B-cell receptor signaling pathways play a role in both chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), as well as other hematologic malignancies. The BTK inhibitor, ibrutinib, has received FDA approval in CLL and CLL patients with 17p deletion, and patients with MCL who have received at least one prior therapy. Therefore, inhibition of BTK is a validated strategy in these patient populations, with many of these patients experiencing relapse influenced by mutations at the Cys481 residue, preventing covalent binding, and BTK inhibition.
Epidemiological studies have revealed that a portion of patients receiving ibrutinib therapy in CLL ultimately experience disease progression, and present with the Cys481Ser BTK mutation. In a longitudinal study presented by 308 patients receiving ibrutinib therapy in CLL, 83 patients experienced progressive disease, including patients with Richter’s Transformation. Of this progressive population, 39 patients possessed mutations of BTK or PLCg2 – the vast majority residing at BTK Cys481 however. Hence, approximately 10-15% of patients experiencing disease progression while on ibrutinib therapy are expected to have BTK mutations at Cys4811.
Mantle cell lymphoma patients also receiving ibrutinib therapy have been described to also experience Cys481Ser mutations in BTK exclusively at relapse. Specifically, longitudinal analyses of serial biopsies of relapsed MCL patients noted the very high incidence of the mutation – 80% frequency of Cys481Ser in both the bone marrow and spleen2.
It would be anticipated that novel inhibitors of BTK that do not rely on the Cys481 residue for inhibition could be effective in the aforementioned patient populations experiencing relapse to ibrutinib, or other covalent, irreversible BTK inhibitors.
- Woyach et al; Ibrutinib Therapy in Patiens with CLL, American Society of Hematology 2016 Annual Meeting, Session 642
- Chiron et al; Cell-Cycle Reprogramming for PI3K Inhibition Overrides a Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma