Poster Session I. - D: Pathological and Oncological Sciences
László Tamás
HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University
Tamás László1, Lili Kotmayer2, Gabriella Szepesi3, Marcell Matúz3, Lajos Hegyi3, Stefánia Gróf3, Judit Demeter4, Ildikó Istenes4, Ilona Tárkányi5, Gergely Szombath5, Péter Farkas5, Zsolt Nagy5, Alexandra Balogh5, Réka Bicskó6, Lajos Gergely6, Róbert Szász6, Gábor Mikala7, Árpád Bátai7, András Masszi8, Péter A. Király8, Erika Szaleczky8, Beáta M. Deák8, Piroska Pettendi9, Natália Jóni10, Nóra Adamkovich11, Timea Gurbity11, Árpád Illés6, Tamás Masszi5, Donát Alpár3, Csaba Bödör3
1: HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University
2: HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University; MTA-SE Lendület Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University; Department of Hematology, St. Jude Children’s Research Hospital, Memphis, US
3: HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University; MTA-SE Lendület Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University
4: Department of Internal Medicine and Oncology, Semmelweis University
5: Department of Internal Medicine and Hematology, Semmelweis University
6: Division of Hematology, Department of Internal Medicine, University of Debrecen
7: Central Hospital of Southern Pest – National Institute of Hematology and Infectious Diseases, Budapest
8: National Institute of Oncology, Budapest
9: Hetényi Géza Hospital and Clinic of County Jász-Nagykun-Szolnok, Szolnok
10: Markhot Ferenc Teaching Hospital, Eger
11: 2nd Department of Internal Medicine and Cardiology Center, University of Szeged
Introduction: In recent years, introduction of targeted treatment modalities has revolutionized the management of chronic lymphocytic leukemia (CLL). Despite having substantial evidence on molecular biomarkers associated with chemo-immunotherapy, there is limited data regarding their prognostic/predictive value or role in resistance in the context of targeted therapies.
Aims: In our study, we aimed to scrutinize the molecular profile and subclonal dynamics of CLL patients treated with targeted agents using a novel comprehensive deep-sequencing approach.
Method: We have collected 48 serial samples from 20 CLL patients treated with ibrutinib and venetoclax. An integrative next generation sequencing (NGS) approach (cCLL-SOPHiA Genetics) was used for molecular characterisation of samples, enabling the assesment of the IGHV- and TP53 status, copy number profile as well as additional prognostically relevant mutations in one reaction.
Results: Our cohort showed high-risk molecular characteristics revealing a median of 3 CLL-related mutations in pre-treatment samples with 95% (19/20) of patients presenting with unmutated IGHV status. NGS demonstrated a robust correlation with Sanger sequencing (r=0.84 Spearman’s correlation) in assessing the IGHV mutation status and outperformed Sanger sequencing which failed to detect clonal rearrangements in 3 cases. Eighty-five percent (17/20) of patients experienced disease progression on ibrutinib, with a median progression-free survival of 32 months, while relapse on venetoclax occurred after a median of 25.5 months. BTK and PLCG2 mutations were identified in 75% (13/17) of cases with ibrutinib failure. One additional case harboured mutation without evidence of disease progression. BCL2 mutations were identified in 6/10 cases with venetoclax failure. No resistance mutations were identified in pre-treatment samples. Most common resistance mutations (BTK and PLG2 for ibrutinib and BCL2 for venetoclax) were validated by ddPCR, demonstrating a strong concordance with NGS (r=0,98, Spearman’s correlation).
Conclusion: We demonstrated the feasibility of cCLL, an integrative, all in one reaction deep sequencing approach in detailed molecular charaterization of CLL in the context of targeted therapies.
Funding: FK20_134253, K21_137948, H2020_739593, BO/00125/22, EKÖP-2024-114, SE250 scholarship