Early toxicity and clinical outcomes after chimeric antigen receptor T-cell (CAR-T) therapy for lymphoma

Abstract

BackgroundChimeric antigen receptor T-cell (CAR-T) infusion is associated with early toxicity. Yet, whether early toxicity development holds ramifications for long-term outcomes is unknown.MethodsFrom a large cohort of consecutive adult patients treated with CAR-T therapies for relapsed or refractory lymphomas from 2016 to 2019, we assessed progression-free survival (PFS), by toxicity development (cytokine release syndrome (CRS), neurotoxicity, or cardiotoxicity]. We also assessed the relationship of toxicity development to objective disease response, and overall survival (OS). Multivariable regression was utilized to evaluate relationships between standard clinical and laboratory measures and disease outcomes. Differences in outcomes, by toxicity status, were also assessed via 30-day landmark analysis. Furthermore, we assessed the effects of early anti-CRS toxicity therapy use (at ≤grade 2 toxicity) on maximum toxicity grade observed, and long-term disease outcomes (PFS and OS).ResultsOverall, from 102 CAR-T-treated patients, 90 were identified as treated with single-agent therapy, of which 88.9% developed toxicity (80 CRS, 41 neurotoxicity, and 17 cardiotoxicity), including 28.9% with high-grade (≥3) events. The most common manifestations were hypotension at 96.6% and fever at 94.8%. Among patients with cardiac events, there was a non-significant trend toward a higher prevalence of concurrent or preceding high-grade (≥3) CRS. 50.0% required tocilizumab or corticosteroids. The median time to toxicity was 3 days; high grade CRS development was associated with cardiac and neurotoxicity. In multivariable regression, accounting for disease severity and traditional predictors of disease response, moderate (maximum grade 2) CRS development was associated with higher complete response at 1 year (HR: 2.34; p=0.07), and longer PFS (HR: 0.41; p=0.02, in landmark analysis), and OS (HR: 0.43; p=0.03). Among those with CRS, relative blood pressure (HR: 2.25; p=0.004), respectively, also associated with improved PFS. There was no difference in disease outcomes, or maximum toxicity grade (CRS, neurotoxicity, or cardiotoxicity) observed, based on the presence or absence of the use of early CRS-directed therapies.ConclusionsAmong adult lymphoma patients, moderate toxicity manifest as grade 2 CRS after CAR-T infusion may associate with favorable clinical outcomes. Further studies are needed to confirm these findings.

Longitudinal Collection of Patient-Reported Outcomes and Activity Data during CAR-T Therapy: Feasibility, Acceptability, and Data Visualization

“…Nonetheless, these observations complement an emerging body of research evaluating the link between the severity of clinician-reported toxicities and patients’ clinical outcomes. For example, Brammer and colleagues found that patients with lymphoma who developed moderate (grade 2) CRS post-CAR-T infusion had better disease response than patients with mild (grade 1) or severe (grade 3) CRS [ 48 ]. Future studies should combine clinician-reported toxicities with other data sources, such as PROs, to identify early risk factors for suboptimal clinical outcomes [ 49 ].…”

Cardiotoxicity of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Pathophysiology, Clinical Implications, and Echocardiographic Assessment

“…In recent years, many studies have specifically reported the cardiovascular outcomes of CAR-T therapy. However, reporting remains heterogeneous, warranting a standardization of methods and endpoints to allow a detailed comparison in future studies [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ] ( Table 3 ).…”

“…Studies have been performed in both adult and pediatric cohorts, with a mean sample size of about 100 patients in more recent series [ 4 , 12 , 20 , 21 , 26 , 29 , 33 , 34 ]. The most reported and frequent complication is hypotension requiring inotropic support, affecting about 25–30% of pediatric patients and 10% of adult patients [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Left ventricular systolic dysfunction affects 5–10% of patients, but its proper assessment is still debated.…”

Inducing immunogenic cell death in immuno-oncological therapies

“…Due to various challenges of external environment, such as immune surveillance and treatment pressures, CCs generally evolve and develop a low immunogenicity for escaping recognition by immune cells, such as dendritic cells (DCs) and T lymphocytes ( 3 - 6 ). Incidentally, an improved disease-free survival is observed in cases where tumors have low immune evasion capacity and a uniformly high infiltration of immune cells, or where tumor cells do not present any evidence of DNA immunoediting or disruption to antigen presentation ( 7 - 9 ). Hence, it remains a formidable challenge to compel CC-specific dying through reprogramming intrinsic immunogenicity during cancer immunotherapy.…”