Treatment of Relapsed and Refractory Chronic Lymphocytic Leukemia

Abstract

The management of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) has undergone significant changes during the last decade. As with first-line treatment, the treatment choice of relapsed CLL patients is dependent on several factors, including age, performance status, comorbidities, and duration of response to previous therapy. The outcome of second, and subsequent, lines of therapy is markedly improved by the addition of CD20-antibodies to established chemotherapeutic regimen, inhibitors of B-cell receptor (BCR), or B-cell lymphoma 2 (BCL-2) antagonists. Large randomized trials have confirmed that chemoimmunotherapy with fludarabine and cyclophosphamide (FC) with rituximab (FCR) or ofatumumab (OFC) in fit relapsed/refractory patients is more effective than FC alone. Bendamustine and a bendamustine/rituximab combination have also shown high efficacy in patients with relapsed/refractory CLL, who have received prior therapy with other alkylating agents or purine analogs. Patients with the presence of del(17p) and/or TP53 mutations should be treated with the BCR signaling inhibitors, ibrutinib or idelalisib. Other patients poorly responding to chemoimmunotherapy in previous lines also require treatment with BCR inhibitors. Patients who do not respond to BCR inhibitors, or do not tolerate them, are candidates for the BCL-2 antagonist venetoclax or other investigational drugs currently in clinical trials. Physically fit patients with refractory CLL or with a del(17p) should be considered for allogeneic hematopoietic stem cell transplantation. Participation in clinical trials of novel agents should be strongly recommended for all refractory patients.