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

Ambrus Gángó, Donát Alpár, Bence Galik, Dóra Marosvári, Richárd Kiss, Viktória Fésüs, Dóra Aczél, Ediz Eyüpoglu, Noémi Nagy, Ákos Nagy, Szilvia Krizsán, Lilla Reiniger, Péter Farkas, András Kozma, Emma Ádám, Szabolcs Tasnády, Marienn Réti, András Matolcsy, Attila Gyenesei, Zoltán MátraiCsaba Bödör

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2 Citations (Scopus)

Abstract

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is inducing durable responses in chronic lymphocytic leukemia (CLL) patients with refractory/relapsed disease or with TP53 defect, with BTK and phospholipase C gamma 2 (PLCG2) mutations representing the predominant mechanisms conferring secondary ibrutinib resistance. To understand the landscape of genomic changes and the dynamics of subclonal architecture associated with ibrutinib treatment, an 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. Mutations in the SF3B1, MGAand BIRC3 genes were enriched during ibrutinib treatment, while aberrations in the BTK, PLCG2, RIPK1, NFKBIE and XPO1 genes were exclusively detected in posttreatment samples. Besides the canonical mutations, four novel BTK mutations and three previously unreported PLCG2 variants were identified. BTK and PLCG2 mutations were backtracked in five patients using digital droplet PCR and were detectable on average 10.5 months before clinical relapse. With a median follow-up time of 36.5 months, 7/9 patients harboring BTK mutations showed disease progression based on clinical and/or laboratory features. In conclusion, subclonal heterogeneity, dynamic clonal selection and various patterns of clonal variegation were identified with novel resistance-associated BTK mutations in individual patients treated with ibrutinib.

Original languageEnglish
Pages (from-to)85-93
Number of pages9
JournalInternational Journal of Cancer
Volume146
Issue number1
DOIs
Publication statusPublished - Jan 1 2020

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Keywords

  • chronic lymphocytic leukemia
  • clonal evolution
  • ibrutinib
  • precision medicine
  • targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Gángó, A., Alpár, D., Galik, B., Marosvári, D., Kiss, R., Fésüs, V., Aczél, D., Eyüpoglu, E., Nagy, N., Nagy, Á., Krizsán, S., Reiniger, L., Farkas, P., Kozma, A., Ádám, E., Tasnády, S., Réti, M., Matolcsy, A., Gyenesei, A., ... Bödör, C. (2020). Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib. International Journal of Cancer, 146(1), 85-93. https://doi.org/10.1002/ijc.32502