Persistent janus kinase-signaling in chronic lymphocytic leukemia patients on ibrutinib: Results of a phase I trial
David E Spaner, Lindsay McCaw, Guizhei Wang, Hubert Tsui, Yonghong Shi, David E Spaner, Lindsay McCaw, Guizhei Wang, Hubert Tsui, Yonghong Shi
Abstract
Methods to deepen clinical responses to ibrutinib are needed to improve outcomes for patients with chronic lymphocytic leukemia (CLL). This study aimed to determine the safety and efficacy of combining a janus kinase (JAK)-inhibitor with ibrutinib because JAK-mediated cytokine-signals support CLL cells and may not be inhibited by ibrutinib. The JAK1/2 inhibitor ruxolitinib was prescribed to 12 CLL patients with abnormal serum beta-2 microglobulin levels after 6 months or persistent lymphadenopathy or splenomegaly after 12 months on ibrutinib using a 3 + 3 phase 1 trial design (NCT02912754). Ibrutinib was continued at 420 mg daily and ruxolitinib was added at 5, 10, 15, or 20 mg BID for 3 weeks out of five for seven cycles. The break was mandated to avoid anemia and thrombocytopenia observed with ruxolitinib as a single agent in CLL. The combination was well-tolerated without dose-limiting toxicities. Cyclic changes in platelets, lymphocytes, and associated chemokines and thrombopoietic factors were observed and partial response criteria were met in 2 of 12 patients. The results suggest that JAK-signaling helps CLL cells persist in the presence of ibrutinib and ruxolitinib with ibrutinib is well-tolerated and may be a useful regiment to use in combination therapies for CLL.
Keywords: chemokines; chronic lymphocytic leukemia; ibrutinib; janus kinases; ruxolitinib; thrombopoiesis.
Conflict of interest statement
D. E. Spaner reports grants from Novartis to support the submitted work and personal fees from Janssen outside the submitted work. The other authors declare no conflicts of interest with respect to this work.
© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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