For patients experiencing aggressive chronic lymphocytic leukemia (CLL), chemoimmunotherapy often leads to remission, but remission is frequently followed by disease relapse. A new treatment option may soon emerge for these patients: the CLARITY study, a phase 2 clinical trial, has found that the combination of ibrutinib plus venetoclax produces minimal residual disease (MRD)-negative responses in individuals with relapsed and/or refractory CLL, with promising rates of progression-free and overall survival. In this interview with i3 Health, CLARITY's lead researcher, Peter Hillmen, MBChB, PhD, discusses the potential impact of the study's results and the future of treatment for patients with CLL.
Can you comment on the significance of your study's findings concerning the efficacy of ibrutinib plus venetoclax in relapsed/refractory CLL?
Peter Hillmen, MBChB, PhD: The CLARITY study demonstrates the safety and efficacy of the combination of ibrutinib plus venetoclax in relapsed CLL. This is a significant study, as it combines the two most effective targeted therapies in CLL with impressive responses, indicating that they are synergistic. In addition, CLARITY is the first study in CLL to define the duration of therapy by response, ie, using MRD to define the duration of an individual patient's treatment.
How does ibrutinib/venetoclax compare with other options being used to treat relapsed/refractory CLL?
Dr. Hillmen: The combination of ibrutinib plus venetoclax is very effective and enables some patients to stop therapy after the eradication of detectable CLL. It is hoped that this approach will reduce the development of resistant disease and therefore allow patients to be re-treated if required.
What additional research advances are on the horizon for CLL?
Dr. Hillmen: The combination of targeted therapies is now being tested in large phase 3 front-line trials. In this context, combinations such as ibrutinib plus venetoclax as pioneered in CLARITY are expected to result in prolonged remissions and, in a proportion of patients, cure. These will probably signal the end of chemoimmunotherapy in CLL. In addition, further therapies are being developed for patients who fail therapies that target B-cell receptor signaling and apoptosis, such as bispecific antibodies and chimeric antigen receptor (CAR) T cells.
Do you have any words of advice for community oncologists who are treating patients with relapsed/refractory CLL?
Dr. Hillmen: A key decision to make when deciding the most appropriate therapy in a patient with relapsed and/or refractory CLL is, "What is the aim of therapy?" Is it disease control with continued therapy or disease eradication with limited duration of treatment? Both approaches are valid, and the choice between the two depends on patient factors and preference. In patients in whom disease control is considered appropriate, continuous ibrutinib would be the therapy of choice. In patients who prefer a defined duration of therapy, the venetoclax combinations are appropriate.
The leading combinations are venetoclax plus obinutuzumab or venetoclax plus ibrutinib. It is clear, however, that patients who have undetectable MRD can stop therapy with usually durable treatment-free remissions, whereas those who are MRD positive will progress relatively quickly after the cessation of therapy.
About Dr. Hillmen
Peter Hillmen, MBChB, PhD, is the Chair of Experimental Haematology at the Leeds Institute of Medical Research at St James's, Faculty of Medicine and Health, University of Leeds, United Kingdom. In addition, he is an Honorary Consultant Haematologist at Leeds Teaching Hospitals NHS Trust. His research interests include both CLL and paroxysmal nocturnal hemoglobinuria (PNH). The lead researcher of trials for eculizumab, he established the UK National PNH Service. He also serves as Chair of the National Cancer Research Institute Haematological Oncology Group in the United Kingdom, which is responsible for UK clinical trials in hematological malignancies. His current research focuses on maximizing the potential of targeted therapies through analyzing their mechanisms of action.
For More Information
Hillmen P, Rawstron AC, Brock K, et al (2019). Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study. J Clin Oncol. [Epub ahead of print] DOI:10.1200/JCO.19.00894
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily represent those of i3 Health.