Masszi23András Matolcsy24Róbert Szász25Csaba Bödör26Donát Alpár27HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungaryHCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungarySouth-Pest Central Hospital, National Institute of Hematology and Infectology, 1097 Budapest, HungaryHCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungaryHCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungaryHCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungaryHCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungaryHCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungaryHCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungaryDepartment of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, HungaryDepartment of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, HungaryDepartment of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, HungaryDepartment of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, HungaryDepartment of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, HungaryDepartment of Internal Medicine and Oncology, Semmelweis University, 1085 Budapest, Hungary2nd Department of Internal Medicine and Cardiology Center, University of Szeged, 6725 Szeged, Hungary1st Department of Internal Medicine, Clinical Centre, University of Pécs, 7622 Pécs, Hungary1st Department of Internal Medicine, Clinical Centre, University of Pécs, 7622 Pécs, HungaryKaposi Mór University Teaching Hospital of County Somogy, 7400 Kaposvár, HungaryHetényi Géza Hospital, Clinic of County Jász-Nagykun-Szolnok, 5000 Szolnok, HungaryDivision of Hematology, Department of Internal Medicine, University of Debrecen, 4032 Debrecen, HungaryMarkusovszky University Teaching Hospital, 9700 Szombathely, HungaryBorsod-Abaúj-Zemplén County Hospital and University Teaching Hospital, 3515 Miskolc, HungaryNational Institute of Oncology, 1122 Budapest, HungaryHCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungaryDivision of Hematology, Department of Internal Medicine, University of Debrecen, 4032 Debrecen, HungaryHCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungaryHCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, HungaryThe 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 <i>BCL2</i> mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common <i>BCL2</i> mutations G101V and D103Y, sensitive (10<sup>−4</sup>) screening for the most common <i>BCL2</i> 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, <i>BCL2</i> 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 <i>BCL2</i> 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 <i>BCL2</i> 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 <i>BCL2</i> uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of <i>BCL2</i> mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which <i>BCL2</i> resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for <i>BCL2</i> resistance mutations in R/R CLL.https://www.mdpi.com/1422-0067/24/6/5802CLLvenetoclaxBCL2therapy resistancemolecular monitoring |
| spellingShingle | Lili Kotmayer Tamás László Gábor Mikala Richárd Kiss Luca Lévay Lajos László Hegyi Stefánia Gróf Tibor Nagy Gábor Barna Péter Farkas Júlia Weisinger Zsolt Nagy Alexandra Balogh Tamás Masszi Judit Demeter Adrienn Sulák Zoltán Kohl Hussain Alizadeh Miklós Egyed Piroska Pettendi Lajos Gergely Márk Plander Zsolt Pauker András Masszi András Matolcsy Róbert Szász Csaba Bödör Donát Alpár Landscape of <i>BCL2</i> Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax International Journal of Molecular Sciences CLL venetoclax BCL2 therapy resistance molecular monitoring |
| title | Landscape of <i>BCL2</i> Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax |
| title_full | Landscape of <i>BCL2</i> Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax |
| title_fullStr | Landscape of <i>BCL2</i> Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax |
| title_full_unstemmed | Landscape of <i>BCL2</i> Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax |
| title_short | Landscape of <i>BCL2</i> Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax |
| title_sort | landscape of i bcl2 i resistance mutations in a real world cohort of patients with relapsed refractory chronic lymphocytic leukemia treated with venetoclax |
| topic | CLL venetoclax BCL2 therapy resistance molecular monitoring |
| url | https://www.mdpi.com/1422-0067/24/6/5802 |
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