Getting to the heart of CAR T-cell therapy’s cardiovascular risks
How much risk is too much? It depends on what is at stake.
For a patient with advanced large B-cell lymphoma who has undergone numerous rounds of failed treatment, a certain amount of risk might be tolerated in search of a cure.
But what if that risk involves the patient’s heart? That requires careful contemplation, and it is a risk many patients who undergo chimeric antigen receptor T-cell therapy will be taking in the coming years.
As indications for CAR T-cell therapy expand, clinicians increasingly will be able to offer these treatments to patients who would have been excluded from clinical trials.
The addition of older, less healthy patients adds risk to a treatment that has already been associated with increased adverse cardiovascular events.
Cell Therapy Next spoke with several cardio-oncology specialists about the known potential for cardiovascular toxicity from CAR T-cell therapy, as well as the questions that remain about the treatment modality’s impact on heart health.
Most evidence about the association between cardiovascular risk and CAR T-cell therapy comes from two retrospective studies.
Lefebvre and colleagues collected data on 145 patients who underwent CAR T-cell therapy, including 31 who experienced some form of major adverse cardiac event (MACE) at a median 11 days after CAR T-cell infusion. Their analysis estimated a 17% chance for MACE at 30 days after infusion. Patients with symptomatic heart failure comprised the largest segment of those with MACE, accounting for 22 heart failure events and a 15% incidence of heart failure at a median 11 days after infusion.
“Patients treated with CAR T-cell therapy are at increased risk for MACE and may benefit from cardiovascular surveillance,” Lefebvre and colleagues concluded.
The group called for further research with large prospective studies to confirm risk factors predictive of MACE.
“There certainly is current evidence to indicate that CAR T-cell treatment is associated with subsequent adverse cardiac events,” Marielle Scherrer-Crosbie, MD, PhD, director of the cardiac ultrasound lab and professor of cardiovascular medicine at University of Pennsylvania, told Cell Therapy Next.
Scherrer-Crosbie, senior author of the study, said the results showed a high rate of cardiac events after the CAR T-cell infusion. Variables independently associated with MACE included baseline creatinine (HR = 15.54; 95% CI, 3.67-65.86), as well as grade 3 (HR = 8.42; 95% CI, 3.48-20.4) and grade 4 (HR = 29.86; 95% CI, 9.8–90.9) cytokine release syndrome (CRS).
“Oncologists should be aware that CAR T-cell treatment is associated with quite a high incidence of adverse cardiac events — in particular, heart failure,” Scherrer-Crosbie said. “Patients who develop moderate to severe CRS should be monitored closely and have a cardio-oncology consult.”
A study by Alvi and colleagues showed cardiac injury and MACE were common among adults after receiving CAR T-cell therapy. The researchers also observed relationships among CRS, elevated troponin and cardiovascular events, with a shorter time from CRS onset to administration of tocilizumab (Actemra, Genentech) associated with a lower rate of cardiovascular events.
Alvi and colleagues created a registry to describe the cardiac effects associated with CAR T-cell therapy. The aim was to determine if any diagnostic or treatment variables are associated with MACE among patients who receive CAR T-cell therapy.
The study included all patients (n = 137) who received CAR T-cell therapy at Massachusetts General Hospital and Moffitt Cancer Center between Jan. 1, 2016, and Nov. 10, 2018. Results showed 17 cardiovascular events (12%), including six cardiovascular-related deaths, six patients who developed decompensated heart failure, and five patients who developed arrhythmias (median time to event = 21 days).
All cardiovascular events occurred among patients who had grade 2 or greater CRS (31%); 95% of these events occurred after an elevated troponin level was recorded.
The investigators noted an association between cardiovascular events and time between CRS onset and administration of tocilizumab, with a 1.7-fold increase in risk with each 12-hour delay to tocilizumab.
Despite being limited by current data, which is observational and retrospective in nature, the findings of previous investigations indicate an increased prevalence of cardiac events in the post infusion period, according to study co-author Matthew J. Frigault, MD, assistant director of the cellular therapy service at Massachusetts General Hospital Cancer Center and member of the Cell Therapy Next Peer Perspective Board.
Frigault said research in the area of cardiovascular risk and CAR T-cell therapy is “shining a light on this important trend” and that further research will need to determine whether subsequent cardiac manifestations are the result of the CAR T cells or complications related to CRS.
“Research in this area is still relatively new but the data are hard to ignore,” he told Cell Therapy Next.
Both cellular therapy clinicians and community oncologists will need to remain abreast of research on the relationship between CAR T-cell therapy and MACE as the treatment expands to more patients.
“It’s fair to say that CAR T-cell therapy has revolutionized the prognosis for patients with certain hematologic malignancies,” Scherrer-Crosbie said. “Because this treatment is so promising, there is a large amount of research into applying it to solid tumors. Knowing the cardiovascular risks that may accompany this treatment is crucial.”
The importance of monitoring for long-term cardiovascular effects is important not only for cellular therapy clinicians, but also for referring community oncologists who are responsible for the longer-term care of patients.
“There are certainly short-term cardiac issues that can develop within the first month after receiving a CAR T-cell infusion, but whether there are longer-term cardiovascular implications is something that will require longer follow-up, in addition to awareness and monitoring by the primary referring oncologist or hematologist,” Yi Lin, MD, PhD, associate professor of hematology at Mayo Clinic in Rochester, Minnesota, told Cell Therapy Next.
For cellular therapy clinicians, being up to date on the latest risks and mitigation strategies is just as important because the field is so new and therefore rapidly adapting to use of these treatments in the real world, she added.
“The technology of CAR-T and how we manage side effects like CRS is changing, so some of the cardiovascular risks may change over time,” she said.
For example, Lin recalled that the initial practice during CAR T-cell therapy was to support patients who experience CRS but to refrain from tampering with the body’s reaction by providing treatments like tocilizumab to resolve CRS. The rationale behind the approach was the belief that introducing a new agent could hinder the effectiveness of the CAR T cells. When CRS moves into more severe grades it can result in symptoms such as hypotension, cardiac arrhythmia or heart failure, Lin said.
“As we have learned through clinical trial experience, giving drugs like tocilizumab to dampen CRS earlier in the course of CAR T-cell therapy will not necessarily lessen the efficacy of the drug,” she said.
This emerging research has led to fewer patients at risk for developing severe cardiac manifestations resulting from CRS, Lin said.
To Consult or Not to Consult?
The population receiving CAR T-cell treatment in the real-world setting is higher risk than that included in most clinical trials because it tends to be older — with an overall increased cardiovascular risk and greater likelihood of exposure to previous toxic treatments, Daniel J. Lenihan, MD, FACC, professor of medicine and director of the Cardio-Oncology Center of Excellence at Washington University in St. Louis, told Cell Therapy Next.
Lenihan, who specializes in treating the cardiovascular complications of CAR T-cell therapy, said the most significant cardiovascular manifestations occur within a week or two of the infusion and often are caused by CRS.
The cardiology department at his institution typically is consulted after the infusion if the patient is having a difficult time responding to treatment. The department will be brought in if the patient develops CRS that does not resolve quickly or if other cardiac manifestations develop.
“We try to be proactive,” Lenihan said. “If patients are going to be treated with a higher-risk therapy, then in general those patients will be at higher risk for cardiovascular problems.”
Lenihan agreed that more research regarding the possible cardiovascular toxicity of CAR T-cell therapy is needed.
“We try to adopt a strategy of sharing information with other cardio-oncology groups across the country,” he said. “As a result, we are constantly learning from each other.”
All patients who undergo CAR T-cell therapy at Mayo Clinic receive preinfusion cardiac evaluations with echocardiograms and electrocardiograms, Lin said. Patients with a history of cardiovascular events receive additional testing to determine their heart function status.
Patients with normal baseline evaluations and no history of cardiovascular events go directly to therapy, whereas those with a history and/or abnormal evaluations are referred to Mayo’s cardio-oncology department.
“Our cardio-oncologists work very closely with us if any cardiac issues were to develop during the course of treatment,” Lin said.
Scherrer-Crosbie said her institution consults its cardio-oncology clinicians when presented with patients who have a history of cardiovascular events or multiple cardiovascular risk factors.
“There are no standardized guidelines currently available when it comes to the role of cardiology consulting in patients undergoing CAR-T,” she told Cell Therapy Next.
Once again, this can be attributed to the relative novelty of CAR T-cell therapy, she added.
Guidance in the Absence of Guidelines
Cellular therapy clinicians and oncologists operate in the absence of guidelines on the cardiovascular risks of CAR T-cell therapy. The body of knowledge comes mostly from sharing anecdotal evidence, as was described in a recent review of the topic by Ganatra and colleagues.
“There is no standardized protocol for pretherapy [cardiovascular] evaluation, and the workup may vary from one institution to another, but it is generally geared toward determining whether patients can tolerate a period of hypotension and volume changes, which typically occurs with CAR T-cell therapy and related CRS,” they wrote.
Despite studies indicating a relationship between MACE and CRS, it is not typical practice to automatically consult cardiology before undergoing CAR T-cell therapy. Such decisions are made on an institutional, patient-by-patient basis, according to Bonnie Ky, MD, MSCE, the Founders Associate Professor of Cardio-Oncology at the University of Pennsylvania.
“The field of cardio-oncology is growing, and we have been working to determine which patients with cancer would benefit most from routine referrals to a cardiologist,” Ky told Cell Therapy Next.
Ky said attempts are being made to develop evidence-based practice guidelines — at the institutional level and more globally — to facilitate clinical decision-making to determine which patients with cancer should be referred to cardiology. Outside of prospective cohort studies, she added, patients are not consistently and routinely referred to cardiology departments.
According to Ky, clinical data published to date suggest that the adverse cardiovascular events observed during CAR T-cell therapy are often associated with CRS. Moreover, patients treated with CAR T-cell therapy may have been exposed to previous cardiotoxic therapies.
“CAR T-cell therapy may not be directly, mechanistically toxic to the myocardium,” she added.
The decision to consult with cardiology before CAR T-cell therapy depends on the baseline cardiovascular and oncologic risks presented by the patient, Ky said.
“Although I am wholly dedicated to the field of cardio-oncology, not every [patient with cancer] will need to see a cardiologist,” she said. “However, those at increased risk for cardiovascular complications should be evaluated to determine how to mitigate those risks.”
Nearly all the experts with whom Cell Therapy Next spoke said more prospective cohort studies that systematically collect blood biomarker and echocardiographic data will be required to show evidence of an association between CAR-T and adverse cardiac events.
“We need to examine whether there is a way to refine this prediction of risk, whether that be by examining cardiac imaging or looking at blood biomarkers,” Scherrer-Crosbie said. “Examining something like cardiac troponin levels may be a good way in the future to monitor for increased cardiac risk after CAR T-cell infusions.”
Additionally, data on which blood biomarkers are predictive of subsequent MACE could be useful in reducing the risk associated with CAR T-cell therapy in certain patients. Knowing which patients are at greatest risk would allow for preemptive mitigation strategies that could increase overall access to these therapies.
The increased incidence of cardiovascular events after CAR T-cell therapy should not come as a surprise, given that patients treated with the therapy tend to have advanced disease in tandem with the inflammation that results from robust clinical responses to the therapy, according to experts interviewed.
“I don’t look at this as a danger or warning signal for cellular therapy as a whole,” Frigault said. “I look at it as an opportunity to potentially optimize outcomes moving forward.”
Frigault said he typically refers patients with a cardiac history or risk factors to an internal cardio-oncologist and to discuss strategies to optimize the effectiveness of CAR T-cell therapy before it is given.
“It’s about optimizing the patient’s chances for success, rather than trying to fix a problem after it has occurred,” he told Cell Therapy Next.
“We don’t currently understand the long-term cardiovascular risks of this therapy,” Lin added. “But based on the limited data available at this point, the long-term cardiovascular risks appear to be relatively low.”
Despite these additional risks, Lin said that CAR T-cell therapy can and should be offered to more patients than are currently receiving it.
“We don’t want to be so strict that the patient has to have perfect heart health to be referred for CAR-T,” she said.
Lin encouraged local oncologists to refrain from prematurely excluding a patient because of a history of cardiovascular risk or disease.
“It’s preferred that the oncologist refers them to a CAR-T center to be seen by a specialist,” Lin said. “Then, in consult with cardio-oncology, we can determine whether there is an acceptable risk in getting the patient into remission and present the patient with the option.”
- Alvi RM, et al. J Am Coll Cardiol. 2019;doi:10.1016/j.jacc.2019.10.038.
- Ganatra S, et al. Cardiol Clin. 2019;doi:10.1016/j.ccl.2019.07.008.
- Lefebvre B, et al. JACC CardioOncol. 2020;doi:10.1016/j.jaccao.2020.04.012.
- For more information:
- Matthew J. Frigault, MD, can be reached at email@example.com.
- Bonnie Ky, MD, MSCE, can be reached at firstname.lastname@example.org.
- Daniel J. Lenihan, MD, FACC, can be reached at email@example.com.
- Yi Lin, MD, PhD, can be reached at firstname.lastname@example.org.
- Marielle Scherrer-Crosbie, MD, PhD, can be reached at email@example.com.