Optimizing Treatment With Ibrutinib in High-Risk CLL

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Historically, there has not been an effective therapy for patients with chronic lymphocytic leukemia (CLL) whose tumors harbor a 17p deletion (del 17p), a group that only represents about 5% to 10% of patients at the time of initial treatment, explains John C. Byrd, MD. However, in 2014, the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib received FDA approval as initial therapy for CLL patients with del 17p and for patients with CLL who have failed at least one prior treatment.

In the phase III RESONATE study, treatment with ibrutinib lowered the risk of progression by 75% in patients with CLL who harbored a 17p deletion and by 78% in the full population of the study when compared with ofatumumab. At 6 months, 88% of patients treated with ibrutinib were progression-free compared with 65% in the ofatumumab group.

A phase II study is showing extended progression-free survival in the majority of patients with relapsed CLL being treated with ibrutinib, Byrd notes. However, as an upfront therapy it may be too soon to use ibrutinib beyond the del 17p group because iburitinib is an immunologically modulating drug that can negatively affect the immune system when moved up earlier in therapy, Byrd suggests.

There are currently phase III studies being conducted to assess the toxicity of ibrutinib as it is tested in the upfront setting. Richard Furman, MD, describes patients’ continued response over time as one of the benefits of ibrutinib. In many situtatoins, complete responses (CRs) and minimal residual disease (MRD)-negative CRs are being maintained for up to 5 years.

Furman also states that researchers must aim to determine whether it is safe to stop ibrutinib therapy in patients once a response is reached. Randomized discontinuation studies are now looking at whether stopping treatment in a patient who is MRD-negative will put them at risk for disease reoccurrence or may breed resistance to iburtinib. Other questions to ask relate to the timing of discontinuation. Should ibrutinib be stopped: 1) At a response plateau? 2) When toxicity becomes intolerable? 3) When a patient progresses? At this time, many of these questions remain unanswered.