BTK, BCL2 Inhibitor Combination Improves Outcomes in Patients With MCL

Dual targeting of BTK and BCL2 may improve outcomes in patients with mantle cell lymphoma (MCL) and a poor prognosis, according to a study published in The New England Journal of Medicine (online march 29, 2018; doi:10.1056/NEJMoa1715519).

Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax have shown activity in the treatment of MCL. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. 

Constantine S Tam, MB, BS, MD, Peter MacCallum Cancer Center (Australia), and colleagues investigated ibrutinib and venetoclax in combination for the treatment of patients with MCL.

Researchers conducted a single-group, phase II study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in at a weekly increasing dose to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events.

The primary endpoint of the study was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide–polymerase chain reaction (ASO-PCR) in blood.

The study enrolled 24 patients with relapsed or refractory MCL (n = 23) or previously untreated MCL (n = 1). Patients were aged 47 to 81 years, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score.

Dr Tam and colleagues noted the complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed PET was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months.

Common side effects were generally low grade and included diarrhea (83%), fatigue (75%), and nausea or vomiting (71%), researchers noted.

“Dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with MCL who had been predicted to have poor outcomes with current therapy,” authors concluded.—Janelle Bradley