PhD Scientific Days 2019

Budapest, April 25–26, 2019

Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib

Gángó, Ambrus

Ambrus Gángó1, Donát Alpár1, Bence Galik2, Dóra Marosvári1, Richárd Kiss1, Viktória Fésüs1, Dóra Aczél1, Ediz Eyüpoglu1, Noémi Nagy1, Ákos Nagy1, Szilvia Krizsán1, Lilla Reiniger1, Péter Farkas3, András Kozma4, Emma Ádám4, Szabolcs Tasnády4, Marienn Réti4, András Matolcsy1, Attila Gyenesei2, Zoltán Mátrai4, Csaba Bödör1

1, MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
2, Vienna Biocenter Core Facilities GmbH, Vienna, Austria
3, 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
4, Department of Haematology and Stem Cell Transplantation, St. István and St. László Hospital, Budapest, Hungary

Language of the presentation


Text of the abstract

Introduction: The Bruton’s tyrosine kinase inhibitor (BTK) ibrutinib is changing the therapeutic landscape of chronic lymphocytic leukemia (CLL) by inducing durable responses in patients with refractory/relapsed disease or with TP53 defect. Although, recurrent mutations in the BTK and PLCG2 genes represent the predominant mechanisms conferring secondary ibrutinib resistance, the landscape of genomic changes and the dynamics of subclonal architecture associated with ibrutinib treatment have not comprehensively been explored to date.
Aims: To delineate the clonal evolution affecting all relevant mutation targets in CLL.
Patients and methods: Ultra-deep next-generation sequencing analysis of 30 recurrently mutated genes was performed on sequential samples of 20 patients, collected before and during single-agent ibrutinib treatment.
Results: Subclonal heterogeneity was observed in all cases with an average of five mutations per patient. Mutations in the SF3B1, MGA and BIRC3 genes were enriched during ibrutinib treatment, while aberrations in the BTK, PLCG2, RIPK1, NFKBIE and XPO1 genes were exclusively detected in post-treatment samples. Convergent evolution defined as acquisition of multiple mutations in the same gene was observed in 50% of patients. BTK and PLCG2 variants co-occurred in 2/8 patients carrying mutations in one of these genes. In addition to the canonical mutation hotspots, four novel BTK mutations and three previously unreported PLCG2 variants were identified in four patients. With a median follow up time of 22 months, 25% of the patients relapsed with a BTK or PLCG2 mutation. These mutations were backtracked in four patients using digital droplet PCR and were detectable on average 10 months before the clinical relapse.
Conclusion: Subclonal heterogeneity, dynamic clonal selection and unique patterns of clonal variegation were observed in individual patients upon ibrutinib treatment. Comprehensive and in-depth interrogation of driver genes can provide extensive disease-relevant genomic characterization of the CLL cell compartment and identify potential targets for treatment response monitoring.

Data of the presenter

Doctoral School: Pathological Sciences
Program: Experimental Oncology
Supervisor: Csaba Bödör