Management of Patients With Relapsed Chronic Lymphocytic Leukemia

The management of chronic lymphocytic leukemia (CLL) has improved significantly over the last decade with multiple new and well-tolerated therapies now available for the majority of patients. Chemoimmunotherapy, with fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR), has been the mainstay for the treatment of patients with CLL, but their use is complicated by significant morbidity, especially in older and frail patients. The majority of patients relapse within five years of initial chemoimmunotherapy and outcomes are even worse in patients with short initial remission. Remission duration also decreases progressively with subsequent therapies. The advent of novel therapeutics including CD20-targeting antibodies such as obinutuzumab, ofatumumab, and BTK and PI3K inhibitors such as ibrutinib and idelalisib respectively, offers an exciting option for patients with comorbid conditions, previously untreated, relapsed, and high-risk disease. These novel agents are generally well-tolerated, have already demonstrated significant activity in all subsets of patients, and have the potential to replace conventional chemoimmunotherapy. However, resistance issues have been identified with ibrutinib and outcomes are poor for this group of patients. Moreover, specific side effects such as bleeding issues, colitis, pneumonitis, and transaminitis, limit prolonged use with kinase inhibitors in a subset of patients. Newer agents such as acalabrutinib, which targets BTK, and venetoclax, which targets the anti-apoptotic molecule bcl-2, have demonstrated extremely promising activity in early-phase trials. These developments herald an era of unprecedented progress for the management of patients with CLL and are already improving the lives of thousands of people around the world.