Role of B-Cell Receptor Signaling Inhibitors in CLL

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Historical treatments for patients with chronic lymphocytic leukemia (CLL) typically involved serial rounds of chemotherapy or chemoimmunotherapy, says Jennifer R. Brown, MD, PhD. Patients were observed initially after diagnosis until they met criteria for treatment, which typically included symptoms, worsening cytopenias, or increasing lymphadenopathy. Often times, patients were then treated with a 6-month course of chemoimmunotherapy, would reach remission, return to a watch-and-wait approach for the duration of remission, and then be retreated with chemoimmunotherapy at the time of relapse. Remissions tend to get shorter with serial rounds of chemoimmunotherapy, notes Brown, and toxicity tends to be greater as is the risk of developing secondary malignancies.

The use of novel agents, such as B-cell receptor signaling inhibitors, becomes sensible in the relapsed setting. However, these agents, primarily ibrutinib and idelalisib, do not result in complete remissions and are unlikely to cure individuals as single agents, Brown says. Combining the novel agents with chemoimmunotherapy or using the novel agents in combination with one another has potential to achieve minimum residual disease (MRD) negativity and complete remissions that might rival what has been seen with FCR (fludarabine, cyclophosphamide, and rituximab) in lower-risk patients with CLL, states Brown.

For younger, fit patients, FCR has been shown to be highly effective, particularly in patients with immunoglobulin heavy chain mutations. For older patients, using novel agents may be preferred because traditional chemoimmunotherapy is often harder to deliver. These patients may be more prone to toxicities, such as developing cytopenias, and weakening the FCR dose was not found to be curative, Brown notes.

For a frailer patient, side effects should be considered. Ibrutinib may cause cardiac toxicity, particularly atrial fibrillation, and is contraindicated with anticoagulation. These are features that become important in an older population, many of whom require anticoagulation or have preexisting atrial fibrillation. Adverse events with idelalisib include immune-mediated events, such as rash, transaminitis, immune-mediated colitis, and drug-related pneumonitis. The side effects associated with idelalisib appear to be increased in the first-line setting relative to later-line settings.