Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib

Guarini A
Peragine N
Messina M
Marinelli M
Ilari C
Cafforio L
Raponi S
Bonina S
Mariglia P
Mauro FR
Gaidano G
Del Giudice I
Foà R

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Publication date

January 2018

DOI

10.1111/bjh.15613

Publisher

Wiley

Abstract

TP53-disrupted chronic lymphocytic leukaemia (CLL) patients show a suboptimal long-term response to ibrutinib. We hereby report that ibrutinib-induced in vitro apoptosis and proliferation inhibition were significantly lower in TP53-mutated (TP53-M) CLL cells compared to TP53 wild-type cells. Contrariwise, venetoclax effectively killed TP53-M cells. Gene expression profile analysis of TP53-M cells revealed a downmodulation of B-cell receptor (BCR)-related genes and an upmodulation of genes with anti-apoptotic/pro-survival activity, suggesting that the survival and proliferation of TP53-M cells are less dependent on the BCR pathway. These observations further support the use of drug combinations for the optimal management ...