Editors' ChoiceCancer

Fighting leukemia with “duel”-targeted therapy

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Science Translational Medicine  04 Apr 2018:
Vol. 10, Issue 435, eaat3887
DOI: 10.1126/scitranslmed.aat3887

Abstract

Combining BCL-2 inhibitor venetoclax with monoclonal CD20 antibody rituximab greatly enhances progression-free survival compared with bendamustine-rituximab in a phase 3 trial of relapsed or refractory chronic lymphocytic leukemia patients.

In 1985, Tsujimoto and colleagues were studying a chromosomal swapping or translocation present in blood cancer (pre–B cell leukemia and follicular lymphoma). They discovered a new gene that they called B cell leukemia/lymphoma 2 (BCL2). Little did they know that this landmark discovery would pave the way for over thirty years of research into understanding how cells die and how cancer cells avoid cell death, and to the realization of therapeutically targeting the antiapoptotic protein BCL-2 in cancer patients.

Chronic lymphocytic leukemia (CLL) is a clonal expansion of immune cells in the body, generally of the B cell variety, and relies on BCL-2 for survival. Through clever design, AbbVie developed the BCL-2 selective inhibitor venetoclax (ABT-199/GCD-0019). But like many things in life—two is better than one! While venetoclax demonstrates single agent activity in several cancers, the true clinical utility of this drug may lie in the ability to combine it with other targeted agents. Seymour et. al. assessed combining venetoclax with rituximab, a monoclonal antibody to CD20, a protein on the surface of B cells. They tested this dual combination treatment in a phase 3, open-label, randomized clinical trial in 389 patients with relapsed or refractory CLL. Remarkably, the venetoclax-rituximab combination caused improved progression-free survival (84.9%) compared with bendamustine (an alkylating agent) and rituximab combination (36.3%). Two years post-treatment, there was already evidence of improved overall survival with the dual venetoclax-rituximab combination, albeit not as striking a result.

A potential caveat of this study is that patients had received prior treatment, often with an alkylating agent, so this may have set the bar a bit high for the bendamustine-rituximab arm due to preexisting resistant cells. The dual targeted combination was well tolerated by the patients, although with the expected on-target neutropenia side effect. Previous clinical trials with venetoclax have shown an increase in tumor lysis syndrome, which is caused by too many cancer cells dying simultaneously. This was somewhat circumvented in this trial (5.2% patients) by starting with a low dose of venetoclax and slowly increasing it before adding the rituximab. All in all, this study highlights that the true potential of venetoclax is in combination with other targeted agents, and it will be interesting to see if this improved patient survival is evident in other forms of leukemia and solid tumors.

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