Cyclic fasting-mimicking diet plus bortezomib and rituximab is an effective treatment for chronic lymphocytic leukemia.

Cyclic fasting-mimicking diet (FMD) is an experimental nutritional intervention with potent antitumor activity in preclinical models of solid malignancies. FMD cycles are also safe and active metabolically and immunologically in cancer patients. Here, we reported on the outcome of FMD cycles in two chronic lymphocytic leukemia (CLL) patients and investigated the effects of fasting and FMD cycles in pre-clinical CLL models. Fasting mimicking conditions in murine CLL models had mild cytotoxic effects, which resulted in apoptosis activation mediated in part by lowered insulin and IGF-1 concentrations. In CLL cells, fasting conditions promoted an increase in proteasome activity that served as a starvation escape pathway. Pharmacological inhibition of this escape mechanism with the proteasome inhibitor bortezomib (BTZ) resulted in a strong enhancement of the pro-apoptotic effects of starvation conditions in vitro. In mouse CLL models, combining cyclic fasting/FMD with BTZ and rituximab (RTX), an anti-CD20 antibody, delayed CLL progression and resulted in significant prolongation of mouse survival. Overall, the effect of proteasome inhibition in combination with FMD cycles in promoting CLL death supports the targeting of starvation escape pathways as an effective treatment strategy that should be tested in clinical trials.