Molecular determinants of outcomes in relapsed mantle cell lymphoma treated with ibrutinib or temsirolimus in the MCL3001 (RAY) trial

Mantle cell lymphoma (MCL) is a rare, incurable lymphoma subtype characterized by heterogeneous outcomes. In order to better understand the clinical behavior and response to treatment, powerful predictive biomarkers are needed. Using residual archived material from patients enrolled in the MCL3001 (RAY) study, we performed a detailed analysis of gene expression and genetic sequencing. This phase III clinical trial randomized patients with relapsed or refractory MCL to treatment with either ibrutinib or temsirolimus. We confirmed the prognostic capability of the RNA expression proliferation assay MCL35 in this cohort treated with novel agents, which outperformed the simplified MCL International Prognostic Index in discriminating patients with different outcomes. Regardless of treatment arm, we demonstrated that this assay captures the risk conferred by known biological factors, such as increased MYC-expression, blastoid morphology, aberrations of TP53, and truncated CCND1 3’untranslated region. We further showed the negative impact of BIRC3 mutations/deletions on outcomes in this cohort, and identified that deletion of chromosome 8p23.3 also has a deleterious effect on survival. Restricted to patients with deletions/alterations in TP53, ibrutinib appeared to abrogate the deleterious impact on outcome. These data illustrate the potential to perform a molecular analysis of predictive biomarkers from routine patient samples that can meaningfully inform clinical practice.EGA study EGAS00001006342