Dual Targeting of BTK and BCL2 in Mantle-Cell Lymphoma

Phase II study of daily oral ibrutinib plus venetoclax combination therapy

Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma (MCL). A single-group, phase II study of daily oral ibrutinib plus venetoclax involving historical controls, showed that a dual targeting of BTK and BCL2 was consistent with improved outcomes in patients with MCL who had been predicted to have poor outcomes with current therapy. The results are published on 29 March 2018 in the NEJM.

Dr. Constantine S. Tam of the Department of Haematology, Peter MacCallum Cancer Centre, Melbourne and colleagues who conducted the NCT02471391 study, wrote in the background that complete response (CR) rates of 21% have been observed for each ibrutinib or venetoclax when administered as long-term continuous therapy. Preclinical models predict synergy in combination of these two agents.

It prompted the study investigators to conduct the single-group, phase II study of ibrutinib and venetoclax combination therapy as compared with historical controls. The patients included in the study commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events.

The study primary endpoint was the CR rate 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 included 24 patients with relapsed or refractory MCL (23 patients) or previously untreated disease (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half of the patients had aberrations of TP53, and 75% had a high-risk prognostic score.

The CR 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 CR rate as assessed by positron-emission tomography was 62% at week 16 and 71% overall. The 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.

The tumour lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhoea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%).

Senior authors of the paper are Drs. John F. Seymour and Andrew W. Roberts who contributed equally to the article. The study team included the researchers from the Peter MacCallum Cancer Centre, Melbourne, the Victorian Comprehensive Cancer Centre, the Faculty of Medicine and Centre for Cancer Research of the University of Melbourne, the Department of Clinical Haematology and Bone Marrow Transplantation, the Royal Melbourne Hospital, and the Division of Cancer and Haematology, Walter and Eliza Hall Institute of Medical Research, Parkville, all in Australia, and the University Hospital of Schleswig–Holstein, Kiel and Klinikum der Universität, Ludwig–Maximilian University of Munich, Munich, both in Germany.

The study was funded/supported by Janssen, AbbVie, the Victorian Cancer Agency, the Leukemia and Lymphoma Society, and the Peter MacCallum Foundation and by fellowship support from the University of Melbourne (to Dr. Tam), the CLL Global Research Foundation (to Dr. Tam), the Snowdome Foundation (to Dr. Anderson), the Haematology Society of Australia and New Zealand (to Dr. Agarwal), the National Health and Medical Research Council of Australia (to Drs. Agarwal and Roberts), the National Breast Cancer Foundation (to Dr. S.-J. Dawson), the Victorian Cancer Agency (to Dr. S.-J. Dawson), Leukemia Foundation Australia (to Dr. M.A. Dawson), and the Howard Hughes Medical Institute (to Dr. M.A. Dawson). 

Reference

Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. N Engl J Med 2018; 378:1211-1223. DOI: 10.1056/NEJMoa1715519