Clinical Trials With BTK Inhibitors in Chronic Lymphocytic Leukemia

Jennifer Brown, MD, PhD: The history of trials of BTK [Bruton tyrosine kinase] inhibitors in the frontline setting started with a 30-patient cohort that was added onto the phase 1B/2 study, which now has 8-year follow-up. The progression-free survival in those 30 patients is over 80%, which is quite remarkable, although those patients were also pretty low-risk.

The other message that I note from that study is that only half of them are still on ibrutinib. They fell off for various toxicities even though their disease has not progressed. That raises the possibility about how long patients can stay on ibrutinib: 5 years may be about the median, but they can still have a sustained remission even after discontinuation.

That was followed up reasonably well by the RESONATE-2 confirmatory frontline registration trial, which compared ibrutinib with single-agent chlorambucil. In 5-year follow-up, the progression-free survival for the ibrutinib arm is 70%. Again, 41% of patients have discontinued, but many are still in remission. It is perhaps similar in a way to what we saw in the earlier PCYC-1102 phase 1 study.

The Alliance trial has shorter follow-up, but this was the first randomized trial that compared a standard chemoimmunotherapy. This was in an older-patient population, over 65 years of age, and it compared ibrutinib with ibrutinib-rituximab with bendamustine-rituximab. It showed an improved progression-free survival for either of the ibrutinib arms compared with bendamustine-rituximab. At 2 years, that progression-free survival is about 88% in the ibrutinib arms. 

Interestingly, the benefit was almost entirely in the patients without IGHV mutation. There was not a significant difference in the patients with IGHV mutations. That has a 2- to 3-year follow-up. There was also no difference in overall survival in the entire study. Another point from that study is that there was no benefit to adding rituximab for ibrutinib. Most of us just use single-agent ibrutinib in the frontline setting.

Stephan Stilgenbauer, MD: Ibrutinib has revolutionized CLL [chronic lymphocytic leukemia] treatments. It has been a first-in-class drug targeting BTK, a critical survival molecule in the CLL cells. Targeting this biology led to good tolerability and high efficacy of the treatment. Nevertheless, compared with classical chemotherapy, we have to adjust our modalities to some new adverse effects that we have not known before. A specific feature of ibrutinib treatment, for instance, is early onset, usually relatively mild diarrhea that goes away with longer treatments. 

There are other adverse effects, cardiovascular disease in particular, such as arrhythmias and atrial fibrillation that require particular management. Over time, patients may suffer from arthralgia, and they may suffer from an increased rate of hypertension. All these adverse effects accumulate over time because ibrutinib is obviously a treatment of indefinite treatment duration; it is not a fixed duration of treatment. Management of the adverse effects of ibrutinib treatment is important because it is critical for treatment adherence and long-term treatment with ibrutinib. Staying on that treatment in the longer run is critical for a good outcomes for the patient.

Transcript edited for clarity.