Dr Stilgenbauer explains the ELEVATE-TN and ASCEND clinical trials; Dr Brown highlights the adverse effects seen with acalabrutinib.
Stephan Stilgenbauer, MD: In the treatment-naïve setting, we have the ELEVATE-TN trial. This was a randomized trial comparing in the standard arm chlorambucil plus obinutuzumab vs 2 experimental arms, namely acalabrutinib monotherapy, and acalabrutinib combined with obinutuzumab. It was a 3-arm randomized trial, designed for patients who are elderly or who have comorbidities and are therefore not amenable to intensive chemoimmunotherapy treatments. It was a frontline trial in a 3-arm randomized design.
The outcome of the trial showed that both acalabrutinib arms were dramatically superior with regard to progression-free survival compared to the chlorambucil-based treatment. Although the trial was not powered to detect the difference, the addition of obinutuzumab to acalabrutinib led to a numerical improvement in progression-free survival, even. On the other hand, the addition of obinutuzumab also increased some of the [adverse] effects, particularly neutropenia, for instance, but there were also some infections in that trial.
Overall, the outcome of that trial is that, compared to classical chemotherapy with chlorambucil-based treatment, acalabrutinib-based treatment leads to increased efficacy with regard to progression-free survival. It had good overall survival data as well, and it was proven to be a well-tolerated treatment. With regard to longer-term treatment tolerability, we have an update of the initial single-arm experience with acalabrutinib in treatment-naïve patients. There, we have outcome data now available with an almost 4-year follow-up time, and this not only showed that the efficacy is durable, but with regard to longer-term follow-up, the tolerability of treatment is good as well.
In the relapsed/refractory setting of CLL [chronic lymphocytic leukemia] treatment focusing on acalabrutinib, we have the ASCEND trial. This was an interesting trial because it compared salvage treatment of patients with relapsed/refractory CLL with acalabrutinib against an investigator’s choice arm in a randomized fashion. Investigator’s choice was of 2 different treatment options: namely either bendamustine plus rituximab, or idelalisib plus rituximab. For the vast majority of patients, about three-fourths of all patients, in that arm, the treatment chosen was idelalisib plus rituximab. For the first time, we have a head-to-head comparison of 2 novel nonchemotherapeutic treatment options. On the one hand was acalabrutinib and on the other hand was idelalisib plus rituximab.
The primary end point of the trial was progression-free survival, and there was statistically significant and clinically meaningful superiority of acalabrutinib compared to the investigator’s choice arm. This is important because as I said, this was the first head-to-head of 2 novel nonchemotherapeutic treatment approaches, and it proved that BTK [Bruton tyrosine kinase]-targeting with acalabrutinib was superior to PI3K-targeting with idelalisib with regard to efficacy, but also with regard to tolerability of treatment, which is obviously important for our patients in the relapsed/refractory setting.
Jennifer Brown, MD, PhD: For the key [adverse] effects of acalabrutinib, the most common is headache, which is generally time-limited. It almost always goes away within a month or two. In most patients, it goes away within a week or two. It is often responsive to caffeine, so it is important to counsel the patient ahead of time for that. We always see infections in our patients with CLL, so that is definitely an [adverse] effect. There is some diarrhea as well with acalabrutinib, less than with ibrutinib.
There is a lot of interest in cardiac [adverse] effects in the ELEVATE-TN study because we know with ibrutinib that we see significant rates of atrial fibrillation, up to 15% to 20%, at a several-year follow-up. Hypertension seems to occur in more than three-fourths of the patients over a several year follow-up. So far, there is no definite signal with the acalabrutinib arms in the ELEVATE-TN study in that regard. There is about a 4% rate of atrial fibrillation in each of the acalabrutinib arms, which is higher than the obinutuzumab-chlorambucil arm, but it is also representing 4 to 5 times as long duration of follow-up.
We are awaiting the head-to-head trial comparing acalabrutinib to ibrutinib, which will hopefully come out sometime in 2021 to clarify the relative cardiac risk. There are some data at ASH [the American Society of Hematology annual meeting] 2020 looking at a network meta-analysis as well as a single institution study from The Ohio State University, both of which showed substantially lower rates of atrial fibrillation or hypertension with acalabrutinib compared to ibrutinib.
The cardiac management with acalabrutinib is not as big an issue, but with all these BTK inhibitors, we have learned that we need to pay close attention to blood pressure in the clinic in our patients on these drugs and manage that aggressively, which was not something we used to do. With atrial fibrillation, you have to keep an eye out for it, but we generally monitor it clinically. If patients are not symptomatic, then you can do rate control and consider anticoagulation. I have gotten a lot more comfortable with anticoagulation in my patients on a BTK inhibitor if we use an oral anticoagulant, such as apixaban, which I typically use. I will sometimes use the lower dose, especially in an older patient even if they do not quite meet the usual criteria for the lower dose. I have had pretty good luck with that. It is also important to stop any antiplatelet agent if you need to add an anticoagulant in a patient already on a BTK inhibitor.
It is also very important with BTK inhibitors to hold them prior to any surgery. Generally, with acalabrutinib, I will do 3 to 5 days, and with ibrutinib, it is 3 to 7 days, based on whether it is a minor or major procedure. That is on either side of the procedure because most of the bleeding that we see with these drugs is periprocedural. Those are a lot of the key points for caring for patients on BTK inhibitors.