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Acalabrutinib MCL Approval Raises Sequencing Questions

Angelica Welch
Published: Wednesday, Nov 15, 2017

I just started my first patient on this drug last week, and it’s a patient who came in with a cardiac history—why tempt fate? We started acalabrutinib first. We will see how that patient does. However, for my other patents with MCL, using ibrutinib or lenalidomide plus rituximab (Rituxan) has been game changing, particularly for patients with indolent disease, for whom you are really trying to manage [their disease] with the least toxic approach possible.

Would acalabrutinib be best used in patients who have failed ibrutinib?

That’s a good question, because that isn't the indication. The label is just for patients with relapsed or refractory MCL. [Looking at] the way that the studies were done, they were not done with an intent to position it behind ibrutinib. The label does not say that patients must have failed ibrutinib; so, your question is spot on. What is going to be the decision making that doctors use to decide between one or the other? I don't think it is entirely clear. People might look at side effect profiles. Physicians are creatures of habit; if they have a good experience with ibrutinib, then they might be more inclined to stick with that. It is very early; it hasn't been approved for that long, but this is going to be an issue.

The bigger issue is going to be, if a patient receives one of these BTK inhibitors, does that kill the opportunity to use the other member in the class? We don't know. Our myeloma colleges have spent years debating that, if they give lenalidomide, how does that take benefit away from pomalidomide (Pomalyst)? If you get bortezomib, how does that portend benefit from carfilzomib (Kyprolis)?

It’s possible that there may be a benefit down the road. If patients can get ibrutinib, then they can manage the disease as a chronic [condition], then perhaps they can come back to a BTK inhibitor down the road. Perhaps that could be a rationale to use the safer one later—where the patient might be more beat up—and less able to tolerate agents. It’s totally unknown, but this will probably be the big question.

What is your current strategy for patients who progress on ibrutinib?

It depends where they are getting ibrutinib in that line of therapy. It depends a lot on their disease growth, symptoms associated with the disease, and the bulk of the disease. If I haven't used lenalidomide, then I might use that. We have a number of clinical trials at Columbia University Medical Center that are also good options for us, but maybe not everyone in the community. We have had very good success with lenalidomide, and I want to point out that in the original study done by Dr Andre Goy, they used 25 mg for 3 weeks out of 4. In that trial, they had good enough response rates and time-to-event metrics that got the drug approved.

Increasingly, we are finding that using a lower dose of lenalidomide, maybe more similar to what our colleagues in CLL are doing, we might use 10 mg or 20 mg and keep them on without a break. We will add rituximab, and we find that the maintenance of lenalidomide without the break actually has less toxicity. The addition of the rituximab, depending on how long it has been since their last [cycle with] rituximab, gives us pretty good results.

What are your thoughts on CAR T-cell therapy possibly entering the MCL landscape?

There are a number of CAR T-cell therapies coming along. MCL expresses CD19, and there are some very nice data from the University of Pennsylvania group that are showing early but promising observations. We are going to need to be extremely diligent about where we look at CAR T-cell therapy in this setting because we need to balance the risks and the benefits. We are going to need to evaluate the toxicities with CAR T-cell therapy, and I would suggest that the kind of patient you take into those studies is the kind of patient who has a chance of benefitting. If we start concentrating on those patents with indolent-behaving disease that may have a lot of alternatives in terms of their management, maybe they are not ideal [choices for CAR T-cell therapy].

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