Effect of prior CD19-directed monoclonal antibody exposure on outcomes in patients subsequently treated with CD19 targeting CAR-T therapy: A multicenter propensity score matched retrospective cohort study

Abstract Background CD19 is a transmembrane glycoprotein expressed throughout B-cell development and is preserved in most B-Cell malignancies, making an attractive target for therapies. CD-19-directed monoclonal antibodies (CD19-mAb), such as tafasitamab and loncastuximab tesirine, are increasingly used in relapsed or refractory B-cell lymphomas. There have not been any large-scale, prospective studies evaluating the impact of prior exposure to CD19-mAb on outcomes in patients subsequently treated with CD19 targeting chimeric antigen receptor T-cell therapy (CD19-CAR-T). Current evidence in the literature has been limited to small case series. Furthermore, pivotal CAR-T trials excluded patients with previous exposure to CD19-mAb. This multicenter retrospective cohort study aims to evaluate the impact of prior treatment with CD19-mAb on outcomes in patients subsequently treated with CD19-CAR-T. Methods This multicenter propensity score matched retrospective cohort study was conducted using TriNetX, a deidentified database encompassing over 140 million patient records. Two cohorts of patients were created: I. Patients with prior CD19-mAb exposure who subsequently underwent CD19-CAR-T within 3 years II. Patients with no prior CD19-mAb exposure who were treated with CD19-CAR-T for malignancy. The primary outcomes analyzed were overall survival, rates of cytokine release syndrome (CRS), delayed immune effector cell-associated neurotoxicity (ICANS), and infection. Kaplan-Meier analysis, hazard ratios (HR), risk ratios (RR), and 95% confidence intervals (CI) were used to assess the primary outcomes. Patients were propensity-score matched (PSM) for demographics, laboratory values, and significant co-morbidities. Results In the unmatched cohort, there were 38 patients with prior CD19-mAb exposure who subsequently underwent CD19-CAR-T within 3 years. There were 4,499 patients with no prior CD19-mAb exposure who were treated with CD19-CAR-T. The incidence of cytokine release syndrome (CRS) was significantly lower in patients with prior CD19-mAb exposure compared to those with no prior exposure (risk ratio [RR], 0.66 [95% CI, 0.46–0.96]). There was no statistically significant difference in the incidence of ICANS between the two groups (RR, 1.41 [95% CI, 0.86–2.33]). Infection rates were not statistically significant between patients with and without prior CD19-mAb exposure (RR, 1.21 [95% CI, 0.97–1.50]). Overall survival was lower in patients with prior CD19-mAb exposure compared to those without prior exposure, with 2-year survival probabilities of 31.91% and 68.23%, respectively (hazard ratio [HR], 2.74 [95% CI, 1.78–4.22]). After PSM, 34 patients were included in each cohort. The incidence of cytokine release syndrome (CRS) was significantly lower in patients with prior CD19-mAb exposure compared to those with no prior exposure (RR, 0.56 [95% CI, 0.36–0.88]). There was no statistically significant difference in the incidence of ICANS between the two groups (RR, 0.77 [95% CI, 0.39–1.51]). Infection rates were comparable between patients with and without prior CD19-mAb exposure (RR, 1.09 [95% CI, 0.79–1.52]). Overall survival was lower in patients with prior CD19-mAb exposure compared to those no prior CD19-mAb exposure, with 2-year survival probabilities of 34.41% and 51.13%, respectively, though this difference was not statistically significant (HR, 1.70 [95% CI, 0.84–3.46]). Conclusion To our knowledge, this is the first large retrospective cohort study to investigate the influence of prior CD19-mAb exposure on outcomes following subsequent CD19-CAR-T therapy. Prior exposure was associated with a significantly lower incidence of CRS but did not significantly impact rates of ICANS or infection. Overall survival was lower in patients with prior CD19-mAb exposure; this trend persisted after PSM but was not statistically significant. However, the relatively small sample size after PSM, limits this study and warrants cautious interpretation. These results highlight the need for careful consideration of prior CD19-directed therapies when planning CAR-T treatment and underscore the importance of prospective studies to optimize sequencing strategies and improve patient outcomes.