Clinical and Molecular Biology Analysis of Patients with Mantle Cell Lymphoma Resistant to BTK Inhibitor

Background. BTK inhibitor(BTKi) has transformed the therapeutic landscape for mantle cell lymphoma(MCL). Results of clinical trials demonstrate the efficacy of BTKi to salvage patients with MCL progression, however, mechanism of MCL patients resistant to BTKi is still lack of study.

Aim In order to describe the clinical and molecular characteristics of BTK inhibitor resistance and guide the clinical rational application of BTK inhibitor.

MethodsWe retrospectively evaluated the 19 consecutive patients(relapsed/refractory MCL ,n=15;Primary MCL,n=4) who received a BTKi(Ibrutinib, n = 13; Zanubrutinib, n = 2; Orelabrutinib, n=4;Acalabrutinib,n=1) ,while the MCL still progressed.Fully detailed information of patients, disease characteristics, treatments and the next generation sequencing collected.

Results Median time of taking BTKi and median time of BTKi efficiency were 10 months and 5 months, respectively. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 14 months and 21 months, respectively. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 19 MCL patients, top 10 genes including ATM(47%)、TP53(47%)、KMT2D(32%)、NOTCH2(26%)、BTK(16%)、NSD2(16%)、BIRC3(11%)、CCND1(11%)、NOTCH1(11%)、KMT2C (11%).B cell activation, histone modification, inflammatory response to antigenic stimulus genes were increased in patients with mantle cell lymphoma resistant to BTKi according to Kyoto Encyclopedia of genes and Genomes pathways on gene-set enrichment analysis.

Conclusions Demonstration of ATM and TP53 genes mutations and related pathways opens the door for future investigations in BTKi resistance in MCL patients.