Examining Toxicities of CAR T-Cell Therapy in Patients With DLBCL

Chimeric antigen receptor (CAR) T-cell therapy has been an important addition to the treatment options for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). However, CAR T-cell therapies are associated with immune-mediated toxicities, and almost any tissue or organ system can be affected. In a report published in Blood Advances, Kitsada Wudhikarn, MD, from Memorial Sloan Kettering Cancer Center (MSKCC) in New York City and colleagues examined the incidence and types of CAR T-cell–associated adverse events (AEs) and their effects on outcomes in 60 patients with DLBCL.

While the authors found that CAR T-cell therapy was associated with a high burden of adverse events, they considered most of these were manageable and the rate of non-relapse mortality was low.

The toxicities varied widely, corresponding author Miguel-Angel Perales, MD, told ASH Clinical News. “Not only does the frequency of each individual toxicity vary, but the timing and impact on patients can also vary,” he said. “Acknowledging the real impact of toxicity burden on patients will guide the clinicians to provide appropriate care to these highly complicated patients.”

In this analysis, the investigators retrospectively reviewed the electronic medical records (EMRs) of adults with relapsed/refractory DLBCL who were treated with either axicabtagene ciloleucel (n=43) or tisagenlecleucel (n=17) at MSKCC. The investigators prospectively reviewed grade ≥2 toxicities from the day of CAR T-cell infusion until 1 year after, or until the time of systemic relapse, treatment reinitiation, death, or last follow-up prior to 1 year. Toxicities were stratified into 4 time periods: those occurring at day 0 to 30, day 31 to 100, day 101 to 180, and day 181 to 365.

The rate of non-relapse mortality was also recorded. Other study endpoints included event-free survival (EFS) and overall survival (OS).

At the time of CAR T-cell infusion, the median age of patients in the study cohort was 63 years (range = 19-85), and patients had received a median of 3 prior treatments (range = 2-9). Approximately one-quarter of patients (n=16) had undergone a hematopoietic cell transplantation before receiving CAR T-cell therapy, the authors noted.

“It remains a challenge for physicians to refine CAR T-cell therapy to make the experience more tolerable for patients.”

Miguel-Angel Perales, MD

The study authors observed a total of 539 grade ≥2 and 289 grade ≥3 AEs in the 60 patients. Most of these (87.2%) occurred within a 100-day period following CAR T-cell infusion. Hematologic, metabolic, infectious, and neurologic complications were the most common grade ≥3 toxicities observed in the sample, with 1-year cumulative incidences of 57.7%, 54.8%, 35.4% and 18.3%, respectively.

Any-grade cytokine release syndrome (CRS; an AE of special interest) was observed in 48 patients (80%). The other AE of special interest, any-grade immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 24 patients (40%). These AEs occurred early, at a median of 2 days (range = 0-11) and 5 days (range = 1-21) post-infusion, respectively. Only 15% of CRS cases (n=7) were grade ≥3, while 18 patients had grade >2 ICANS (representing 75% of those with ICANS).

During a median follow-up of 9 months, 55% of patients experienced disease relapse or progression, and 35% of patients died. Disease progression was the most common cause of death (n=19). This translated to estimated 1-year EFS and OS of 40% and 69%, respectively.

The authors conducted a univariable analysis to characterize the association between AEs and mortality, finding that patients with grade ≥3 severe pulmonary complications had a 3-times higher risk of death than those without pulmonary complications (hazard ratio [HR] = 2.92; p=0.04). However, statistically significant associations were not observed between OS and either severe CRS (HR=2.43; p=0.11) or neurological toxicities (HR=1.66; p=0.30). There also was no association between grade ≥2 toxicities and mortality, or between organ toxicities and EFS.

The investigators then evaluated the association between baseline characteristics and the occurrence of grade ≥3 AEs in each organ system. As seen in the TABLE, impaired performance status was linked to a higher incidence of metabolic complications, while elevated lactate dehydrogenase (LDH) levels were associated with a higher incidence of both neurologic and pulmonary complications. Patients who developed CRS were at a significantly higher risk of experiencing severe complications in other organ systems.

“By providing detailed information on both early and delayed toxicities related to CAR T cells, this study could help clinicians better understand and properly follow patients at varying time points along their treatment course,” Dr. Perales said. However, because this study is a retrospective review of patient EMRs, it is possible that organ toxicities were under- or over-recognized. The study population was small, which also could have resulted in missed identification of rare toxicities, and all patients were treated at a single center.

“Despite the evolution of supportive treatment patterns over recent years, the essence of the toxicity burden from CAR T-cell therapy remains high,” said Dr. Perales, “and it remains a challenge for physicians to refine CAR T-cell therapy to make the experience more tolerable for patients.”

He added that the study demonstrates the importance of a value-based approach to treatment of this patient population. “[Our findings] highlight the need for research on patient-oriented outcomes or novel supportive measures to improve the quality and experience of patients who undergo CAR T-cell treatment,” he concluded.

The authors report no relevant conflicts of interest.

Reference

Wudhikarn K, Pennisi M, Garcia-Recio M, et al. DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality. Blood Adv. 2020;4:3024-3033.