A Novel Triplet of Alisertib Plus Ibrutinib Plus Rituximab Is Active in Mantle Cell Lymphoma.

Background/

Objectives

Aurora (AK) A/B are oncogenic mitotic kinases that when over-expressed are poor prognostic markers in mantle cell lymphoma (MCL). Methods and

Results

Alisertib, an AK-A inhibitor, has anti-tumor activity in relapsed/refractory (r/r) MCL patients. We evaluated alisertib plus ibrutinib in MCL to abrogate ibrutinib resistance. Alisertib plus ibrutinib was therapeutically synergistic on both Granta-519 insensitive to ibrutinib and JeKo-1 cells sensitive to ibrutinib. Alisertib decreased PI-3K, BTK, p38, HCK, and RSK kinases, indicative of its multipotent effect on cellular proliferation and growth. A mouse xenograft model of Granta-519 demonstrated that alisertib plus ibrutinib had a comparable anti-tumor response to ibrutinib plus rituximab. However, alisertib plus ibrutinib plus rituximab demonstrated significantly stronger tumor growth inhibition than the doublets.

Conclusions

Both double and triple combinations showed enhanced survival versus ibrutinib alone. Ibrutinib insensitivity can be disrupted by alisertib plus ibrutinib in MCL.