Ruxolitinib in the Treatment of Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the commonest leukemia in adults and, until recently, had limited treatment options. However, the combination of fludarabine, cyclophosphamide, and rituximab (FCR) produces impressive clinical responses and prolongs survival of many CLL patients with symptomatic disease. Unfortunately, FCR is a toxic regimen that cannot generally be tolerated by patients over the age of 65 years who constitute more than 70% of the CLL patient population. In addition, FCR is contraindicated in patients whose leukemia cells harbor deletions of chromosome 17, where the tumor suppressor p53 is located, because such cells are intrinsically resistant to genotoxic drugs. This group constitutes 10-15% of patients of all ages who require first-line therapy. Better therapies for these two large groups of patients are needed.

The initiating event in CLL is thought to be genetic damage to a class of B lymphocytes that prevents proper functioning of apoptotic pathways. However, disease progression is driven by signals from the proliferation centers in tumor microenvironments where circulating CLL cells originate. Signals that cause CLL cells to proliferate include antigens that activate B-cell receptors (BCRs), Toll-like receptor ligands, chemokines, and cytokines. CLL cells that respond strongly to these microenvironmental signals exhibit more aggressive clinical behavior and resistance to cytotoxic drugs. These observations have motivated the use of signal transduction inhibitors to treat CLL and initial results of targeting kinases in the BCR-signaling cascade, such as Bruton's Tyrosine Kinase (BTK), suggest this strategy is effective and likely to change the treatment paradigm for CLL.

BCR signaling is not the only driver of CLL proliferation in vivo. Cytokines and chemokines in the tumor microenvironment activate Janus Kinases (JAKs) and mediate many of the pathological features of CLL cells. Cytokine signaling pathways have been shown to be rewired in aggressive tumor cells to support rapid growth and will eventually overcome the effects of inhibiting BCR-signaling. Preclinical findings suggest that JAK inhibitors will also have a place in the treatment of CLL.

Based on this strong theoretical rationale and pre-clinical evidence, along with its known toxicity profile, Ruxolitinib is expected to have significant activity with limited toxicity as a single agent in CLL. This trial is designed to investigate the efficacy and toxicity of Ruxolitinib in patients who are otherwise unfit for first-line therapy with FCR.