Alexey V. Danilov, MD, PhD: In this patient, we were lucky that we could use radiation—and that his disease was sensitive to radiation—to bring him to CAR [chimeric antigen receptor] T-cell therapy. Quite a few patients who progress on BTK [bruton tyrosine kinase] inhibitors present with rapidly progressive explosive disease. You can’t take them off the BTK inhibitor, and you have to come up with something in the meantime. Bijal, what do you do? How do you treat these patients before you give them CAR T?

Bijal D. Shah, MD: I’m unique, as you’ve probably learned. I use a lot of lenalidomide-rituximab as a run-in. If they don’t have explosive disease, lenalidomide-rituximab works well at diagnosis. For patients with this TP53 background who are going to go to CAR if they’re progressing, I’m using my BTK as a bridge. This way, I’m not running into that difficulty: “I used my BTK, but now it’s explosive. What do I do?” In fact, for the other case we discussed, I was getting palpitations because that’s often what we see. Pirtobrutinib has a signature for activity in BTK-refractory disease. I don’t know whether that case was intolerance or refractory, but it was progressing on the lower-dose ibrutinib. If that bears out in practice, then I’m going to work to do that.

There were some interesting data from the UPenn [University of Pennsylvania] group looking at venetoclax and how it may help to sensitize or improve CAR T-cell output. That’s largely preclinical but interesting. Venetoclax does cause T-cell lymphopenia more broadly, but if it’s beneficial for the right subset of T cells, there may be some opportunities to exploit the use of venetoclax after the apheresis, perhaps to improve the outcome. Even in the context of CAR, though the cytopenia can be difficult, you try to pick something that will work. When your back is against the wall, you don’t have a lot of breathing room. In practice, we’re not restricted to the trial design. We’re not restricted to steroids as it was on the trial or continuation of the BTK. We can pull from other things on the shelf; that’s helpful. That’s why most of the patients are making it to the CAR once we collect their T cells.

Alexey V. Danilov, MD, PhD: Matt, do you still use bortezomib in this setting?

Matthew J. Matasar, MD: I don’t. Because we have so many other tools, it’s not common for me to reach for bortezomib. But I agree with Bijal that we often have a lot that we can cobble together—a little of this, a little of that, some steroids. Mantle cell lymphoma is indeed a highly radiosensitive disease, as your patient thankfully experienced. [We use] a bit of “spot welding” to treat sites of rapidly progressive symptomatic disease. Vitamin A, Ara-C [cytarabine] is still a good drug. TP53 aberration decreases chemotherapy sensitivity in the long run, but you can often get people stabilized or get them bridged with good old chemotherapy.

Alexey V. Danilov, MD, PhD: One thing is clear: we need more novel therapies, not just for these patients but for patients intolerant of BTK inhibitors.

Transcript edited for clarity.