Cardiopulmonary Comorbidities and CRS Risk After CAR T-Cell Therapy in DLBCL: Insights From Real-World Data

Key Takeaways:

• Cardiopulmonary comorbidities may increase cytokine release syndrome (CRS risk): Real-world data suggest that patients with diffuse large B-cell lymphoma (DLBCL) undergoing chimeric antigen receptor (CAR) T-cell therapy who have preexisting cardiac or pulmonary conditions may face a higher risk of CRS, underscoring the importance of comprehensive pretreatment evaluation.
• Enhanced risk stratification and monitoring are warranted: Baseline cardiac and pulmonary assessments, multidisciplinary care coordination, and risk-adapted monitoring strategies may help optimize outcomes for higher-risk patients without limiting access to potentially transformative CAR T-cell therapies.
• Real-world evidence can inform evolving clinical pathways: As CAR T-cell therapy expands into broader patient populations, real-world data analyses can help refine toxicity management protocols, patient selection criteria, and operational models across both academic and community settings.

In this interview, Heidi Cho, MD, vice president, franchise head and global therapeutic area head for hematology at Parexel, discusses findings from her study, "Impact of Pulmonary and Cardiac Comorbidities on Cytokine Release Syndrome Incidence in Chimeric Antigen Receptor (CAR) T-Treated Diffuse Large B-Cell Lymphoma (DLBCL) Patients: A Real-World Data Analysis." Drawing on real-world evidence, the study examines how common cardiopulmonary comorbidities may influence CRS risk and explores the implications for patient selection, pretreatment assessment, toxicity monitoring, and clinical pathway development as CAR T-cell therapy becomes more widely adopted.

Heidi Cho, MD: My name is Heidi Cho, and I am the franchise head of hematology at Parexel. I'm a board-certified pediatric hematologist oncologist with about 10 years of experience in industry. I also have extensive experience in clinical research, medical monitoring, and strategic development for many different types of advanced therapies, including CAR T-cell products. Over the course of my time at Parexel, I have supported numerous global hematology and oncology trials across both early and late phase development.

Can you give some background about your study and what prompted you to undertake it?

Dr Cho: This study was motivated by the ongoing challenges that we're seeing in clinical trials and in the real world of predicting and managing CRS) which is fairly well known as one of the most clinically significant toxicities associated with CAR T-cell therapy. And while the field has made progress in understanding the pathophysiology behind CRS, what's less known is how common preexisting comorbidities that are fairly common in the more elderly population—like pulmonary and cardiac diseases—affect the CRS risk and real-world practice. These comorbidities are highly prevalent in the DLBCL population but are often under underrepresented in clinical trials. So, to address this gap, we conducted a real-world data analysis using the TriNetX network to evaluate whether or not patients with these comorbidities experienced different CRS rates or survival outcomes after CAR T-cell therapy.

Our primary goal from this analysis was to help generate evidence that could inform risk stratification, monitoring strategies, and potentially form a pathway for this population that needs to be more closely reflected in everyday clinical practice.

Given the increased risk of CRS in patients with pulmonary and/or cardiac comorbidities, how should oncology practices and pathway committees rethink pre-treatment risk stratification before CAR T-cell therapy? Are there specific cardiopulmonary assessments or multidisciplinary evaluations you believe should become standard before initiating treatment?

Dr Cho: Our findings indicate that cardiopulmonary comorbidities should be considered meaningful risk modifiers for CRS, and our data suggest that it might be beneficial for hematology practices and pathway committees to strengthen the pretreatment risk stratification. This could potentially include standardized evaluations such as a baseline echocardiography and pulmonary function testing for patients who have known disease.  Multidisciplinary review, particularly involving the cardiac and pulmonary subspecialists, should also potentially be incorporated routinely before a patient receives CAR T infusion. In addition, ensuring comorbidities such as hypertension, chronic obstructive pulmonary disease, asthma, sleep apnea, and ischemic heart disease are optimally controlled prior to lymphodepletion is also going to be essential for this patient population. And for higher risk patients, utilizing risk-adapted monitoring plans, including earlier inpatient observation or consideration of extended post-infusion monitoring may be appropriate for patients who have these associated comorbidities. And again, these comorbidities don't preclude a patient from receiving CAR T therapy, but warrant a more structured or proactive evaluation of these patients before they receive CAR-T therapy.

The study leveraged real-world data from TriNetX rather than a clinical trial population. From a clinical pathways perspective, how valuable are these real-world findings in shaping CAR T toxicity monitoring protocols across community and academic settings? Do you see real-world data analyses increasingly influencing pathway decisions in cellular therapy?

Dr Cho: The real-world data is particularly valuable in cellular therapy because CAR T eligible patients often have complex comorbidities and clinical trajectories that are not fully captured in controlled clinical trial settings. And our analysis reflects a bit more diversity in terms of patients who are treated in both the community and academic centers, which makes these findings relevant for pathway development.

From a clinical pathways perspective, real-world evidence can oftentimes identify risk factors not observed in clinical trials. They can highlight variability and practice patterns and support evidence-based adjustments to monitoring protocols, triage criteria, and supportive care algorithms. Real-world data also provides early signals that can inform resource planning such as ICU readiness or multidisciplinary staffing. And as CAR T utilization expands, as we have seen rapidly over the last several years, I anticipate that real-world data analyses will increasingly influence these pathway decisions, particularly when it comes to toxicity management and patient selection.

What additional patient-level factors would you most want future studies to capture to better personalize CRS risk prediction?

Dr Cho: To better personalize CRS risk prediction, future studies would benefit from more granular patient-level data, which is not feasible using the TriNetX system. So, for future studies that include the severity and the control status of the cardiopulmonary comorbidities, having more access to baseline inflammatory markers such as C-reactive protein (CRP), ferritin, interleukin-6 (IL-6), and lactate dehydrogenase (LDH) in the functional status and measures such as Eastern Cooperative Oncology Group (ECOG) performance status or frailty indices would be beneficial to dig deeper onto the patient level. Additional factors of interest include disease burden metrics such as tumor volume or circulating tumor DNA, as well as CAR T specific variables like cell dose, expansion kinetics, and bridging therapy.

Another important factor would be medication history. Whether or not the patient is on medication such as corticosteroids, beta blockers, anticoagulants, and immunosuppressants would also enhance risk modeling. So collectively, having these additional data points would support more sophisticated multi-variable models and personalized risk stratification tools. Hopefully we can focus on some of these data points in our future research projects.

As CAR T-cell therapy moves earlier in treatment algorithms and becomes more widely used, what operational or clinical pathway changes may be necessary to safely manage patients with significant comorbidities?

Dr Cho: As CAR T cell therapy moves earlier in the treatment algorithms and becomes more widely used, hematology and oncology programs need to evolve both operationally and clinically to support a broader and more medically complex patient population. Having an integrated care model that includes cardiology, pulmonary, and critical care expertise in CAR T programs will become increasingly important. Standardized pre-infusion optimization pathways will help ensure that comorbidities are stabilized or controlled before the patient undergoes lymphodepletion. It'll be interesting to see how treatment in CAR T programs evolves, whether or not there may be risk-tiered monitoring frameworks that may allow lower-risk patients to be managed more safely in an outpatient setting, whereas high-risk patients could receive enhanced observation and potentially longer hospital stays.

Expanded community academic partnerships could also be further pursued or considered for these lower-risk patients where the infusion occurs at the specialized center or the academic center, but then follow-up could then be transitioned safely into an outpatient clinic. This would require enhanced training for community practices so they can quickly pick up on CRS, ICANS, or neurotoxicity, and cardiopulmonary decompensation would be critical for this pathway. And then ultimately, these changes would help ensure that patients with significant comorbidities can safely access and receive CAR T therapy without compromising the efficacy or outcomes.

Do you have any final thoughts or specific takeaways that you'd like our audience to take away from the study?

Dr Cho: How CAR T therapy evolves will be very interesting to watch, particularly in the next 1 to 5 years. There is a lot of interest in moving from ex vivo to in vivo therapy. And how we monitor those patients from a safety perspective and how we follow these patients more long-term will determine how this field changes over the next few years. Ultimately, what these therapies provide for these patients is an opportunity for them to treat their underlying disease and have improved quality of life and a longer progression-free survival. Considering how these treatments affect patients is our main priority and being able to safely administer these therapies to as many patients as possible is a key focus area.