Matthew Frigault, MD, clinical director of the Cellular Immunotherapy Program at Massachusetts General Hospital, discusses differences in the toxicities experienced with CAR T-cell products used in the treatment of patients with leukemias and lymphomas.

The question of safety is a difficult one, as different institutions and cancer centers have different treatment algorithms and approaches, according to Frigault. Based on the results of the ZUMA-1 trial, axicabtagene ciloleucel (axi-cel; Yescarta) appeared to have a higher toxicity rate compared with what has been reported with tisagenlecleucel (Kymriah) in the JULIET trial and lisocabtagene maraleucel (liso-cel; JCAR017) in the TRANSFORM trial. Institutions also use different grading systems for toxicities, which makes comparing data yielded from the different pivotal studies difficult, adds Frigault.

Real-world data from the JULIET study showed that severe cytokine release syndrome (CRS) occurred in less than 5% of patients, although 22% of patients experienced this effect in the pivotal study, according to Frigault. These findings prove to be comparable with what was seen with liso-cel in that this agent also showed much lower rates of severe CRS and neurotoxicity according to real-world data versus findings reported in the clinical trial. The reduced rates of toxicity observed with these products underscores the evolution of how these patients are being managed in clinical practice, Frigault concludes. 

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Matthew Frigault, MD, discusses differences in the toxicities experienced with CAR T-cell products used in the treatment of patients with leukemias and lymphomas.


Dr. Frigault on Toxicity Differences Among CAR T-Cell Products in Leukemias, Lymphomas

I hope CAR T-cells have continued growth, because I’m banking my career on it and I have seen huge successes in patients. The way it’s impacted their lives is unquestionable. I have many high hopes for CAR T-cells moving forward. The exciting thing for me is that the CAR T-cells that we’re currently using in patients were things that we were working on 15 years ago. This is the Model T of CAR T-cells. Given the influx of research, excitement, and patient advocacy, commitments from institutions to develop this as a therapy are helping us to push CAR T-cell therapy forward exponentially.

Not only do we have other antigens beyond CD19 CAR T, but we have dual specific CARs [chimeric antigen receptors] targeting CD19, CD22, CD20, and CD79b. Those are in B cell malignancies. We have BCMA [B-Cell Maturation Antigen]-targeted CAR T-cells for multiple myeloma. We’re seeing tumor-infiltrating lymphocytes and other cellular therapies for things like lung cancer, head and neck cancer, cervical cancer, and melanoma. We’re seeing the boundaries get pushed and seeing patients who are refractory to all other modern therapies gain benefit. We’re just seeing the beginning. I could go on and on about all the different technologies that are currently being used, explored, or investigated. But I don’t think we have time for that.

It’s hopefully going to be a huge area of growth that’s going to lead to a benefit for patients. I’m really excited to see that happen. We’re also really pushing the boundaries in terms of patients who are ineligible and trying to understand how they work in CNS [central nervous system] disease and other atypical presentations. We’re finding that they provide benefit there, as well. As we learn how to manage the toxicities better, we open up possibilities for harder-to-treat patient populations, which will only improve outcomes and help benefit more patients. The world is our oyster in CAR T-cell therapy, and I’m excited for continued growth in that.

As for community oncologists, my biggest piece of advice is to refer early and get patients in. Once a patient shows any kind of chemotherapy refractoriness to second-line chemotherapy, they, by definition, meet eligibility for CAR T-cells and for FDA approval. When you’re thinking about this, adding and attempting a third line or using other agents may not necessarily be in the patient’s best interest as the disease progresses. We just weaken the immune system further, decrease lymphocyte counts, and make it harder to manufacture a CAR T-cell product. I would recommend referring early. From our center’s perspective, our goal is not to take patients and keep them. Our goal is to evaluate patients for CAR T-cells and cellular therapies, treat them, collaborate with you, and have the patients go back so that they can get closer to home and back to a team that they probably know better. We want to allow them to continue to gain benefit from the therapy.

For us, it’s about getting access to a therapy that’s very complicated. But the earlier the referral, the better. My email is probably online on a publication somewhere. I’m happy to discuss it with anyone if they have any questions, but refer early. That’s important, because with some recent approvals like bendamustine, rituximab, and polatuzumab vedotin, giving those types of agents is short-term beneficial. However, things like bendamustine do decrease lymphocyte quality and quantity significantly for weeks or months.

If you’re referring a patient after bendamustine, rituximab, and polatuzumab vedotin, it can sometimes be hard to successfully manufacture a CAR T-cell product. It’s not so much that we want to prevent that therapy from being given. It’s more about timing, strategy and the sequencing of therapies to get a patient to CAR T-cells as quickly as possible.

The Future of CAR T-Cell Therapy in Diffuse Large B-Cell Lymphoma 

For better or for worse, COVID-19 [coronavirus disease 2019] is here to stay. It will likely be here for the foreseeable future, regardless of our access to a vaccine. The difficulty with COVID-19 has been multifaceted. That includes patient access, patient referral, and patients’ concern for their own safety in coming into the hospital. There are concerns about bringing patients into the hospital safely, treating them, and having enough capacity within hospitals. It’s been multifold. We strive to continue prescribing these products and doing life-saving clinical trials, even through COVID-19, especially given that many of these patients don’t have other options.

Although COVID-19 has complicated things, we have to find newer and more creative ways of dealing with patients, helping them, and getting them to treatment. We’ve adapted more of a virtual approach, so we’re doing a lot of virtual screening from home and trying to limit patient contact with the health care system. We are doing multiple COVID-19 screenings prior to starting chemotherapy and cell infusion, and with fevers following cell infusion. We’re trying to do as much as we can in an outpatient setting to keep patients out of the hospital and avoid capacity issues. Simultaneously, we are balancing the follow-up requirements so they’re not having to come back and forth to a high-risk area multiple times.

Overall, our resources have been stretched thinner. But these are life-saving therapies, so we’re going to find a way to do them. As we look toward a second surge, we’ll hopefully learn from what we went through the first time. Boston was hit pretty hard. Despite that, having over 90% of our hospital at capacity with COVID-19, we were still actively treating patients with CAR [chimeric antigen receptor] T-cell therapy. That was in an isolated unit, and we were able to do so successfully without any complications related to COVID-19 in that population.

It requires a lot of infrastructure, thinking, and commitment. I have to commend the staff for the work they did during that time. I’ll also point out that CAR T cells may, in some ways, help us understand the mechanisms of toxicity related to COVID-19. There are ongoing clinical trials using multiple agents targeting the cytokine storm phenomenon. It is similar to CRS [cytokine release syndrome], although not entirely the same. There is a potential marker, IL-6, that may be associated with COVID-19–related mortality. Altogether, CAR T cells continue to benefit patients. It’s putting stress on the system, but we’re finding ways to deliver care. Hopefully, we can learn something to help in the pandemic from the work we’re doing with toxicity management in CAR T-cell therapy.

Resource utilization has become more complicated because we’re having to put more resources into getting the same amount of work done while keeping patients separate. We have separate elevators, a separate clinic, and separate everything for patients who have COVID-19 and for patients who are at risk of getting COVID-19 or are immunocompromised. That has put a strain on the system. Unfortunately, we’ve also seen a strain on staff. With the way the world has been, a lot of people are having to stay home and take care of their families, which is the right thing to do. But it is stressing the system as we continue to try to push on and move beyond this. From a physical resource perspective, in terms of masks and PPE [personal protective equipment], our institution did a fantastic job allocating those resources.

We’re doing everything we can and are seeing continued growth in our CAR T-cell prescribing and access. Although it’s more heavy lifting on all parts within the hospital, more resource utilization, and doing more with less, we are still able to move forward and will continue to do so. In terms of monitoring patients in the outpatient setting, as we move forward, 1 question is what would happen if we were to have another surge. In general, the majority of patients do just fine. Based on that Stanley Riddell abstract I previously mentioned, about 60% of patients in that cohort were treated outpatient. The median number of days of hospitalization for patients receiving tisagenlecleucel was only 2.

Patients can be safely treated in the outpatient setting. That also helps them avoid contact with the inpatient services. That helps with the capacity issue and with potential risks of exposure from staff and being in the hospital. I do feel that CAR T cells can be given safely in the outpatient setting. Altogether, it’s not so much a safety profile. There is definitely a minimum safety profile. If every patient has severe CRS within 24 hours, there’s no sense in doing it in the outpatient setting.

But for a lot of these products, especially tisagenlecleucel and axicabtagene, the onset of CRS is on the order of days following infusion. Only a very small subset of patients actually have severe and life-threatening CRS or neurotoxicity. As such, you need the infrastructure to be able to deliver the care. You need the nursing education. You need pharmacy for the REMS [Risk Evaluation and Mitigation Strategy] component. You need staffing to see the patients at least daily, early on, and then thereafter.

You need the means to get a patient into the hospital—your hospital, not a local satellite hospital—right away if toxicities are noted. We’ve put systems in place that have patients housed nearby. They’re seen very frequently at multiple points of contact throughout the day. Tocilizumab and steroids are available anytime, as are routine laboratory tests. Continuity of care is preserved so we can assess for neurotoxicity and allow for patient access. This will allow us to treat more patients, hopefully more safely and with multiple products, as we move forward despite COVID-19.

Impact of COVID-19 on CAR T-Cell Therapy for R/R DLBCL 

 There’s been a lot of talk about real-world data, how those play a role in decision-making for specific products, and whether these products are holding up to the pivotal studies. A lot of these pivotal studies had strict eligibility criteria.

We’re excited to have data that follow up the ZUMA-1 and pivotal JULIET studies. We look forward to having updated data in the real-world setting to follow. Let’s see how they stand up to the TRANSCEND data following FDA approval. I look forward to those data, which should be forthcoming following FDA approval.

What we’re really looking for is, how do these products act in the real world, given that nearly anyone with a hybrid B-cell lymphoma is now eligible for a CAR [chimeric antigen receptor] T-cell therapy.

We’re seeing in the real-world setting that largely, these products are holding up to what we saw in pivotal studies. We’re saying 

, but what we mean is retrospective cohorts that we’re analyzing following approval. There have been a couple of key abstracts that we can discuss that get at that point. The first abstract was from ASH [American Society of Hematology Annual Meeting] this past year by Karl Kilgore. It looked at Medicare patients receiving chimeric antigen receptors. The main point here is looking at whether, because these patients tend to be older, they can tolerate the treatment. We can see that even though they had multiple comorbidities, these patients actually can be treated successfully and safely.

When you look at the period of time leading up to CAR T-cell therapy vs the period of time after CAR T cell therapy, there doesn’t seem to be significant treatment-related mortality for CAR T, despite patients being considered “older.” That’s a very promising and exciting thing to be able to say. However, Lindsey Fitzgerald also published another abstract at ASCO [American Society of Clinical Oncology Annual Meeting] looking at patients over age 75. They were looking at what types of factors predict inferior outcomes.

Once you start going over the age of 65, they were able to show that overall survival decreases, although comparable PFS [progression-free survival] was seen with use of things like axicabtagene. That’s probably because of the increased toxicity and increased need for steroids for neurotoxicity. This is a retrospective cohort of patients, so we’re somewhat limited by selection bias in all these abstracts that we’re looking at. Higher-grade B-cell lymphomas, older age, high-risk features, and poor performance status going in were typically predictive of poorer responses.

But I’ll go back to the same point. There were patients who did well. There were patients who survived, and a majority of patients did well and will likely be cured from these therapies. When we say that they have inferior outcomes, we’re comparing the median progression-free survival of 6 months with almost 100% mortality. When we’re looking at this, we have to put things in context.

There are also some other published retrospective series. Both are published in 

. Those were by Loretta Nastoupil from The University of Texas MD Anderson Cancer Center and Caron Jacobson. Both were multicenter, retrospective cohorts analyzing axicabtagene in the real-world setting. We could see that overall, patients did well. All patients appeared to have similar responses, and the durability of responses was holding.

But interestingly, only half the patients in both cohorts actually met eligibility criteria for the initial ZUMA-1 cohort. This suggests that even though patients were sicker and older, had more comorbidities, and would not have been treated on the clinical trial, they did gain clinical benefit from the CAR T cells. Both of these studies were telling. Because there are 2 independent, retrospective, multicenter analyses with hundreds of patients, that largely validated the axicabtagene ciloleucel data from the pivotal ZUMA-1 study. There are also other abstracts that were key. Peter Riedell presented additional data at ASH 2019 looking at comparisons between axicabtagene and tisagenlecleucel prescribing habits across different centers.

Not to compare efficacy directly, but we were able to show that in different independent retrospective series looking at both products, the response rates, safety, and toxicity were largely the same. If anything, for tisagenlecleucel, the safety profile was improved compared with the pivotal study, given that they were using the updated ASTCT [American Society for Transplantation and Cellular Therapy] grading criteria. There are additional data that were updated at ASH 2019, with the most recent by Samantha Jaglowski, et al. It’s actually the CIBMTR [Center for International Blood and Marrow Transplant Research] registry data looking retrospectively, using the FDA-mandated registry as part of the REMS [Risk Evaluation and Mitigation Strategy] program. That is part of the mandated 15-year follow-up with the FDA. We have data for poor patient outcomes, toxicities, and adverse events. That is using the Center for International Bone Marrow Transplant Research Database, or CIBMTR, registry that we used for transplant.

In this cohort, they looked at patients who received tisagenlecleucel. They had a significant number of patients, although it was approved later. Therefore, we only had about 70 patients, at least with significant follow-up to look at. However, we’re seeing that overall response rates were comparable to pivotal studies. CR [complete response] rates were comparable to pivotal studies. Most important, the question of viability was addressed. Following the approval of tisagenlecleucel, the FDA requires a certain testing to be performed on the products. This is for all products.

However, 1 of the criteria is a viability component. Cells have to be greater than 80% viable. That doesn’t mean you don’t have an appropriate CAR T-cell dose. It’s just an independent variable. For some products, it hasn’t been an issue with manufacturing, but it was an issue with tisagenlecleucel. The viability cutoff of 80% at product launch wasn’t being met for a subset of patients. They were able to show in cohorts of patients, who had viability greater or less than 80%, that there were no differences in CR rates, PR [partial response] rates, or overall response rates.

As we start moving forward, this type of release testing should probably be reevaluated by the FDA.Ultimately, you can have a low viable percentage of cell population but have an equal CAR T dose. We have to understand that the real need that matters is the viable CAR-positive dose of cells that are going in. As long as we reach that, we’re seeing clinical benefit.

Real-World Data for CAR T-Cell Therapy for R/R DLBCL 

 There are 3 main studies of CAR [chimeric antigen receptor] T cells in DLBCL [diffuse large B-cell lymphoma]. The first, ZUMA-1, was published in 2017 in the

. This was published by Sattva Neelapu from MD Anderson Cancer Center. It was 1 of the first studies published. It was also what led to the first approval for CAR T cells in lymphoma for axicabtagene ciloleucel.

The exciting component of this clinical trial is that they had about 111 patients who were treated. They had a 99% manufacturing success rate. Then they had an objective response of about 82%, with a complete response [CR] rate of about 54% at a median follow-up of 15.4 months. They subsequently updated those data, which have shown that these responses are durable. The most common adverse effects were cytokine release syndrome and neurotoxicity, which were seen in a high percentage of patients, but were manageable on this study. All participants received inpatient treatment.

That led to the FDA approval with an accompanying REMS [Risk Evaluation and Mitigation Strategy] program, which many of us are trained in as we prescribe. That was the first clinical trial that was published. It led to the first approval for CAR T cells in lymphoma. The first CAR T-cell approval overall was tisagenlecleucel for pediatric and young adult B ALL [B-cell acute lymphoblastic leukemia]. However, that same tisagenlecleucel product was then subsequently approved a few months later based on the JULIET study. That was published in the

 in 2019. The lead author is Steve Schuster. That study comprised 93 patients who had a median follow-up of about 14 months.

The best overall response rate was around 52%, with a 40% CR rate. That is lower than what we saw in ZUMA-1. However, when you go out 12 to 24 months, the progression-free survival [PFS]—meaning the percentage of responders who end up relapsing—is around 35% to 40% for both studies. They’re likely comparable from a PFS benefit perspective.

We’re currently looking at whether subpopulations benefit more from 1 product or another. But high response rates mean nothing unless those response rates are durable. When I try to critique these studies, I’m looking at the 6-, 12-, and 24-month durability of those responses. They do appear to be comparable across all products. The difference in study design between ZUMA-1 and JULIET was that patients were enrolled at apheresis. Patients were screened, and if they met eligibility and there was a spot available, they were then enrolled. Patients went on to get apheresis and treatment without bridging therapy being available. Patients were very sick, had progressive disease, and did well anyway. For JULIET, patients were enrolled and collected, and then their cells were stored as they were awaiting a manufacturing slot.

Bridging therapy was allowed because there was a much longer delay between enrollment, apheresis, obtaining a manufacturing spot, and subsequent treatment. There’s a bit of selection bias and differences in bridging therapy and management. However, ultimately, these patients were also very sick. They had chemotherapy-refractory disease and they were getting chemotherapy as bridging therapy, which is not felt to be curative. As such, they were very sick. The most recent trial that came out was published from someone at our institution, Dr Jeremy Abramson. That was the TRANSCEND-NHL-001.

This was the largest cohort of patients at multiple dose levels using the product lisocabtagene maraleucel, which is currently being reviewed by the FDA for commercial approval. That included about 344 patients—a large cohort—at multiple dose levels with the recommended target dose of about 100 million cells. We can see here that the overall response rate was around 73% with a complete response rate around 53%. Again, we’re still looking at around 40% progression-free survival going out to 12 months. It’s very similar.

There are some differences, though, in toxicity across these products. When you’re looking at things like axicabtagene ciloleucel in ZUMA-1, they tended to have higher CRS [cytokine release syndrome] and higher neurotoxicity rates. That was using the Lee grading system from [Daniel] Lee, et al in 2014. When you look at JULIET for tisagenlecleucel, it was prior to having a consensus on an appropriate grading system, which led to them using the Penn criteria. I will speak about that shortly, but it tended to overestimate grade 3 toxicities.

Following the JULIET study, there are also some safety differences that we’re seeing in TRANSCEND-NHL-001, which was published in 

 in 2020 by Jeremy Abramson. Overall, they had very low CRS and neurotoxicity rates. They’ve seen them in about 40% of patients. There are around 10% and probably 2% of patients who had severe neurotoxicity and severe CRS. Overall, we’re seeing improvements, whether they are product-specific attributes or we’re learning from the prior studies how to manage these patients.

We’re using tocilizumab and steroids earlier, and as such, we’re seeing lower rates of severe CRS in subsequent studies.

However, there has been an evolution in management of these patients. When we go back to 2017, management was typically tocilizumab or steroids for grades 2 and 3 CRS. The same is true in JULIET. We weren’t sure at that point in time whether steroids or tocilizumab inhibited CAR T cells and whether they were detrimental to the overall outcomes.

We now think that tocilizumab is safe to give and does not impact CAR T function. TRANSCEND-NHL-001 benefited from that knowledge by being able to treat earlier and therefore, having less severe CRS and neurotoxicity. Taken together, this is a win across all 3 studies. We have 3 great products that offer PFS of around 40% for all comers. That is effectively curing high-risk patients who are otherwise chemotherapy refractory. It offers new treatment options for all patients with large cell lymphoma.

CAR T-Cell Therapy Clinical Trials for R/R DLBCL 

 What makes CAR [chimeric antigen receptor] T cells so fundamentally different from prior therapies is that they are immunotherapy designed from the patient’s own immune system. Patients have an apheresis or leukopoiesis process that collects peripheral blood mononuclear cells, or PBMC. This is done through an apheresis machine. It can be done over 4 to 6 hours using peripheral access. Those cells are then sent off a manufacturing facility where T cells are isolated or bulk PBMC is manufactured. The goal is to generate a population of CAR T cells that are now genetically modified and are instructed to target lymphoma.

What we’ve always tried to do with graft-vs-leukemia, graft-vs-lymphoma, or graft-vs-tumor in the allogeneic stem cell transplant setting is elicit an immune response against specific aspects of tumors, leukemias, and lymphomas. Unfortunately, that does come at some cost, and that cost is graft-vs-host disease. The thought behind CAR T cells is that rather than leaving it up to random HLA [human leukocyte antigen] mismatch or minor antigen presentation to elicit that immune response, we’re engineering exactly what we want the T cells to go after. In the case of the FDA-approved and currently pending products for lymphoma and leukemia, they’re going after an antigen called CD19. CD19 is fundamentally expressed on most, if not all, B cells and is thought to be expressed in low levels in multiple myeloma.

The thinking is that, by wiping out all CD19-positive cells, you knock out not only the lymphoma but normal, healthy B cells. As we’ve seen in follow-up data from patients after B-cell aplasia and hypergammaglobulinemia, which can result from B-cell aplasia, this does not seem to be detrimental overall with appropriate maintenance. Rather than using chemotherapy or targeted radiation therapy, it’s an immunotherapy using a gene therapy that retargets a patient’s own immune system to eradicate lymphoma or leukemia.

Based on all the outcomes we’ve looked at, this is a fundamentally game-changing therapy. These are novel mechanisms. Therefore, mechanisms that the tumors develop to be resistant to typical therapies—whether those tumors are high-risk 

-mutated CLL [chronic lymphocytic leukemia], another type, or double-hit lymphomas—don’t play out in cellular therapy as much as they do in historical chemotherapy. It’s very promising.

Mechanism of CAR T Cells in R/R Diffuse Large B-Cell Lymphoma 

 Prior to CAR [chimeric antigen receptor] T cells, we classified diseases into 2 main categories in the relapse or up-front refractory setting: chemotherapy refractory and chemotherapy sensitive. The distinction here is trying to determine who will gain benefit from addition of an autologous stem cell transplant using high-dose chemotherapy preconditioning. Typically, when patients relapsed following first-line therapy, depending whether it was within a certain time period of 12 months or so, we would classify these patients as high risk, chemotherapy refractory, or chemotherapy sensitive. Based on that distinction, we proceed forward to salvage chemotherapy, typically in the second line, with the hopes that we’ll get an adequate response to then bring these patients on high-dose chemotherapy and stem cell rescue or an autotransplantation.

We know that patients who had at least a partial response or more—ideally a complete response—to salvage therapy would then have a relatively high success rate with autologous stem cell transplant and high-dose chemotherapy. The premise is that high-dose chemotherapy for chemotherapy-sensitive disease would impart a survival benefit. However, we’ve seen over time that the degree of partial response does matter, and any residual disease following salvage therapy may be concerning. Those patients do have higher rates of relapse, as opposed to those who have a complete response following cycle 2 of salvage therapy.

It is typically recommended that patients are assessed, and if they do have an adequate response, they proceed to autologous stem cell transplant. However, we’re seeing the field evolve. For patients who do not achieve an adequate, complete response, may be in a partial response, or are considered high risk, we sometimes consider consolidation with CAR T cells as defined by calling that chemotherapy-refractory disease. This is constantly evolving. There are multiple clinical trials that are underway. They are looking at randomized phase 3 studies of all 3 major products—tisagenlecleucel, lisocabtagene maraleucel, and axicabtagene ciloleucel—comparing autologous stem cell transplant following salvage chemotherapy with up-front CAR T cells.

They are looking to see which approach has overall survival and progression-free survival benefits. This is a very evolving field. The goal at this point in time is to attempt salvage chemotherapy and proceed forward with autologous stem cell transplant if appropriate. If a patient were to relapse, the options then include things like CAR T cells, recently approved polatuzumab, or recently approved CD19 antibody MOR208.

From my standpoint, when we’re looking at patients following salvage chemotherapy, our goal is to find that truly chemotherapy-sensitive population. The field, at least at our institution, is moving forward or moving toward complete responses going on to autologous stem cell transplant. However, any partial response is going directly to CAR T cells. This is mainly based on the fact that historical data have shown us that partial responses do have inferior outcomes and CAR T cells do allow for ongoing benefit. This includes other abstracts and papers that were published in the past few years looking at retrospective analysis of JULIET. Patients who had CAR T-cell consolidation following third-line salvage therapy without measurable disease had benefit from CAR T-cell therapy. That was published in 

That is our practice. As we look at patients who are candidates for CAR T cells, it’s not so much who is a candidate for CAR T cell therapy, but how do you optimize the patient for CAR T cells? Later, we’ll get into the ideal patient population. They are older patients, patients we may not consider to be transplant eligible. That is defined by being older age, having lower ECOG performance scores, and being higher risk for comorbidities. However, we have successfully been able to treat patients well into their 80s, patients with cardiac disease, and patients with renal dysfunction.

It’s all patient optimization, and early and up-front discussion with the patient, as well as some co-consultants, to come up with an appropriate strategy for bringing the patient forward to CAR T-cell therapy, given that these are lifesaving therapies. You can expect upward of 40% to have progression-free survival with all 3 of these products going out 12 to 24 months. These fundamentally changed how we treat patients. We’re saving lives. There are obviously competing risks, but appropriate optimization can usually get a patient safely through CAR T-cell therapy.

Matthew J. Frigault, MD

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