PhD Scientific Days 2018

Budapest, April 19–20, 2018

Dissection of Clonal Evolution By Temporal Mutation Profiling in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib

Kiss, Richárd

Richárd Kiss1, Donát Alpár1,2, Dóra Marosvári1, Viktória Fésüs1, Ambrus Gángó1, Noémi Nagy1, Péter Farkas3, Szabolcs Tasnády4, Marienn Réty4, Andras Matolcsy1, Zoltán Mátrai4 and Csaba Bödör1

1 MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Cancer Research, Semmelweis University, Budapest, Hungary; 2 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Hungary; 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

English

Text of the abstract

Introduction: The Bruton tyrosine kinase inhibitor ibrutinib has produced remarkable responses in patients with chronic lymphocytic leukemia (CLL) in first line as well as in relapsed CLL. However, approximately 18% of patients develop resistance and relapse in the first 3 years of BTK inhibitor therapy. In the majority of resistant patients BTK and/or PLCG2 mutations can be detected, often even 10 months before the clinical relapse.

Aims: Given the very poor outcome of patients discontinuing ibrutinib, our aims were to further understand the mechanisms of ibrutinib resistance and to dissect the clonal evolution in the context of all relevant mutation targets in CLL.

Methods: We performed a temporal mutation profiling of 31 recurrently mutated genes using the TruSeq Custom Amplicon approach (Illumina) in sequential peripherial blood samples from 20 CLL patients treated with ibrutinib, with a median follow up of 24 (3-36) months.

Results: The ultra-deep NGS analysis revealed a total of 473 somatic mutations in the 20 paired samples across the 31 genes analyzed. The post-treatment samples carried a considerably higher number of mutations compared to the pre-treatment samples with more than half of the variants representing subclonal alterations.. The most frequently mutated genes at baseline included TP53 (50%), NOTCH1 (50%) and POT1 (28%) with similarly high mutation frequencies in the post-treatment samples. MYD88, BIRC3 and SF3B1 mutations were enriched in the post-ibrutinib samples. As for the BTK and PLCG2 mutations, none of the pre-treatment samples carried a mutation in either of these genes, however, we detected emerging subclonal BTK and PLCG2 mutations in almost one quarter of the post-treatment samples, including mutations affecting previously unreported amino acid residues.

Conclusions: The NGS analysis provided a significant insight into the mutational repertoire and it has revealed a profound subclonal heterogeneity that seems to be further enhanced by ibrutinib therapy.

Data of the presenter

Doctoral School: Pathology
Program: Oncology
Supervisor: Csaba Bödör, Donát Alpár
E-mail address: kiss.richard@med.semmelweis-univ.hu