Both the BTK inhibitor ibrutinib and the BCL-2 antagonist venetoclax have impressive efficacy in patients with B cell malignancies. Now, results of the phase II AIM study in patients with mantle-cell lymphoma (MCL) show that these agents can be combined safely to enhance clinical responses.

This historically controlled trial included 23 patients with relapsed and/or refractory MCL and one with untreated disease, 75% of whom had a high-risk prognostic score. Ibrutinib monotherapy was commenced at 560 mg daily, with venetoclax added after 4 weeks followed by weekly dose escalation to 400 mg daily, in order to avoid tumour-lysis syndrome (TLS). The primary end point was the complete remission (CR) rate after 16 weeks of treatment.

“True to preclinical models, ibrutinib and venetoclax seem to be synergistic in the clinic with a final CR rate of 71% and >80% of patients in CR achieving minimal residual disease negativity,” states lead investigator Constantine Tam, emphasizing that “these results are significantly better than those of either drug alone.” Indeed, the CR rate at week 16 was already 42%, double that observed previously with long-term continuous use of either agent alone (21%). In the historical control group from the phase II PCYC-1104-CA study, the CR rate to ibrutinib monotherapy at 16 weeks was 9% (P < 0.001). Importantly, 78% of responses to the combination therapy were ongoing at 15 months. Common adverse events were generally of a low grade, and included diarrhoea, fatigue, and nausea or vomiting; although, TLS occurred in two patients (8%).

“This study sets a new platform of combination targeted therapies for MCL and related diseases, including chronic lymphocytic leukaemia (CLL); multiple large phase II and III confirmatory studies of this combination are now underway in MCL and CLL,” Tam explains. “Ultimately, this combination could provide an effective chemotherapy-free treatment of limited duration, rather than the current standard of indefinite single-agent targeted therapy.”