Abstract
Relapsed/refractory T cell acute lymphoblastic leukemia (T-ALL) is difficult to salvage especially in heavily pretreated patients, thus novel targeted agents are sorely needed. Hyperactivated JAK/STAT and BCL2 overexpression promote increased T-ALL proliferation and survival, and targeting these pathways with small molecule inhibitors like ruxolitinib and venetoclax may provide an alternative therapeutic approach to re-induce clinical remissions. Ruxolitinib and venetoclax show a dose-dependent effect individually, but combination treatment synergistically reduces survival and proliferation of Jurkat and Loucy cells in vitro. Using a xenograft CXCR4+ Jurkat model, the combination of ruxolitinib and venetoclax fails to improve survival, with the primary cause of death from hind limb paralysis. Despite on-target inhibition of the drugs on total STAT1, pSTAT1, total STAT3, total STAT5 and pSTAT5 as well as BCL2, histopathologic analysis demonstrates increased leukemic infiltration into the central nervous system (CNS), which expresses CXCL12, as compared to the liver or bone marrow. Liquid chromatography-tandem mass spectroscopy shows that neither ruxolitinib nor venetoclax can effectively cross the blood-brain barrier, limiting efficacy against CNS T-ALL. Deletion of CXCR4 on Jurkat cells by CRISPR/Cas9 results in prolonged survival and a reduction in overall and neurologic clinical scores. While combination therapy with ruxolitinib and venetoclax shows promise for treating T-ALL, additional inhibition of the CXCR4-CXCL12 axis will be needed to eliminate both systemic and CNS T-ALL burden and maximize the possibility of complete remission.
Key Points
Ruxolitinib & venetoclax treat T-ALL in vitro; fail to treat CNS burden in vivo.
CXCR4-CXCL12 recruits T-ALL to CNS and accelerates lethality.