Emerging Strategies in CLL and Follicular Lymphoma

Individuals treated with ibrutinib for chronic lymphocytic leukemia (CLL) who develop relapse tend to have high-risk disease, such as that with 17p deletion or complex cytogenetics, explains Jennifer Brown, MD. Approximately half of these individuals relapse with Richter’s transformation, while the other half have progressive CLL. The optimal salvage therapy after ibrutinib remains unknown, comments Brown.

Combination data with ibrutinib is relatively limited, notes Brown. A combination study with rituximab has been reported from MD Anderson, where patients fared well and showed high response rates, but the progression-free survival was not that different from what is expected from single-agent ibrutinib. Ongoing randomized clinical trials are assessing whether ibrutinib with rituximab is superior to ibrutinib alone in terms of progression-free survival. In the phase III HELIOS trial, combining ibrutinib with standard bendamustine and rituximab lowered the risk of disease progression by 80% in patients with relapsed/refractory CLL and small lymphocytic lymphoma (SLL).Venetoclax, or ABT-199, binds to the BCL-2 protein, inducing apoptosis in CLL cells, states Richard Furman, MD. The rapidity and depth of response with venetoclax differ from those seen with ibrutinib and idelalisib. Patients receiving ibrutinib and idelalisib initially achieve either stable disease or a partial response with lymphocytosis, which evolves slowly over time and may take 2 to 3 years for patients to reach a complete response. Venetoclax rapidly induces deep responses, with patients responding almost immediately. Minimum residual disease (MRD) negativity is often achieved very early on, says Furman.

Venetoclax may cause tumor lysis syndrome, which has been associated with 2 deaths in early studies. An important matter to consider moving forward is how to optimally use these agents, says Furman. It may be beneficial to adopt a treatment strategy where patients are treated ahead of time with obinutuzumab, ibrutinib, or idelalisib, allowing disease burden to lessen, and then administering venetoclax to eliminate residual disease.

Goals of therapy for individuals with follicular lymphoma include maintaining long-term outcomes, states Furman. This goal requires effective and well-tolerated medications that will not induce long-term toxicities or damage to the bone marrow. Bendamustine and rituximab have been shown to be superior to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with previously untreated follicular lymphoma. Studies have shown equivalent response rates but improved progression-free survival and reduction in toxicities, such as alopecia, in individuals receiving bendamustine and rituximab.