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

Abstract

Summary Background Disease-related symptoms impair the quality of life of countless patients with chronic lymphocytic leukemia (CLL) who do not require systemic therapy. Currently available therapies are not specifically aimed at symptom control. Because stimulation of the B-cell receptor activates Janus kinase (JAK)-2 in CLL cells and the JAK2 inhibitor ruxolitinib improves symptoms of patients with myelofibrosis, we hypothesized that ruxolitinib would improve disease-related symptoms in CLL patients. Methods Ruxolitinib (10 mg twice daily) was administered to symptomatic CLL patients who did not require systemic therapy for CLL. Scores on the brief fatigue inventory (BFI), CLL module of the MD Anderson symptom inventory (MDASI) and symptom-associated interference in daily activities (interference score; IS), were assessed prior to treatment and after 3 months of treatment. Plasma cytokine/chemokine levels were measured at baseline and at 3 months. Findings Forty-one CLL patients (25 untreated and 16 previously treated) were enrolled. Thirty-two (78%) of the participants experienced ≥20% reduction in the average BFI score or in the average MDASI score. 59% of the participants had ≥2 units reduction in worst fatigue score in 24 hours as assessed by the BFI. The mean percentage reductions in BFI, MDASI, and IS scores were >42% (p<0.0001). Improvements in the three symptom scores correlated with reductions in levels of IL-6, C-reactive protein, CXCL10, osteopontin, TNF-α, ICAM-1/CD54, VCAM-1/CD106, and beta-2 microglobulin. Furthermore, treatment with ruxolitinib increased and then decreased lymphocyte counts to baseline levels or lower. Grade 3/4 cytopenias were recorded in three patients. Interpretation In CLL patients, ruxolitinib significantly improved disease-related symptoms, reduced cytokine and chemokine levels, and increased and then decreased lymphocyte counts, likely through mobilization followed by apoptosis of CLL cells. Further studies aimed at testing the therapeutic efficacy of ruxolitinib in CLL are warranted. Funding Supported by the Incyte Corp., MD Anderson Cancer Center Support Grant CA016672 and Award Number P01 CA049639 from the National Cancer Institute.

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

“…While the first trial reported a decrease of lymph node size in almost 50% of patients, the study was stopped early due to a high incidence of severe anemia [47]. The second trial showed that ruxolitinib significantly improved disease-related symptoms, decreased serum cytokines, and caused leukemic cell mobilization from lymphoid organs [48]. These trials provide preliminary observation of the positive effect of JAK2/STAT3 targeting in CLL, either alone or in combination with BTK inhibitors.…”

Development and validation of a clinically applicable score to classify cachexia stages in advanced cancer patients

“…Anderson symptom inventory (MDASI) and the Functional Assessment of Anorexia Cachexia Therapy (FAACT) scale, to assess their symptom burden and quality of life. The MDASI has been validated and is a frequently used questionnaire for assessing symptom . We used the MDASI to assess the symptom burden of our patients.…”

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

“…Here it could be shown that anti-IgM mediated BCR stimulation induces STAT3 activation signaling in CLL (42). In a clinical trial inhibition of JAK2 by ruxolitinib decreases symptoms (43), however therapeutic impact regarding relevant endpoints such as PFS and OS remains to be clarified. Finally, Kondo et al could show that ibrutinib treatment of CLL cells also inhibits STAT3 phosphorylation and described suppression of IL10 and PD-L1 in ibrutinib treated CLL patient cells (44).…”