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Preclinical observations that killing of chronic lymphocytic leukemia (CLL) cells was dexamethasone (DEX) were enhanced by concomitant inhibition of Bruton’s tyrosine kinase and janus kinases (JAKs) motivated a phase II trial to determine if clinical responses to ibrutinib could be deepened by DEX and the JAK inhibitor ruxolitinib. Patients on ibrutinib at 420 mg daily for 2 months or with abnormal serum β2M levels after 6 months or with persistent lymphadenopathy or splenomegaly after 12 months were randomized to receive DEX 40 mg on days 1–4 of a 4‐week cycle for six cycles alone (three patients) or with ruxolitinib 15 mg BID on days 1–21 of each cycle (five patients). Ruxolitinib dosing was based on a previous phase I trial. Steroid withdrawal symptoms and significantly decreased serum IgG levels occurred in all patients regardless of their exposure to ruxolitinib. A fatal invasive fungal infection was seen in a patient taking DEX without ruxolitinib. Complete responses anticipated with addition of ruxolitinib were not seen. Gene expression studies suggested ruxolitinib had turned off interferon signaling in CLL cells and turned on genes associated with the activation of NFκB by TNF‐α. Ruxolitinib increased blood levels of TNF‐α by cycle 3 and decreased the inhibitory cytokine IL‐10. These results suggest ruxolitinib releases activating signals for CLL cells that persist in patients on ibrutinib. This inhibitory JAK signaling may contribute to the therapeutic activity of ibrutinib. Thus JAK inhibitors provide no added value with ibrutinib for disease control and should be used with caution in CLL patients. Combining glucocorticoids with ibrutinib may increase the risk of serious infects., Ibrutinib with ruxolitinib and dexamethasone is generally well‐tolerated but provides no benefits over ibrutinib alone. Ruxolitinib blocks inhibitory signals that suppress CLL cells in patients on ibrutinib.

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.

Glucorticoids (GCs) such as dexamethasone (DEX) remain important treatments for Chronic Lymphocytic Leukemia (CLL) but the mechanisms are poorly understood and resistance is inevitable. Proliferation centers (PC) in lymph nodes and bone marrow offer protection against many cytotoxic drugs and circulating CLL cells were found to acquire resistance to DEX-mediated killing in conditions encountered in PCs including stimulation by toll-like receptor agonists and interactions with stromal cells. The resistant state was associated with impaired glucocorticoid receptor-mediated gene expression, autocrine activation of STAT3 through Janus Kinases (JAKs), and increased glycolysis. The JAK1/2 inhibitor ruxolitinib blocked STAT3-phosphorylation and partially improved DEX-mediated killing of stimulated CLL cells in vitro but not in CLL patients in vivo. An automated microscopy-based screen of a kinase inhibitor library implicated an additional protective role for the PI3K/AKT/FOXO pathway. Blocking this pathway with the glycolysis inhibitor 2-deoxyglucose (2-DG) or the PI3K-inhibitors idelalisib and buparlisib increased DEX-mediated killing but did not block STAT3-phosphorylation. Combining idelalisib or buparlisib with ruxolitinib greatly increased killing by DEX. These observations suggest that glucocorticoid resistance in CLL cells may be overcome by combining JAK and PI3K inhibitors.

B cell receptor (BCR)-signaling inhibitors such as Ibrutinib and Idelalisib do not cure CLL, suggesting the importance of other pathways.1 Cytokines are also important in CLL biology and mediate transcription of oncogenic genes such as miR-17 by activating signal transducer and activator of transcription (STAT) proteins including STAT5A/B and STAT3 through Janus kinases (JAKs).2–4 We hypothesized that Ruxolitinib, a selective JAK1/2 inhibitor licensed for myelofibrosis,5 might have unrecognized activity in CLL and designed a single center phase II trial to evaluate it in patients considered unfit for FCR on the basis of age and comorbidities.6 The demonstrated safety of Ruxolitinib in myelofibrosis was felt to make it ethical to use as first-line therapy for elderly CLL patients. The primary endpoint was overall response rate (ORR) assessed after 7 treatment cycles.7 Secondary endpoints were safety and tolerability.7 The study was approved by the Sunnybrook REB and Health Canada and registered with ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT02015208","term_id":"NCT02015208"}}NCT02015208.