Fig. 6: Combined Bcl-2 and BTK inhibition delays and overcomes secondary venetoclax resistance in vivo.

a–d MISTRG mice were injected intravenously with 1 × 10⁷ RIVA cells; IVIS images were recorded on the indicated days (a) and the radiance was plotted longitudinally over time (b). IVIS images are shown for four representative mice per condition in a, and means ± SD are shown for all four to seven mice per treatment condition in b, along with the p values for the relevant comparisons (determined by one-way ANOVA of AUC). Mice received either two or five doses per week of 40 mg/kg venetoclax, either alone or in combination with 25 mg/kg ibrutinib via oral gavage, initiated once lymphomas were clearly detectable in all mice of the cohort (after two weeks of growth; treatment window indicated by gray shading in b). All mice were subjected to the quantification of their lymphoma burden in the hind leg bone marrow at the study endpoint by flow cytometric staining for hCD45 and mouse CD45. Human tumor cell frequencies among all (human and mouse) CD45⁺ cells are shown in c, and absolute counts are shown in d. *p < 0.05, **p < 0.01, ***p < 0.005, as determined by one-way ANOVA. e–h MISTRG mice were injected intravenously with 1 × 10⁷ RIVA cells, and were treated as described in a–d with five doses per week of venetoclax or venetoclax plus ibrutinib. After an interval of two weeks without drug treatment leading to lymphoma progression in a subset of mice, combination salvage therapy was re-initiated for another two weeks where indicated. IVIS images are shown for all six mice per condition in e, and means ± SD are shown in f. The flow cytometric quantification of the lymphoma burden in the hind leg bone marrow is shown in g and h for the study endpoint at 9 weeks post injection.