Activity of autologous anti-CD19 chimeric antigen receptor T-cell therapy in CD19-negative large B-cell lymphoma: A cell therapy consortium real world experience

Abstract Introduction Pivotal trials that led to the approval of autologous anti-CD19 CAR T-cell therapy (CART) either excluded patients with prior CD19-directed therapy or required CD19 expression. Therefore, the activity of anti-CD19 CART in patients with CD19-negative lymphoma remains unknown. While due to practice heterogeneity and technical sensitivity, accurate detection of CD19 expression by immunohistochemistry (IHC) or flow cytometry may be limited, these are the only two assays clinically available. As CD19-negative large B-cell lymphoma (LBCL) cases are becoming increasingly frequent, we present the first retrospective multi-center real world experience using CART in patients with CD19-negative LBCL. Method Retrospective data from the Cell Therapy Consortium were utilized for this analysis. LBCL patients treated with autologous anti-CD19 CART in second line and beyond between April 2016 and June 2021, and with available CD19 expression status by either IHC or flow cytometry, were included in this study. Patients who had received prior CD19-directed therapy were excluded. Baseline characteristics prior to the initiation of lymphodepleting chemotherapy were collected. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy guidelines, and response was assessed by investigator according to the Lugano 2014 criteria. Chi-square test or Fisher's exact test was used to evaluate the association between baseline categorical characteristics and CD19 expression, while Wilcoxon rank sum test was used to evaluate the difference in continuous variables between CD19 expression groups. Log-rank test was used to compare the differences in progression-free survival (PFS) or overall survival (OS) between/among patient groups. Results Among 211 LBCL patients, 81 (38.4%) had CD19 status available by IHC, 193 (91.5%) by flow cytometry, and 63 (29.9%) by both. Of interest, no patient who received CART in the second line had CD19 status available, and all patients included in the analysis had received CART in the third line and beyond. Overall, 37 patients (17.5%) were CD19-negative before CAR T-cell therapy by either test. No significant differences in baseline characteristics were observed when comparing CD19-negative to CD19-positive cases, including age, sex, histology, product type, performance status, international prognostic index, refractory status, history of autologous or allogenic stem cell transplant, bridging therapy, and prior lines of treatment, except for a significantly lower median hemoglobin in CD19-positive patients (10.6 vs. 12.0 g/dL, p = 0.0054). CD19-negative patients experienced a 2-fold lower incidence of ICANS of any grade (21.6% vs. 43.1%, p = 0.0151) and over 5-fold lower G3-5 ICANS (5.4% vs. 28.7%, p = 0.0015). No significant differences in CRS of any grade (67.6% vs. 73.0%, p = 0.50), G3-4 CRS (5.4% vs. 8.0%, p = 0.74), and day-30 G3-4 cytopenia (40.0% vs. 54.0%, p = 0.24) were observed when comparing the two groups. At day-90 assessment, no difference in overall response rate (51.7% vs. 60.0%, p = 0.41) or complete response rate (37.9% vs. 51.1%, p = 0.20) was observed when comparing CD19-negative to CD19-positive patients. With a median follow up of 18.7 months (95% confidence interval 14.4 – 21.5), no significant difference in PFS (median 3.48 vs. 7.33 months, estimated 2-year 30.1% vs. 30.6%, p = 0.55) or OS (median 22.3 vs. 13.7 months, estimated 2-year 45.7% vs. 44.4%, p = 0.84) was observed when comparing the two groups. Conclusion Our large real-world experience shows that, when using IHC or flow cytometry for CD19 expression assessment, patients with CD19-negative LBCL experience lower ICANS rates with anti-CD19 CART, potentially due to lower CD19 density, but overall efficacy is comparable to what is observed in CD19-positive LBCL. While our results support the use of anti-CD19 CART in CD19-negative LBCL, future larger studies with more sensitive CD19 testing than IHC and/or flow cytometry are warranted.