Nicole Lamanna, MD: You talked a little about some of the adverse effects and long-term consequences of potential of FCR [fludarabine, cyclophosphamide, rituximab] with MDS [myelodysplastic syndromes] and AML [acute myeloid leukemia] and the risks of those types of toxicities. What about with the BTK inhibitors? What toxicities do we all see in common practice with ibrutinib? And we could talk about acalabrutinib as well, but Farrukh, you want to start about with ibrutinib some of the toxicity profiles for patients?

Farrukh Awan, MD: Other than the hematologic issues that we are all aware of, for most of the agents that we use as a class, we are beginning to discover all these newer adverse effects. A lot of these adverse effects are unique to this class of drugs. For example, the bleeding risk is definitely enhanced, and we see that it’s an early issue that happens with a lot of the patients who get BTK inhibitors. That then again takes us into another area: how do we manage those issues? Somebody has to be on chronic, almost like an anticoagulant, for 10 years. Do they stop it when they get a colonoscopy? Do they stop when they get a cholecystectomy? There are so many lifestyle decisions that you have to make.

The other thing we’ve all seen, and we kind of caught a hint from the ALLIANCE data, were cardiac issues, atrial fibrillation, ventricular arrhythmia, sudden cardiac deaths. Luckily there are small percentages for those. The atrial fibrillation has been an issue, and as we have all seen, the real-world data, because a lot of our patients have multiple comorbid conditions, they have cardiovascular issues when they start these drugs. It can be a challenging condition to manage also, because then you have to anticoagulate a lot of those patients. So you might have to, and then you already have almost a drug that causes a bleeding diathesis.

Those are challenging issues that as physicians we all need to be aware of. The unfortunate thing is that there is no standard way of managing those. It’s not as if you do this and this, and it’ll be fine. That’s a challenge that happens in a lot of patients.

The other thing we’re now studying more and more and discovering is the risk of hypertension. That’s a very clear risk, and it gets worse with time—not only the worsening or the development of new hypertension but the incidence of major adverse cardiac events, which have also shown to be increased in patients who stay on at least ibrutinib for a while.

Whether this is a class effect or a drug effect, I think that’s where the debate is right now. There are certain adverse effects—like bleeding, for example. I think we all feel fairly comfortable that that would be a class effect. You might have some lower grades with 1 and some higher-grade events with the others. That’s a separate issue, but I think we all feel that the bleeding issue is a class effect.

With regard to the cardiovascular issues, we frankly don’t have those head-to-head comparisons in the real-world data to really comment on how that will pan out and whether that would be a class effect or a drug effect. I think it’ll be a bit of both in my opinion.

Richard R. Furman, MD: Just to add to that, I think what’s really very important from both the ECOG and ALLIANCE data—and I’m of course comparing 2 studies with each other—is the impact of age on the cardiac risk. Certainly, the hope is that we will be able to sort of risk stratify our patients for toxicities and choose different therapies for patients who really would need different therapies. That was what I found so interesting from the ECOG and ALLIANCE data.

Farrukh Awan, MD: You don’t see that signal on the ECOG study, and you do see a clear-cut signal in the ALLIANCE trial, even though luckily the numbers are very small. That takes us back to the first point, whether we still have to stratify by age as we were doing in the chemoimmunotherapy era. We’re back to square one about how we sequence these and when do we use what novel therapies.

Javier A. Pinilla-Ibarz, MD, PhD: At the end of the day, I fully agree. I think as we have more agents available for treatment, we need to start to learn how to customize therapy, depending on age, comorbid conditions, risk stratification, and things like that. We are learning as we go, right? We may see more toxicity with certain agents as they age. Maybe the fact that oral agents, though we don’t have the comparative studies, may have less toxicity, may be more amenable for a younger population or not really…while in other cases, BCL2 inhibitor may be a better choice for those patients.

We’re always bringing back the long-term duration versus the short-term or limited duration, and I think it’s something our patients really bring into clinics and into the conversation that we have about frontline therapy. There are multiple areas of discussions with patients these days, and more when we have more agents available. I think we should recognize that, and we should learn as we go what the best drug is for each patient.

Transcript Edited for Clarity