Impact of tocilizumab on anti-CD19 chimeric antigen receptor T-cell therapy in B-cell acute lymphoblastic leukemia.

BACKGROUND: Tocilizumab is commonly used for the management of chimeric antigen receptor (CAR) T-cell therapy-associated cytokine release syndrome (CRS). However, it remains unknown whether tocilizumab or its dosage affects the efficacy and safety of CAR T-cell therapy. The objective of this multicenter retrospective study was to explore the impact of tocilizumab on CAR T-cell therapy. METHODS: In total, 93 patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving humanized anti-CD19 CAR T cells were recruited from May 2016 to November 2022. Forty-five patients received tocilizumab (tocilizumab group), whereas 48 patients did not (nontocilizumab group). Thirteen patients received >1 dose of tocilizumab. The primary end point was the effect of tocilizumab on the efficacy and safety of CAR T cells. Additionally, proliferation, killing, and cytokine assays of CAR T cells were performed in vitro in the presence of tocilizumab. RESULTS: The median age of the patients was 33 years, with 47 males and 46 females. Patients in the tocilizumab group showed similar complete response (CR) rate, overall survival (OS), and event-free survival (EFS) compared with the nontocilizumab group. Compared with patients who received ≤1 dose of tocilizumab, receiving >1 dose of tocilizumab did not affect their CR rate, OS, or EFS. In the tocilizumab group, all patients experienced CRS and 26.7% experienced immune effector cell-associated neurotoxicity syndrome (ICANS). In the nontocilizumab group, 64.6% of patients experienced CRS and 8.3% experienced ICANS. Up to 75% of ICANS and 87.5% of grade ≥3 ICANS occurred in the tocilizumab group. In vitro, tocilizumab did not impair the proliferation and killing effects of CAR T cells. CONCLUSIONS: Tocilizumab does not affect the efficacy of CAR T cells but may increase the likelihood of ICANS.

Value of the prognostic nutritional index (PNI) in patients with newly diagnosed, CD5-positive diffuse large B-cell lymphoma: A multicenter retrospective study of the Huaihai Lymphoma Working Group.

BACKGROUND: CD5-positive diffuse large B-cell lymphoma (DLBCL) is a clinically rare subtype of DLBCL with aggressive clinical manifestations and a poor prognosis. It has been demonstrated that the prognostic nutritional index (PNI), an indicator of nutritional status and systemic inflammation, is a significant prognostic factor for several types of lymphoma. The objective of this multicenter retrospective study was to explore the prognostic value of the PNI in patients with CD5-positive DLBCL. METHODS: In total, 207 patients with CD5-positive DLBCL were recruited from 11 centers of the Huaihai Lymphoma Working Group. Maximally selected rank statistics analysis was used to identify optimal cutoff points for the PNI. A Cox proportional hazards model was used for univariable and multivariable analyses. Kaplan-Meier curves were used to calculate survival rates and draw survival curves, and the log-rank test was used to compare differences between groups. RESULTS: The median age at diagnosis was 61 years, and the 5-year overall survival rate was 47.5%. According to the maximally selected rank statistics analysis, a score of 49.7 was the optimal cutoff point for the PNI. Subgroup analysis showed that the PNI could re-stratify patients in BCL-2-negative, MYC-negative, high-intermediate-risk and high-risk International Prognostic Index, BCL-6-positive and BCL-6-negative, high Ki-67 score (≥0.9), Ann Arbor stage III/IV, Eastern Cooperative Oncology Group performance status ≥2, and germinal center B subgroups. Multivariable analysis revealed that PNI, age, Eastern Cooperative Oncology Group performance status, albumin level, and red blood cell count were independent prognostic factors for CD5-positive DLBCL. CONCLUSIONS: The PNI was a significant prognostic indicator for CD5-positive DLBCL and was able to re-stratify the prognosis for clinicopathologic subgroups of patients with CD5-positive DLBCL.

Anti-PD-1 Therapy Enhances the Efficacy of CD30-Directed Chimeric Antigen Receptor T Cell Therapy in Patients With Relapsed/Refractory CD30+ Lymphoma.

Anti-CD30 CAR-T is a potent candidate therapy for relapsed/refractory (r/r) CD30+ lymphomas with therapy limitations, and the efficacy needed to be further improved. Herein a multi-center phase II clinical trial (NCT03196830) of anti-CD30 CAR-T treatment combined with PD-1 inhibitor in r/r CD30+ lymphoma was conducted. After a lymphocyte-depleting chemotherapy with fludarabine and cyclophosphamide, 4 patients in cohort 1 and 3 patients in cohort 2 received 106/kg and 107/kg CAR-T cells, respectively, and 5 patients in cohort 3 received 107/kg CAR-T cells combined with anti-PD-1 antibody. The safety and the efficacy of CAR-T cell therapy were analyzed. Cytokine release syndrome (CRS) was observed in 4 of 12 patients, and only 1 patient (patient 9) experienced grade 3 CRS and was treated with glucocorticoid and tocilizumab. No CAR-T-related encephalopathy syndrome was observed. Only two patients in cohorts 2 and 3 experienced obviously high plasma levels of IL-6 and ferritin after CD30 CAR-T cell infusion. The overall response rate (ORR) was 91.7% (11/12), with 6 patients achieving complete remission (CR) (50%). In cohorts 1 and 2, 6 patients got a response (85.7%), with 2 patients achieving CR (28.6%). In cohort 3, 100% ORR and 80% CR were obtained in 5 patients without ≥3 grade CRS. With a median follow-up of 21.5 months (range: 3-50 months), the progression-free survival and the overall survival rates were 45 and 70%, respectively. Of the 11 patients who got a response after CAR-T therapy, 7 patients (63.6%) maintained their response until the end of follow-up. Three patients died last because of disease progression. Taken together, the combination of anti-PD-1 antibody showed an enhancement effect on CD30 CAR-T therapy in r/r CD30+ lymphoma patients with minimal toxicities.

Development and Validation of a Novel Prognostic Nomogram for CD5-Positive Diffuse Large B-Cell Lymphoma: A Retrospective Multicenter Study in China.

BACKGROUND: CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a rare subtype of DLBCL with invasive clinical features and poor prognosis. Current clinical variables based on prognostic systems for DLBCL are inadequate to accurately stratify the prognosis of CD5+ DLBCL. METHODS: A total of 195 CD5+ DLBCL patients were retrospectively recruited from nine centers in Huaihai Lymphoma Working Group. MaxStat analysis was used to identify optimal cutoff points for continuous variables; univariable and multivariable Cox analyses were used for variable selection; Kaplan-Meier curve was used to analyze the value of variables on prognosis; and C-index, Brier score, and decision curve analysis were measured for predicting model performance. RESULTS: The derivation and validation cohorts consisted of 131 and 64 patients. Of the whole cohort, median age at diagnosis was 61 years, of whom 100 (51.28%) were males and the 5-year overall survival rate was 42.1%. MYC, BCL-2, and the coexpression of MYC/BCL-2 could distinguish the survival of CD5+ DLBCL. Multivariable analysis showed that age, IPI, red blood cell count, neutrophil count, MYC expression, and hepatosplenomegaly were independent predictors, and the prognostic nomogram was developed. The C-index of the nomogram was 0.809 in the derivation and 0.770 in the validation cohort. Decision curve analysis proved that compared with IPI, the specific nomogram showed a better identification in CD5+ DLBCL. CONCLUSION: The proposed nomogram provided a valuable tool for prognosis prediction in patients with CD5+ DLBCL.