ABSTRACT
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma that is incurable with existing therapies, and therefore presents a significant unmet clinical need. The ability of this disease to overcome therapy, including those that target the B cell receptor pathway which has a pathogenic role in MCL, highlights the need to develop new treatment strategies. Herein, we demonstrate that a distinguishing feature of lymph node resident MCL cells is the expression of phosphatidylinositol 3-kinase γ (PI3Kγ), a PI3K isoform that is not highly expressed in other B cells or B-cell malignancies. By exploring the role of PI3K in MCL using different PI3K isoform inhibitors, we provide evidence that duvelisib, a dual PI3Kδ/γ inhibitor, has a greater effect than PI3Kδ- and PI3Kγ-selective inhibitors in blocking the proliferation of primary MCL cells and MCL cell lines, and in inhibiting tumour growth in a mouse xenograft model. In addition, we demonstrated that PI3Kδ/γ signalling is critical for migration of primary MCL cells and cell lines. Our data indicates that aberrant expression of PI3Kγ is a critical feature of MCL pathogenesis. Thus, we suggest that the dual PI3Kδ/γ duvelisib would be effective for the treatment of mantle cell lymphoma.
Subject(s)
Lymphoma, Mantle-Cell , Phosphoinositide-3 Kinase Inhibitors , Animals , Humans , Mice , Cell Proliferation , Disease Models, Animal , Lymphoma, Mantle-Cell/drug therapy , Phosphatidylinositol 3-Kinases , Phosphoinositide-3 Kinase Inhibitors/pharmacologyABSTRACT
Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma (NHL) that is aggressive and incurable with existing therapies, presenting a significant unmet clinical need. MCL occurs mainly in elderly patients with comorbidities; thus, intense treatment options including allogeneic stem cell transplantation (Allo-SCT) are not feasible. New treatment options are emerging for this elderly/unfit treatment group, we therefore conducted a systematic review to determine whether they offered an advance on the existing recommended treatment, R-CHOP. The search strategies to identify MCL therapies were designed to capture the most relevant studies from 2013 to 2020. Following preferred reporting items for systematic reviews and meta-analyses and population,interventions, observations and study design analysis, R-CHOP, ibrutinib and bendamustine plus rituximab (BR) were taken forward for critical and statistical analysis. All three therapies were effective in increasing the overall survival (OS) and progression-free survival of elderly/unfit patients with MCL. However, none resulted in a significant increase in OS compared to R-CHOP. In addition, R-CHOP had a better toxicity profile when compared to both ibrutinib and BR. We therefore conclude that treatment of elderly/unfit patients with MCL is still a significant unmet clinical need; and suggest that outside of the clinical trial setting, R-CHOP should remain the recommended front-line treatment for this patient group.
