Tox Check: Chimeric Antigen Receptor T-Cell Therapy

Dr. Rahul Gosain: Hello and welcome back to the Oncology Brothers podcast where we continue to focus on recent advances in hematology and oncology. I'm Rahul Gosain here with my brother and co-host Rohit Gosain. Today, our topic is understanding the side effects and management of one of the most rapidly evolving treatments in cancer, CAR T-cell therapy. This therapy is currently approved for multiple hematologic malignancies, but early-phase studies are already exploring this in solid tumors as well.

To guide us through this complex subject, we're joined by Dr. Surbhi Sidana who leads the Myeloma CAR T Program at Stanford University, and Dr. Jason Westin, director of the Lymphoma Clinical Research Program at MD Anderson Cancer Center. Jason and Surbhi, welcome.

Dr. Rohit Gosain: Jason and Surbhi, thank you so much for joining us. Rahul, you're right. As CAR T has transformed the treatment landscape for hemalignancies, it is entering the solid tumor world as well, but we'll see how that plays out. We have several CAR T therapies available since the first approval in 2017. We now have Axi-cel, Brexa-cel, Liso-cel, and Tiso-cel for lymphoma, and Ide-cel and Cilta-cel for myeloma. Surbhi, we'll start off with you. If you can briefly touch on mechanism of action of CAR T-cell therapy and exactly how it works.

Dr. Surbhi Sidana: The mechanism of action for CAR T is that we take patients' lymphocytes and engineer them to have receptors that can identify target proteins on the cancer cell. For lymphoma CD19 for myeloma BCMA, and we want to find proteins that are expressed in cancer cells and not expressed widely on other cells to avoid toxicity.

And this is independent of any MHC or HLA. And so all of these CAR T cells when infused back in the patients go and target the cells that have that protein, and they are living therapy so they expand in the patient and they don't last forever, at least not in myeloma patients, but they last for a few weeks, two months. They do the job of killing the cancer cells they see.

Dr. Rahul Gosain: Surbhi, thanks for that foundation. Jason, anything you would like to add here for any oncologists to better understand this treatment modality?

Dr. Jason Westin: I think that's a great description. The way I describe it to my patients is that you take the basic infantry, their soldiers that they have floating around their blood, you send them off to boot camp, and when they come back, now they're the elite fighting force. They're the Army Rangers or the Navy Seals, whatever you want to call them, as some special fighting force that can see the wolf in sheep's clothing, can see the cancer cells that are floating around right in plain sight, but look close enough to normal cells that normally the immune cells are not attacking them. Now, this living drug is going after the cancer with a vengeance and that's why there's side effects of the CAR T-cells that look a lot like infection because you have this overwhelming immune response. And we'll dive into these side effects in a moment, but when those living drug cells grow and expand and multiply, you have an explosion of cytokines that come along with that and that's where all the drama happens.

Dr. Surbhi Sidana: I love it. I may take that and explain that to my patients as well. It's the elite fighting force.

Dr. Rohit Gosain: Right. Especially as well because when we are describing these to our patients before going to tertiary quaternary centers, it is important for us as community oncologists to understand them better as well. And we have seen improvements from the managing of side effects since the inception where the acute adverse events, which was rather scary for the initial part that was CNS toxicities and CRS, but now we are getting more comfortable in managing whether that's in hospital setting or in outpatient.

To start off, we'll divide this into acute side effects versus chronic side effects. Acute ones is what we see in hospital settings shortly after the administration of the treatment. And chronic side effects is where a bit of community oncology does get involved because these patients are in outpatient settings now. Surbhi, can you start us off in discussing some of the acute side effects and clinical pearls around managing these side effects?

Dr. Surbhi Sidana: Sure. And the acute side effects of CAR T are unique and there was a lot of attention being paid to it the first several years after CAR T started. I do think we've learned to manage those. So those include cytokine release syndrome. As Jason said, these CAR T-cells expand. They have a massive immune response. The cells secrete cytokines and they cause what looks like severe infection, fever, fever with low blood pressure. And when it's very severe, patients might even require pressures almost like they have septic shock but they don't have septic shock.

That happens at different time periods with... Some of the products happen after a couple of days. The other products happens after seven to eight days, but usually within the first two weeks. Then shortly thereafter, these cytokines can also cause neurotoxicity, what we call ICANS or immune effector cell-associated neurotoxicity syndrome where these cytokines almost cause an encephalopathy-like syndrome. Mild cases, just a little bit confusion or disorientation. But severe cases patients are obtunded. And so these two again happen in the first couple of weeks usually when patients in the hospital, rarely can happen later.

Dr. Rohit Gosain: Jason, are these adverse effects like a class effect or do they vary based on the type of disease, or do we see different side effects in lymphoma?

Dr. Jason Westin: They're more of a class effect for CAR T-cells in general. We do see unique side effects in particular CAR T-cells that may be subtly different but as a class, cytokine release syndrome and neurologic toxicity are the two main side effects we look for in the acute phase. We think this is because of the expansion of the immune cells and whether it's a BCMA target or CD19 or others, the expansion and the cytokines that come along with it are relatively similar across the board. Some CAR T-cells may have a greater risk of neurologic side effects than others. So it could be that within the class effect there's a greater risk in this group versus that group.

But as mentioned, these are all acute side effects. I would highlight for community physicians that if you see a patient who's had CAR T-cell and they're developing fever and their blood pressure is low, and it's three months later, that's very likely to be UTI as opposed to CAR T-cell side effects. Same for confusion or other issues, if they occur late, it could be CAR T-cell, but I would have a broad differential. These side effects are usually within that first month, which is often why patients with CAR T-cell therapy will stay near a CAR T-cell center for a finite few weeks, and the late side effects are usually not cytokine release syndrome or neurologic toxicities.

Dr. Rahul Gosain: And just to get a number, because I would like to believe this number is actually getting better, the severe patients that are getting obtunded be it with myeloma, CAR T, or lymphoma, what is the prevalence of this?

Dr. Surbhi Sidana: For myeloma, based on our real-world data for major centers doing this, it's less than 5% for severe neurological toxicities. Also less than 5% for severe cytokine release syndrome that requires people to be in the ICU. So 95% of the patients, we can manage with mild to moderate side effects on the routine floors.

Dr. Rahul Gosain: And Surbhi, does the tumor burden play a role in the severity of these acute adverse events to patients with heavy tumor burden experience? More serious treatment-related complications?

Dr. Surbhi Sidana: Yes. And I would love to hear what Jason has to say for lymphoma. But for myeloma, absolutely. The more antigen that you have in terms of tumor burden, the more it drives these CAR T-cells to expand. And the more CAR T-cells are there, there's more side effects. So we see that. If you go in with a high tumor burden, the likelihood of getting more severe cytokine release syndrome, neurologic toxicities, and even some of the delayed toxicities with myeloma CAR T-cells is more.

One part to community oncologists is that bridging in myeloma is critical. And even if your CAR T-cells are ready, I would bridge the patients down to as low disease burden as possible before taking them to CAR T, at least for myeloma. But Jason, what do you think for lymphoma? How do you approach bridging and disease burden prior to CAR T?

Dr. Jason Westin: Yeah, it's a great question. And to me, this is still an undefined area. I don't think we know yet enough to have a complete answer because clearly, the same for myeloma, and lymphoma disease burden does correlate with risk of side effects and bad outcomes. If a person has lymphoma coming out of their ears, an explosion of disease that's everywhere, that person's at high risk for toxicities and worse outcomes for their CAR T-cell. What we don't yet know is that something that bridging therapy will modify that risk? Is it the actual disease burden, or is it why they have the disease burden? Is it the adverse risk factors that are causing the lymphoma cells to proliferate to expand so much? Is that driving the bad outcomes or is it just the bulk of the disease?

It makes sense that the risk of toxicities would be correlated with a high disease burden. As you mentioned, you've got a lot of antigen, the CAR-T cells are expanding, and they've got a lot of opponents to go after. There's going to be more cytokines released. But the question about outcomes, are you improving outcomes if you debulk the patient? If you try and give a bridging therapy, are you going to improve their chance of having a long-term durable remission after CAR-T cells? That's something we don't yet know.

There is ample data for lymphoma that bridging therapy is associated with inferior outcomes. Although, that's probably a chicken or egg problem. Who gets bridging therapy? It's somebody who's got the disease that's growing in front of your eyes. Who doesn't? It's the patient who's got less aggressive disease. That probably is a major part of it. So we definitely need more bridging approaches, and there's clinical trials that are evaluating what would be the optimal bridge.

But definitely, the disease burden is relevant for toxicities and I would say that's a key factor. Community oncologists to refer your patient before they get to the explosion of the disease. If you're thinking CAR T-cells may be in the future, having that conversation as early as possible and referring that patient as early as possible is really critical. So they're not showing up in our clinic and having to be admitted to the hospital. And now, we're on a different footing toxicity-wise. Whereas if we'd seen them a month earlier, maybe we could have had a less adverse outcome.

Dr. Rohit Gosain: I just have to plug in that anytime one is deciding to give any therapy, especially for aggressive lymphomas or now even CLL, we have approved CAR-T options to get tertiary-coronary center support, whether that's for approved option or even for clinical trials.

Dr. Rahul Gosain: Absolutely. And so far, in the acute phase, we worry about CRS, neurological side effects. But when it comes to chronic side effects, we need to monitor for cytopenias, chronic infections, and increased risk of secondary malignancies. Jason, with CAR T therapies now approved for almost seven years, what are some things for community oncologists to keep in mind for chronic side effects once these patients return home after their initial treatment? Again, be it Liso-cel, Axi-cel, any of these agents.

Dr. Jason Westin: Yeah, we've definitely learned a lot over the past few years. In the early days, we didn't really know what the late side effects would look like. We did expect there could be late side effects specifically related to target B cells. If you're depleting B cells, we've done that for a long time with Rituxan and we know that there's risk of infections, although not overwhelming risks, but some infections. What's important for community oncologists to know for patients who've received CAR T-cell therapy is the risk of pneumocystis pneumonia is not zero. You'll see a patient come back to you and they're on Bactrim and do they really need that and they're having some side effects.

We did unfortunately lose a few patients very early on in the CAR T-cell story when we had late occurrence of pneumocystis pneumonia. And that can be an overwhelming infection that can go from not bad to potentially fatal in a relatively short timeframe.

Most patients who get CAR T-cell have a near-mandatory need to do some type of prophylaxis usually we say for about a year, although that's a relatively soft timeline. The other infectious prophylaxis we usually use is for zoster. That's something that reoccurs. And it's not usually life-threatening but can be painful or uncomfortable for patients, and it's relatively easy to prophylax against. So both of those are really important.

I think one of the things we've seen more recently is we've gotten additional data about late side effects of CAR T-cells is the risk of infection and death of infection. That's probably the greatest risk for our patients long-term. Although their blood count may look okay, they may not have anything obvious in terms of immune deficiency in terms of something that jumps right off the page at you, risk of infection and infections going from mild to severe more quickly, that's something to note. And I think we could also talk about immunoglobulin replacement as a potential thing that's useful for patients too.

Dr. Rohit Gosain: I want to come back to some of those points you stated, Jason, with regards to antibiotic prophylaxis to cover PCP. And antiviral, you mentioned one year. Is that for both antiviral as well as antibiotic?

Dr. Jason Westin: In our practice, usually, we will do a year, and then we will recheck the patient's CD4 counts. If they've recovered back to normal or near normal, then we can stop the prophylaxis. There are some patients that just continue to have cytopenias long-term, and that may be due to lots and lots of pre-treatment, multiple lines of chemotherapy, and their bone marrow is a little bit burned. A year may not be an adequate timeframe, but that's a round number. And we usually will discuss that with patients at the outset of their treatment. So the patient's already on board. It's not a surprise at a late time point. But reinforcing that is important to patients. They should stick with those treatments because of risk of infections is really important for community oncologists.

Dr. Rohit Gosain: And Surbhi, would you do the same? Also, is there any role of antifungal in this scenario as well?

Dr. Surbhi Sidana: Sure. I completely agree with Jason. I cannot emphasize enough the role of IVIG, PJP prophylaxis, Zoster, and sometimes even when the counts are low like Neupogen, at least for myeloma patients, if they're very profoundly neutropenic. We do it a little bit longer. Again, some of this is just practice patterns. We will say 18 months or when their CD4 counts are 200 or more.

In our experience, by one year only about half of the myeloma patients have recovered their CD4 counts to about 200. So we go a little bit longer for those patients, but again, not antifungal as much. Antifungal only when people are on prolonged steroids. The other delayed side effects we didn't talk about from myeloma can be delayed neurotoxicity, which is different than acute neurological toxicity. One of the CAR T constructs Cilta-cel more than Ide-cel right now, including cranial nerve palsies that start around week three and four can even manifest when the patient's back in the community around two or three months later.

Personality changes or Parkinsonian toxicity. Thankfully, these are rare, so the cranial nerve palsy about 5% of the time with Cilta-cel. Parkinsonian with good debulking, about 2% of the time. Sometimes patients need to be on long-term steroids. And if they do it for this or maybe ICANS early on, that's when I put antifungal prophylaxis for a short duration.

Dr. Rohit Gosain: And anything from a monitoring standpoint that is monitoring any TLS, tumor lysis syndrome labs, electrolyte imbalance as well, which we tend to see. And `for IVIG, you tend to rely on IgG level of 500 or less to administer IVIG.

Dr. Surbhi Sidana: My practice is the functional IgG because myeloma can also be IgG myeloma, the most common type of myeloma. If someone has an IgG myeloma and their IgG is 800, make sure that's not a disease. So look at the M spike. If their functional IgG is 400 or less milligrams per deciliter, we do IVIG every month. Again 400, 500, I think these are arbitrary cutoffs. If you talk to immunologists they will say, "That's too low. You should target 800." But I think at least a bare minimum cutoff of that is important.

Dr. Rahul Gosain: Jason, what's your practice around IVIG? Because again, if we were to ask five different hematologists, you get 10 different answers.

Dr. Jason Westin: Yes. It depends on which day of the week for me. No, I'm just kidding. I think that the myeloma world is definitely more aggressive at using IVIG than in the lymphoma world. For lymphoma, we will use it, but it's not something that's strongly advised. If a patient has low IgG, sometimes we will give them IVIG as a replacement. Other times, we'll wait and see if they develop any upper respiratory infections. It's something that we expect we'll recover. Usually, a patient's B cells begin to recover somewhere around six months after the CAR T-cell therapy, and so in some ways is a bit of a surrogate for, are the B cells recovering?

If the patient's frail, if the patient has other comorbidities, if they have upper respiratory infections in the past, it is appropriate to not wait for the patient to tell you they've got a chronic crud kind of thing like a post-Rituxan upper respiratory infection they can't clear. But it's not something that is mandatory that every patient needs to get after they've had a CD19-directed therapy. But like you said, you ask five different folks who may get different answers. There's nothing wrong with giving IVIG. In a community practice setting, that's your practice that if a patient has had a chronic Rituxan course or a CAR T-cell therapy or bispecific antibody, you want to just have a unified approach and that's what you do. No objections to that. It's definitely something that can benefit patients.

Dr. Rahul Gosain: That's a good point. Surbhi, as we come to an end and we're starting to wrap up, any last thoughts for community oncologists who are treating these patients or considering CAR T therapy for their patients?

Dr. Surbhi Sidana: I will just say that we are still learning about these toxicities. Some we have a good handle on, like CRS and neurologic toxicities that happen early on. But at least from myeloma, where the CARs came to market four or five years after lymphoma, we are still figuring out some of the late side effects. For example, we recently found out there's a small risk of colitis or diarrhea that is not infectious, but some of the CARs, and that's 1% that was never seen in the trial. We only found out because we thought about it, put our heads together. If something is unusual, reach out to the tertiary center where the patient got CAR T because more communication is always better. We are still learning about these side effects.

Dr. Rahul Gosain: Absolutely. And the other one that ends up being risk of secondary malignancies with these as we're learning more and more as these patients have been out of this treatment for longer, Jason, any final thoughts from your end?

Dr. Jason Westin: My final thoughts on that, it is a risk. This is something that as patients develop cancer A, they've got something wrong with the DNA repair mechanisms. Developing secondary cancers has been part of malignancy from the 1970s to the current timeframe. And they think about patients treated for Hodgkin lymphoma in the 1970s with aggressive radiation. A lot of them develop secondary cancers. This is the evolution of if you treat this cancer successfully, the patient lives long enough they could potentially develop another cancer. May it be related or just due to the underlying fertile soil for malignancy with a patient who's developed a first cancer, hard to know for sure. But I would be on the lookout for that for your patient. If they develop cytopenias, if their blood counts are getting softer over time, consider getting a bone marrow to see if potentially MDS. If they have a weird rash, getting a biopsy to see if this could be a cutaneous T-cell lymphoma.

This is not something that we would avoid giving a patient, potentially curative for large B-cell lymphoma, but for other malignancies, maybe not curative. But people who are getting CAR T-cells have a potentially fatal cancer and living long enough to get a secondary cancer is in many ways a luxury. We hope our patients don't get those secondary cancers, but they didn't die of the aggressive cancer they had that normally would've taken them. So it's a concern, but it's not to me a barrier.

One other thought in terms of communication from community oncologists to the CAR T-cell centers. Most CAR T-cell centers should do a good job of handing off information about the patients taking this medicine, the patient should come back on this date. If you're not getting that or you feel like you don't have a good comfort level, call the worker who gave the CAR T-cell therapy and reaching out and saying, "Hey, could you walk me through this? Or do you have a coordinator that could help me?" That should be something that you feel empowered to do as a CAR T-cell treating physician. I want to have a good relationship with our community partners and that should be a two-way street. This should not be something that's a scary process or something you feel like you're on your own. Having that open-door policy with your CAR T-cell center should be essential.

Dr. Rahul Gosain: Jason and Surbhi, thank you so much for your insights around CAR T therapy. It's crucial for us in the community settings to recognize that these therapies can lead to durable remissions, but this comes with unique side effects that we need to manage carefully. For our listeners, let's go over a quick recap from today's discussion.

Over the last few years, multiple CAR T therapies have been approved for large cell lymphoma, follicular lymphoma, CLL, mantle cell, and multiple myeloma. However, these treatments come with their own unique set of side effects. Early recognition and management of these adverse side effects is crucial. Today, we've discussed adverse events and clinical pearls and how to manage these side effects with Dr. Surbhi Sidana from the Stanford University and Dr. Jason Westin from the MD Anderson Cancer Center.

Dr. Rohit Gosain: We have covered the importance of managing acute side effects like cytokine release syndrome, CNS toxicities, and electrolyte issues in hospital settings, and the need to monitor for chronic issues like secondary malignancies, cytopenias, and chronic infections. Approval is just the beginning. Managing adverse events is equally important. Thanks for joining us. Make sure to check out our other discussions around FDA approval, treatment algorithms, and conference highlights. We are the Oncology Brothers.