Improving Outcomes in Relapsed/Refractory Diffuse Large B-Cell Lymphoma - Episode 6
John P. Leonard, MD: Kami and then Matt, when I look at ASCO [American Society of Clinical Oncology], what I look at ASH [American Society of Hematology], I was just looking at EHA [European Hematology Association] abstracts. It's session after session of safety of CAR [chimeric antigen receptor] T cells. My eyes glaze over as a nontransplanter. We know there's cytokine release. We know there are neurologic toxicities. We know that steroids can potentially affect efficacy. How do you package all this together in a way that tells us what to do going forward? First, Kami, your thoughts and then Matt after that.
Kami Maddocks, MD: As you mentioned, the neurotoxicity and the cytokine release are the two biggest concerns with these therapies. There is a difference in the two approved products: one has a higher rate of higher-grade neurotoxicity, one has a higher rate cytokine release syndrome. Early treatment and preventing toxicity has gotten better over time, as Matt has already mentioned.
Looking at early use of steroids was shown to be able to decrease the toxicity, although a recent abstract suggests that that maybe high dose steroids, early on in the course, has a higher rate of decreasing response. Other agents such as IL-6 receptor antagonist tocilizumab have been used to prevent or help with higher grade cytokine release syndrome. Intrathecal chemotherapy has been used to help with neurotoxicity. There is a score developed to help gauge if patients are developing neurotoxicity and the grade at which that is. Over time, certainly we been able to recognize what these toxicities are and treat them early on to prevent them from being higher grade.
John P. Leonard, MD: Matt, how do you look at these toxicities? Something else I'll ask you to comment on is, I think we focus on CRS [cytokine release syndrome] in neurotoxicity but there's also low immunoglobulins, infections, neutropenia, all those things that people in the community may be getting these patients back 6 months later and have to be aware of at least. So, your thoughts on those.
Matthew Lunning, DO: We're still learning in the what I call the day 28 and before. We're absolutely still learning in the day 29 and beyond. You're absolutely right, Dr Leonard, when you send these patient back out in the community, you're having those discussions. I call it the double dip. You see the CYFLU cytopenias and then they recover. Then you see potentially cytopenias that occur again in the midday 20s that can extend to people who are transfusion dependent. They do require intermittent growth factor support for neutropenia. Sometimes, it's 1 dose. Sometimes, it's multiple doses. Over time you can see that they can improve. There has been data looking at that, that the cytopenias do improve. We don't often know when to incorporate IVIG [intravenous immunoglobulin]. I sort of use the CLL [B-cell chronic lymphocytic leukemia] principles as a sign of recurrent sinopulmonary symptoms rather than an IgG level that I would start to use IVIG, given that we have a national shortage of it from that standpoint.
I try to comfort the community physicians, saying that if this person is at day 100 and ACR [albumin‐to‐creatinine ratio] in their hemoglobin is 8.5 and their platelets are 50 and their neutrophils are 1.1, that's good because the alternative is having those same counts in progressive large cell lymphoma. The data has shown us that it's hard to get those patients post CAR T-cell [transplant] with prolonged cytopenias on a clinical trial so they are not well represented. I'll take a person in a CR1 after double refractory disease but with a persistent not grade 4 cytopenias but grade 2 to 3 cytopenias.
John P. Leonard, MD: Just briefly, are you doing outpatient administration at University of Nebraska Medical Center? I know that there are been some data presented at ASCO around outpatient and readmissions and other things. What's your take on that at your center?
Matthew Lunning, DO: We do outpatient autos. We are set up to do outpatient CAR-T. We were ready to do it on TRANSCEND but then accrual was held. We have not done it in an axi-cel product to date. I think that it would require substantial outpatient but a floor above us in the hospital type of approaches to outpatient. I do think the data, which is the pilot study with liso-cel as well as some other experiences and TRANSCEND, was looking at where there was outpatient administration. If you have later onset of CRS and neurotoxicity, you may be able to get several days beyond infusion before they may need to be brought into the hospital. For a fair number of people, when you start off in the outpatient, the general expectation is that you're going to spend some of your CAR T cell in inpatient. You may get away with doing it completely as an outpatient in a small percentage. But the safety profile is going to matter.
John P. Leonard, MD: To close our discussion with on CAR Ts, I want to ask Nathan just to remind the audience, from your perspective, of patient selection because for many people in the community, they're not going to be administering. They might be, but for most people it's going to be referring the patients. We want to be sure that people at least know who to refer to for a consultation and a discussion. Any kind of guidelines you would give people as to who to send as far as the disease, the timing, the age, CNS involvement from your perspective?
Nathan H. Fowler, MD: A good rule of thumb is if you have a patient that is not eligible for a transplant, for example due to age, but has a good heart—meaning good ejection fraction—and normal kidney function, that's a great patient to send for a CAR T cell. There is now, again a couple of retrospective looks looking at patients that are elderly that would not qualify for transplant and do quite well. I've referred patients and have given CAR T cell to patients all the way up to age 86 and many of them have done quite well. That's transplant ineligible but otherwise have good organ function. The other large group of patients, are transplant failures. Those patients should be evaluated for CAR T cell. It's the most appropriate and the most effective option for those kind of folks.
I think those are the two big buckets. Generally, chemo refractoriness means that patients don't do too well with auto transplants. To Matt's point, in patients who have refractory disease, even before they fail their second line, I'm already thinking about CAR T cell. So those are patients that are not in the FDA label yet but the majority of patients that are primary refractory are going to end up a CAR T cell. The sooner you start thinking about them, the better.
John P. Leonard, MD: Kami, I think the unmet needs around CAR T cell are very similar to where we started this discussion around R-CHOP, more effective therapy, less toxic therapy, easier to do. Are there any other unmet needs that you would throw into the CAR T-cell scenario? Clearly, there are a number of new drugs that are being combined. The question is will they make it more effective or less toxic?
Kami Maddocks, MD: You're exactly right. There are studies looking at improving upon CAR T, so using different constructs, adding other medications, either pre-or post-infusion to try to improve the efficacy, and then all of the areas that you mentioned.
Nathan H. Fowler, MD: John, something you mentioned and I didn't talk about is relapsed large cell lymphoma in the brain. There is some data with CNS lymphomas. Now that I think about it, that is another population, relapsed large cell, that I would consider for in the brain.
John P. Leonard, MD: We've seen some small studies at ASCO and otherwise that have suggested that responses can be seen and potential value in that setting.
Transcript Edited for Clarity