Anti-IgM induced signaling is reduced during ibrutinib therapy. CLL cells taken before and at weeks 1, 4, and 12 of ibrutinib therapy were stimulated with anti-IgM, and signaling was measured by flow cytometry or immunoblotting. (A) Intracellular iCa²⁺ mobilization at different time points of therapy is shown as fold change relative to pretherapy (n = 15) (left). Pretherapy values were set to 1. Mean + SEM is shown. Representative plot showing reduced but maintained iCa²⁺ during ibrutinib in a patient with CLL with high sIgM levels (right). (B) pERK/ERK inducibility was measured as aIgM/basal pERK/ERK at each time point of therapy in 15 patients with CLL and is shown as fold change relative to pretherapy (pretherapy inducibility was set to 1) (left). Representative immunoblot showing persistence of ERK phosphorylation during therapy (right). P values at each time-point in both panels are relative to pretherapy values.