Cell death induction in drug-resistant CLL cells by the combination treatment of CD20 mAbs and cytotoxic drugs. (A) CD40-stimulated CLL cells were incubated with different concentrations of bortezomib, nutlin, fludarabine, chlorambucil, or bendamustine alone or in combination with GA101 or GXL. After 48 hours, cell death was analyzed by measuring MitoTracker signal by flow cytometry. Averaged results are presented as percentage cell death (mean ± SEM). *.01 < P < .05, **.001 < P < .01, and ***P < .001 significant difference compared with control. M indicates mutated IGHV genes (n = 7); UM, unmutated IGHV genes (n = 5); and p53d, p53-dysfunctional CLL cells (n = 3). Black bars indicate controls; white bars, low-concentration and gray bars, high-concentration cytotoxic drug (bortezomib 15 and 30nM; nutlin 5 and 10μM; fludarabine 25 and 50μM; chlorambucil 5 and 10μM; and bendamustine 50 and 100μM, respectively). (B) Averaged results from 4 CLL patients (3 with mutated and 1 with unmutated IGHV genes) treated with RXL, G, GXL, and fludarabine 12.5, 25, or 50μM or with RXL, G, and GXL and 12.5, 25, or 50μM cisplatin. After 48 hours, apoptosis was analyzed by MitoTracker staining by flow cytometry. Data are presented as percentage cell death (mean ± SEM). *.01 < P < .05, **.001 < P < .01, and ***P < .001 significant difference compared with control.