Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial: Beyond the Abstract

 It is well known that disease-related symptoms significantly impact the quality of life of patients with chronic lymphocytic leukemia (CLL).1 Yet, adequate control of CLL patients’ symptoms has not been a major focus of clinical investigation. According to iwCLL treatment guidelines2, severe disease-related symptoms are an indicator for systemic therapy, whereas management of disease-related symptoms that are not “severe” has not been addressed. In the current routine clinical practice, most patients with symptomatic CLL are treated with supportive care measures that provide minimal clinical benefits. 

Disease-associated symptoms such as fatigue, low-grade fever, night sweats, and weight loss have been associated with elevated levels of circulating inflammatory cytokines and chemokines.3 Therefore, we presumed that like in other diseases, symptomatic CLL patients might benefit from drugs which block cytokine/chemokine signaling pathways. For example, in patients with myelofibrosis, a disease in which cytokine levels correlate with disease associated symptoms4, inhibition of the Janus kinase (JAK) signaling pathway significantly improves patients’ disease-related symptoms and quality of life.5 

We had previously reported that stimulation of the B cell receptor (BCR) activates JAK2 in CLL cells and that the JAK1/2 inhibitor ruxolitinib blocks the JAK2 signaling pathway and induces apoptosis of CLL cells.6 Because like in myelofibrosis, chronic activation of JAK2 results in over-production of a variety of cytokines and chemokines, we sought to determine whether ruxolitinib would reduce cytokine/chemokine levels and improve CLL patients’ symptoms. In the current study7 we evaluated the effect of ruxolitinib on CLL patients’ disease-related symptoms and assessed the correlation between symptom score changes and patients’ plasma cytokine/chemokine levels. Symptom questionnaires utilized in this study included the brief fatigue inventory (BFI), the CLL module of the MD Anderson symptom inventory (MDASI), and the symptom interference scale (IS) of the MDASI. Plasma cytokine/chemokine levels were analyzed in all participants, and a linear regression analysis was performed to estimate the association between changes in plasma cytokine/chemokine levels and percentage change in symptom scores at 3 months. Our data7 showed that ruxolitinib significantly improved fatigue and other disease related symptoms in patients with CLL not requiring systemic therapy, and that the ruxolitinib-induced decrease in symptom burden significantly correlated with a reduction in inflammatory cytokines and chemokines levels, suggesting that excessive activation of the JAK2 pathway induces disease related symptoms. Furthermore, our results also suggests that ruxolitinib induces a therapeutic effect as we observed lymph node shrinkage and a corresponding increase in peripheral blood lymphocyte counts, similar to the effect BCR inhibitors exert in patients with CLL.8 

Overall, our data suggest that ruxolitinib reduces inflammatory cytokine/chemokine levels and significantly improves the symptoms and quality of life of patients with CLL. Additional studies aimed at evaluating the effects of ruxolitinib on patients’ symptoms and disease burden are warranted. 


Written by: Preetesh Jain and Zeev Estrov
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas


References:
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2. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.

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4. Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol. 2011;29(10):1356-1363.

5. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.

6. Rozovski U, Harris DM, Li P, et al. Stimulation of the B-Cell Receptor (BCR) Induces Successive Activation of STAT3 and Nuclear Factor-Kappa-B in CLL Cells. Blood. 2015;126(23):4125-4125.

7. Jain P, Keating M, Renner S, et al. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol. 2017.

8. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.