Defining resistance mechanisms and clonal dynamics in mantle cell lymphoma treated with novel targeted therapies

Abstract

Mantle cell lymphoma (MCL) is a B-cell malignancy and often an incurable disease. Novel targeted therapeutics are poised to significantly change the natural history of this disease. The combination of ibrutinib and venetoclax targets two critical oncogenic pathways in MCL and has recently shown promising results in the treatment of high grade MCL. The AIM clinical trial combining ibrutinib and venetoclax in patients with relapsed and refractory MCL has demonstrated a complete response rate of 71%. Despite this important success, over 20% of patients in the study were primary refractory to the combination therapy and a further 10% relapsed following initial response. Key to the future clinical success of this approach will be the real-time assessment of therapeutic response and the identification of molecular determinants of therapeutic resistance.

To understand the molecular factors that influence response to venetoclax and ibrutinib in MCL we performed exome and low coverage whole genome sequencing of tumor tissue at enrolment for all patients on the AIM study. Remarkably, the genomic profile clearly dichotomized patients into responders and non-responders with mutations in ATM present in 12/18 patients who achieved a complete response, and loss of chromosome 9p21.1-p24.3 and/or mutations in components of the SWI/SNF chromatin remodeling complex present in all patients with primary resistance (5/5). Moreover, these genomic determinants of resistance also emerged in 2/3 patients with relapsed disease.

All patients were prospectively monitored using circulating tumor DNA (ctDNA), multi-parameter flow cytometry and allele-specific oligonucleotide PCR. This prospective analysis showed that ctDNA was an effective strategy for disease monitoring that provided additional prognostic information and enabled real-time assessment of therapeutic response and emerging resistance.

Modeling of primary resistance demonstrated that functional compromise of the SWI/SNF complex facilitated transcriptional upregulation of BCL-xL and provided a selective advantage against ibrutinib and venetoclax. We show that this therapeutic escape mechanism can be effectively overcome by concurrent inhibition of BCL-xL.

Together these data reveal important insights into the molecular elements of response to ibrutinib and venetoclax in MCL and provides a paradigm for the assessment of novel biomarkers and resistance mechanisms, concurrent to the clinical evaluation of innovative-targeted therapies.