Persistent janus kinase‐signaling in chronic lymphocytic leukemia patients on ibrutinib: Results of a phase I trial

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.

Effect of Ibrutinib on the IFN Response of Chronic Lymphocytic Leukemia Cells

“…IFN-a2, IFN-g, IL-18, CXCL10, CCL3, and TNF-a were measured as before by Eve Technologies (Calgary, AB, Canada) using Multiplexing LASER Bead Technology (3,22). Concentrations were determined from standard curves.…”

“…In a prior phase 1 trial, the JAK inhibitor ruxolitinib was added to 12 patients on ibrutinib for 3 out of 5 wk and repeated seven times in an attempt to deepen clinical responses (3). Ruxolitinib blocks signaling through IFNAR and IFNGR along with many other cytokine receptors (3,7,26).…”

“…An aberrant cytokine and chemokine network is associated with symptomatic CLL (3,4). These cytokines include IL-4, IL-6, type I and II IFNs, and others that activate JAKs and promote the growth and survival of CLL cells (3)(4)(5)(6)(7)(8)(9)(10). Ibrutinib normalizes the levels of many of these cytokines (11), which may contribute to its therapeutic activity.…”

<p>Ibrutinib in Chronic Lymphocytic Leukemia: Clinical Applications, Drug Resistance, and Prospects</p>

“…87 Therefore, the combination of a JAK inhibitor and ibrutinib can restore the sensitivity of CLL cells to apoptosis, thus rendering a promising alternative treatment for patients with IR. 97 Spaner et al explored the efficacy of the JAK1/2 inhibitor ruxolitinib plus ibrutinib in 12 patients with CLL who did not achieve remission after treatment with ibrutinib, including splenomegaly or persistent lymphadenopathy after 12 months or abnormally elevated serum β-2 microglobulin (β2-MG) levels following 6 months of ibrutinib therapy. 75 Two of the patients achieved PR, and six had diminution of splenomegaly and residual lymphadenopathy; the level of β2-MG decreased during each treatment cycle but was recovered after 2 weeks of interruption of ruxolitinib therapy.…”

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

“…A pilot study in 2019 suggested the possible role of ruxolitinib in the treatment of Hodgkin’s disease (HD) [ 26 , 27 ]. The effects of ruxolitinib in association with ibrutinib (an FDA approved Bruton’s tyrosine kinase (BTK) inhibitor) against chronic lymphocytic leukemia (CLL) were investigated in a phase 1 study and encouraging results were obtained [ 28 ]. In 2014, ruxolitinib was further approved for the treatment of polycythemia vera (PV) [ 29 ].…”