Blood. 2015 Apr 2. pii: blood-2015-01-621391. [Epub ahead of print]
Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia.
Hing ZA1, Mantel R2, Beckwith KA1, Guinn D2, Williams E2, Smith LL2, Williams K2, Johnson AJ3, Lehman AM4, Byrd JC2, Woyach JA2, Lapalombella R5.
1Medical Scientist Training Program, The Ohio State University, Columbus, OH, United States;
2Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States;
3Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, United States;
4Center for Biostatistics, The Ohio State University, Columbus, OH, United States.
5Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States; rosa.lapalombella@osumc.edu.
Despite the therapeutic efficacy of ibrutinib in CLL, complete responses are infrequent and acquired resistance to BTK inhibition is being observed an increasing number of patients1,2. Combination regimens that increase frequency of complete remissions, accelerate time to remission, and overcome single agent resistance are of considerable interest. We have previously shown that the XPO1 inhibitor selinexor is pro-apoptotic in CLL cells and disrupts BCR signaling via BTK depletion. Herein we show the combination of selinexor and ibrutinib elicits a synergistic cytotoxic effect in primary CLL cells. The combination increases overall survival compared to ibrutinib alone in a mouse model of CLL. Selinexor is effective in cells isolated from patients with prolonged lymphocytosis following ibrutinib therapy. Finally, selinexor is effective in ibrutinib-refractory mice and in a cell line harboring the BTK C481S mutation. This is the first report describing the combined activity of ibrutinib and selinexor in CLL, which represents a new treatment paradigm and warrants further evaluation in clinical trials of CLL patients including those with acquired ibrutinib resistance. |
