Our results support the inclusion of everolimus with a BTK inhibitor in the treatment of aggressive CLL cohorts, as we show an inhibition of eEF2K/EF2 signalling axis in an aggressive B cell leukemia model in vivo in the presence of rapamycin, which is enhanced in combination with  IB, leading to reduction in cell survival. Here, BTK is linked to B-cell chronic lymphocytic leukemia.