Emerging Treatments for Chronic Lymphocytic Leukemia

The selective BCL2 inhibitor venetoclax (ABT-199) has demonstrated significant results as both a single agent and in combination with rituximab (Rituxan) for patients with relapsed or refractory chronic lymphocytic leukemia, says Javier Pinilla-Ibarz, MD, PhD. Venetoclax is potent, with high efficacy in clearing disease from blood and bone marrow, notes Jennifer Brown, MD, PhD.

The primary side effect for venetoclax is tumor lysis syndrome, which must be carefully managed in the first 4 to 6 weeks of administration. The agent is relatively well tolerated once patients have achieved their target dose, says Brown. Its use is being explored in phase II and phase III studies in the relapsed/refractory setting and offers potential for patients who have experienced progression on a B-cell receptor inhibitor and require further therapies, comments Pinilla-Ibarz.

Duvelisib is a phosphoinositide-3 (PI3)-kinase delta inhibitor that differs from the current FDA-approved PI3-kinase inhibitor idelalisib (Zydelig) in that duvelisib also inhibits the gamma isoform of PI3 kinase. This could potentially affect T-cells and myeloid cells, explains Brown, which may result in improved efficacy, but also increased immune dysfunction.

Ublituximab (TG-1101) is a novel monoclonal antibody that targets CD20 and has similar features to those of ofatumumab (Arzerra) and obinutuzumab (Gazyva). However, ublituximab has higher affinity for Fc receptor binding. This may confer superior antibody dependent cell-mediated cytotoxicity (ADCC) than currently available anti-CD20 monoclonal antibodies, says Pinilla-Ibarz.

Other CLL treatment strategies in development include chimeric antigen receptor (CAR) T cell therapies and monoclonal antibodies against checkpoint inhibitors, such as PD-1 and PD-L1, says William Wierda, MD, PhD. CAR T cells may have a role in consolidation therapy for patients on B-cell receptor pathway inhibitors, particularly those with high-risk disease, states Brown.

Other challenges in CLL management include addressing secondary cancers, states Wierda, noting that patients with CLL have a higher incidence of developing a secondary malignancy and have shorter survival outcomes than their age-matched population.