VIDEO: Future research directions in mantle cell lymphoma

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There's a lot of places where people can dig their teeth in. The first thing I would say is there are still very, very high-risk patients, and these are patients who don't seem to derive much benefit from the BTK inhibitors, from REVLIMID, even from chemoimmunotherapy or CAR T-cell immunotherapy. And you can see that reflected in those same survival curves I mentioned, right? The response rate to CAR T-cell therapy is upwards of 90%. But if you fast forward six months, we're not still batting 90%. You know, many of those patients progress and when they progress, it can be very, very challenging to rescue them. In particular, if they've already seen a BTK inhibitor, venetoclax, or other, you know, active agents, that's a reflection of mutations that we're all quite familiar with. TP53 and NOTCH being two mutations in particular that I worry a lot about in my mantle cell patients. So I think, from a therapeutic standpoint, we're still trying to figure out how best to take care of those patients. I am very excited about bispecifics, and you know what we're doing with CAR T-cell immunotherapy, what we're doing with REVLIMID-based immunotherapy. You're probably sensing a trend here, but for patients who have central nervous system involvement, for example, those are not going to be... CAR T can work in some cases, but shy of that, bringing so small molecules into the space is gonna be tougher, especially if they've already seen and failed a BTK inhibitor where they come into that setting. So we know that patients who have more proliferative mantle cell are more likely to carry these mutations, are more likely to show these patterns of resistance, and so when we see a KI-67 of 80 or 90%, it worries us. And you know, those are patients where, you know, you have to be thinking really hard about how to get them to CAR T-cell immunotherapy in the best possible sort of disease burden state you can, and really following them closely, and really making sure that you try and catch the diseases relapsing early. 'Cause sometimes you catch it, you can give things like radiation alone, and render these patients, you know, put these patients back into a sustained remission. But I'm veering away from your question, which is you know, what are those therapeutic spaces where we still need to see improvement? And one of those is what's called high-risk mantle cell lymphoma, right? So you can call it high risk by virtue of its proliferative rate. You can call it high risk by virtue of the therapies they've seen and now progressed on. But that is an area where we really need to see drug development. And so I think that post-CAR T space is going to be where we see a lot happening. Again, I'm hopeful, I'm excited about that. The second thing that I think is a little bit more nuanced is, you know, it has to do with how we treat mantle cell lymphoma. And mantle cell lymphoma is a lymphoma that benefits from maintenance therapy. You know, some very, you know long durations of rituximab, you know, at least two years some would say, at least three years, some would say until progression, depending on the trial that you read. There can also be long durations of BTK or REVLIMID, you know, depending on the trial and depending on how those trial data are applied. That's a long time to be on medicine. And, you know, we learned during the COVID pandemic that Rituxan maintenance, for example, can come with, you know, much, much more severe COVID, and in some cases even lead to, you know, to the patient's death. And that's the last thing that you want to do is to have a patient on Rituxan maintenance doing exceptionally well, you know two and a half years in, and to see them pass away from COVID. So, you know, we have to account for what we're doing to the immune system with these maintenance approaches. We have to account for, you know, this accumulation of low-grade, you know, these grade one and grade two toxicities that look great when you present the data at a national conference, but are not things that patients necessarily want to have to deal with day in, day out for years on end. And so I think trying to understand how we pivot to a CLL model in mantle cell, it's gonna be hard because mantle cell is not CLL, but understanding how we use minimal residual disease monitoring to try to guide what we're doing therapeutically. It may allow for some treatment de-intensification, right? It may not allow us to completely, you know, omit the rituximab, for example, but maybe we can come off of the REVLIMID. Or maybe we can come off a BTK inhibitor and then extend that rituximab maintenance until we start to see the MRD creep up again, and then reintegrate, you know, our novel agent. And so I think these are approaches that that we're gonna be pushed to figure out, right? Because, you know, our patients, if we can extend their livelihood, we also wanna extend that quality of life.