VIDEO: Recent FDA approvals for mantle cell lymphoma

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So if we're talking FDA approval, there's no question that ZUMA-2 has changed our practice in how we treat mantle cell lymphoma. We saw from the ZUMA-2 data that patients who had TP53 mutations, patients who had very proliferative or blastoid variant mental cell lymphoma, they could still benefit from CAR T-cell therapy. This is a group of patients who did not derive a significant benefit from high-dose chemoimmunotherapy from autologous transplant and the like. And so, you know, that FDA approval has allowed us to bring CAR T-cell immunotherapy for these very high-risk mantle cell lymphoma patients. And I do think, you know, in clinical practice it's significantly improved our outcomes in that space. There is another drug which doesn't yet have an FDA approval specifically for mantle, and that's venetoclax. And so, you know, this is data, you know, published by Constantine Tam and colleagues in the New England Journal of Medicine. Maybe three or four years ago, I can't remember how long ago it was, but it's a little while back, but it led to an NCCN designation saying that, "You know, yes, this medicine can be delivered for patients with mantle cell." And so I think venetoclax has provided therapeutic benefit for some of our patients with mantle cell lymphoma. You know, I can think of some who were starting to show resistance to a BTK inhibitor is a good example where we then added the venetoclax to that treatment regimen and were able to bring the mantle cell back into sustained remission and so that's been nice to see. I think we're still looking for those predictors who's gonna benefit most from bringing this particular medication, you know, into their regimen. You know, there's early data looking at cyclin D1 mutations, you know, cyclin D1 normally leaves the nucleus, it goes into the cytoplasm of the cells where it sequesters a protein called Bax. And Bax is a pro-apoptotic protein. And so if it's sequesters it, it makes it harder for the cell to die. Well, when cyclin D1 is mutated, it can get locked into the nucleus, can't make it out into the cytoplasm where it's not able to perform that same function. And so this may be a mutation that sensitizes patients, meaning improves the likelihood of seeing a response with venetoclax. And importantly, that mutation also seems to lead to some therapeutic resistance to the BTK inhibitors. So now you're seeing that sort of perfect storm, right? I bring in my BTK inhibitor, I have my venetoclax and now I'm more likely to see a therapeutic response despite seeing, you know, more difficult to treat mantle cell lymphoma. And so those are some of the things that I think we need to get more data for, you know, how do we think about other commonly observed mutations in Wsc1, in Notch1 or Notch2, you know, as well as some of these non-canonical NF-kB mutations that tend to predict for resistance to BTK inhibitors. And so, you know, having the ability to bring these agents into therapy, having the genomic data to help, I hope learn from that experience, but also then for subsequent patients to guide therapeutic decision making. It's a powerful thing. And so I'm glad that we have more tools now at our disposal. We are starting to see data emerge with bispecific antibodies. Really excited about this. So epcoritamab, glofitamab, mosunetuzumab and more that I can't pronounce. And so it's gonna be really interesting to see how that story develops. We now know from CAR T that we can use the immune system to help get patients into remission, to put it bluntly but it will be fascinating to know, "Hey, does Bendamustine have that same inhibitory influence on the likelihood of response with these bispecifics? Are there things that we can combine with bispecifics like the BTK inhibitors and others that may actually improve the toxicity profile?" And these are studies that are ongoing. Are there other medicines like Revlimid which maybe increases the side effects a little bit but also, you know, improves on the efficacy component of these bispecific antibodies. And so all things that I think we're gonna see in the clinic, in the form of clinical trials, and I'm hopeful that, you know, with these, it's so funny that they start as these small phase two trials but they really have a significant, you know, benefit, right? If you're looking at that, you know, event-free survival curve and it's just flat at 100% and you're three years out, you're scratching your head and say, "Okay, yes, it was 40 patients, but wow, this is really incredible." And so these are the kinds of studies that I'm really looking forward to see, we could performed, and celebrated in mantle cell lymphoma where, you know, we want to ultimately change this old paradigm, right? It used to be called the most aggressive B-cell lymphoma. And I think we've already moved away from that, but I'm hoping we continue to make strides in that direction.