Subgroup analysis of the best ORR (CR + PR) in patients in the Trial A.

Clinical characteristics of Trial A and B after PSM.

BACKGROUND AIMS:CD19 chimeric antigen receptor (CAR) T-cell therapy has shown promise in treating post-transplant lymphoproliferative disorder, but the risk of graft rejection is acknowledged and there is no consensus on the use of calcineurin inhibitors with CAR T-cell therapy. METHODS:We report a kidney transplant recipient with refractory Burkitt lymphoma who received cyclosporine A (CsA) following CD19 CAR T-cell infusion. Serial peripheral blood sampling was performed before and after CsA administration, and samples were analyzed via single-cell RNA sequencing. RESULTS:The patient exhibited robust CAR T-cell expansion and achieved a complete response. In vitro analyses demonstrated that CsA did not profoundly inhibit CAR T-cell activation, expansion or cytotoxicity. CONCLUSIONS:This case illustrates that the use of CsA following CAR T-cell therapy may be feasible and provides preliminary evidence supporting its investigation as a strategy for lowering the risk of graft rejection in patients with post-transplant lymphoproliferative disorder.

CRS, ICANS and cytopenias happened in Trial A and B.

Multivariate analysis of prognostic factors for PFS after PSM and IPTW.

Background: Chronic active Epstein-Barr virus disease (CAEBVD) faces a challenging prognosis due to its inflammatory and tumorigenic nature and lack of standard treatment. The outcomes of adults are more disheartening. We aim to elucidate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adult CAEBVD, while clarifying whether the combination of antithymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) can improve survival and reduce transplant-related complications. Methods: We conducted a retrospective study analyzing adult CAEBVD patients who underwent allo-HSCT sequentially in the Department of Hematology at Tongji Hospital, Huazhong University of Science and Technology, from June 2015 to January 2022. Results: Of 20 patients included. The median age at diagnosis was 30.5 years, and the median follow-up time post-transplantation was 26.9 months. The 5-year overall survival (OS), progression-free survival (PFS), GVHD-free and relapse-free survival (GRFS), and non-relapse mortality (NRM) rates were 54.5%, 39.4%, 44.4%, and 37.4%, respectively. These data were similar in ATG alone (50.0%, 33.3%, 33.3%, and 40.0%) and ATG+PTCy (56.3%, 41.7%, 49.0%, and 37.5%). On multivariable Cox regression, pretransplant hemophagocytic syndrome (25.0% vs. 75.0%, P=0.029) and higher EBV copies (25% vs. 61.9%, P=0.048) reduced the OS. On multivariable logistic regression, ATG+PTCy showed a lower incidence of grade II-IV acute GVHD (14.3% vs. 66.7%, P=0.037) and chronic GVHD (14.3% vs. 66.7%, P=0.037). Additionally, faster EBV clearance (P=0.002) and lower EBV reactivation (P=0.018) were observed in ATG+PTCy. Conclusion: Allo-HSCT can facilitate long-term survival in approximately half of adult CAEBVD. ATG+PTCy regimen did not improve survival but demonstrated advantages over ATG alone in reducing GVHD, eliminating EBV, and decreasing EBV reactivation.

Cellular kinetics of CD19 and CD22 CAR transgenes in peripheral blood and B cell aplasia

To investigate the risk factors for corresponding infections following chimeric antigen receptor (CAR) T-cell infusion in Carbapenem-resistant Enterobacteriaceae (CRE) carriers and to provide insights for managing such cases. A retrospective analysis was performed on the clinical presentation, laboratory findings, treatment, and prognosis of a patient with preexisting colonization who developed CRE intracranial infection after CAR T-cell therapy. A systematic review of the literature was conducted to explore optimal antibiotic strategies for CRE-associated central nervous system infections. Carbapenem-resistant Klebsiella pneumoniae was detected in perianal swabs before preconditioning chemotherapy, and the patient subsequently received high-dose corticosteroids for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome following CAR T-cell infusion. Despite broad-spectrum coverage, recurrent fevers and convulsions ensued. Metagenomic next-generation sequencing of cerebrospinal fluid on day +14 confirmed Kbsiella pneumoniae infection, later identified as a multidrug-resistant strain. Clinical and microbiological clearance was achieved following combination therapy centered on intravenous ceftazidime-avibactam, supplemented with intrathecal polymyxin B, guided by antibiotic susceptibility testing. The patient ultimately died three months later due to lymphoma progression. Defining optimal management strategies for CRE carriers is essential to integrate infection risk mitigation into the personalized framework of CAR T-cell therapy.

Subgroup analysis of the best ORR (CR + PR) in patients in all patients.

Survivals of patients with Trial A and Trial B after IPTW

Prognostic impact of risk factors in patients with R/R DLBCL.

Cytopenias occour in Trial A and B

Subgroup analysis of the best ORR (CR + PR) in patients in the Trial B.

The lymphocyte subsets of the peripheral blood of Trial A and B.

Representativeness of Study Participants

We conducted a comparative analysis of the long-term efficacy and safety of two single-arm trials for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL): CD19/CD22-directed chimeric antigen receptor (CAR19/22) T-cell cocktail therapy alone or combined with autologous stem cell transplantation (ASCT). The study included 124 patients not in remission after bridging therapy. Cytopenia (36.92% vs. 52.54%) and infection (29.68% vs. 28.81%) were the predominant late grade ≥3 adverse events. CAR19/22 T-cell cocktail therapy combined with ASCT achieved a higher overall response rate (best overall response: 78.46% vs. 93.22%, P = 0.023) and superior progression-free survival (median, 5.68 months vs. not reached, P < 0.001) and overall survival (median, 27.61 months vs. not reached, P < 0.001) than CAR19/22 T-cell cocktail therapy alone. Independent predictors of longer progression-free survival and overall survival included achieving a complete response at 3 months and receiving combination therapy. The associations remained statistically significant after adjustment in sensitivity analyses incorporating propensity score matching and inverse probability of treatment weighting. SIGNIFICANCE:CAR19/22 T-cell therapy combined with ASCT significantly improves response and survival in R/R DLBCL, including high-risk patients. This approach seems to enhance the efficacy-safety balance and offers a clinically actionable strategy to optimize CAR T-cell combination therapies.

CD19 chimeric antigen receptor T (CAR-T) cell therapy has shown promise in treating posttransplant lymphoproliferative disorder, but the risk of graft rejection is acknowledged, and there's no consensus on the use of calcineurin inhibitors with CAR-T cell therapy. We report a kidney transplant recipient with refractory Burkitt lymphoma who received cyclosporine A (CsA) following CD19 CAR-T infusion. The patient exhibited robust CAR-T cell expansion and achieved a complete response. In vitro analyses demonstrated that CsA did not profoundly inhibit CAR-T cell activation, expansion, or cytotoxicity. This case illustrates that the use of CsA following CAR-T therapy can be feasible, and provides preliminary evidence supporting its investigation as a strategy to lower the risk of graft rejection in patients with posttransplant lymphoproliferative disorder.

Background: Adult patients with chronic active Epstein-Barr virus (CAEBV) infection face a challenging prognosis. Increasing evidence shows that adult patients with CAEBV infections exhibit higher disease incidence and significantly poorer transplantation outcomes, characterized by faster progression and more aggressive disease. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative intervention，but the 3-year OS of adults was 31%, which was much lower than that for children (100%) and adolescents (57%) in some studies. However, most existing literature is outdated. While allo-HSCT theory and technology have advanced significantly over the past decade, it is crucial to determine whether these advancements have improved survival and transplantation outcomes for patients with CAEBV infection in adult haematology units. Furthermore, there is limited research into the impact of various GVHD prophylaxis strategies, such as post-transplant cyclophosphamide (PTCy), anti-thymocyte globulin (ATG), or a combination of the two, on post-transplant complications and prognosis in adult CAEBV patients. Methods: This study retrospectively reviewed patients receiving allo-HSCT at Tongji Hospital's Department of Hematology. Results: Of 20 patients included, 6 (33.3%) received anti-thymocyte globulin (ATG) as graft-vs-host disease (GVHD) prophylaxis strategy, 14 (66.7%) received combination of ATG and post-transplant cyclophosphamide (ATG+PTCy). Median age at diagnosis was 30.5 years, and 65% of patients were male; 55% received combination chemotherapy prior to transplantation. An HCT-CI score greater than 3 was observed in 35 % of patients. Hemophagocytic syndrome (HPS) was observed in 40% of patients prior to transplantation. The median follow-up from diagnosis to transplantation was 4.02 months, and 55% of patients received a haploidentical transplant. The median follow-up post-transplantation was 26.9 months. The 5-year overall survival (OS), progression-free survival (PFS), GVHD-free, relapse-free survival (GRFS), and non-relapse mortality (NRM) rates were 54.5%, 39.4%, 44.4%, and 37.4%, respectively. OS, PFS, GRFS, and NRM were similar regardless of GVHD prophylaxis strategy on multivariable Cox regression analysis. However, pre-transplant hemophagocytic syndrome (25.0% vs. 75.0%，P =0.029) and higher EBV copies (25% vs. 61.9%, P =0.048) reduced the OS. On multivariable Logistics regression analysis, ATG+PTCy showed a lower incidence of grade II-IV acute GVHD (14.3% vs. 66.7%, p=0.037) and chronic GVHD (14.3% vs. 66.7%, P=0.037). Additionally, faster EBV clearance (P=0.002) and lower EBV reactivation (P=0.018) were observed in ATG+PTCy. Conclusions: Allo-HSCT can facilitate long-term survival in approximately half of adult CAEBV patients,with the ATG+PTCy regimen demonstrating advantages in GVHD prophylaxis over ATG alone.

e14515 Background: The Epstein–Barr Virus (EBV) infects over 95% of the global population. The WHO has definitively identified EBV as the first human tumor-associated virus, thereby underscoring the necessity for novel therapeutic options. KSD-101, a First-in-class autologous dendritic cell (DC) vaccine which is loaded with the EBV-related antigen, is specifically tailored to target EBV-associated lymphoproliferative diseases (EBV-LPDs). Methods: Patients (pts) with EBV-LPDs and have not respond to or relapsed after standard treatment will be enrolled. Pts will receive monotherapy with KSD-101 via subcutaneous injection once every 2 weeks for 3-5 doses, without requiring pre-treatment lymphodepletion. The study used a 3+3 dose-escalation design, aiming primarily to assess tolerability, safety, dose-limiting toxicities (DLT) and maximum tolerated dose (MTD), with secondary objective to explore clinical efficacy and immune responses. Results: Between January 16, 2023, and May 21, 2024, 11 pts were ultimately enrolled and treated with KSD-101. In the escalation phase, 3 pts received 5.0 × 10 6 cells/dose and 2 pts received 7.5 × 10 6 cells/dose. Based on the safety, preliminary efficacy, and feasibility assessment, we decided to cancel the third dose group and apply 5.0 × 10 6 cells/dose to the expansion phase. In all pts, neither DLT nor MTD were explored. Vaccinations were well tolerated. Pts experienced KSD-101-related adverse events were injection site reactions (grade 1, 90.9%), fever (grade ≤ 2, 72.7%), lymphadenopathy (grade 1, 54.5%) and lymphocythemia (grade 1, 9.1%). The data cutoff was August 14, 2024 and the median follow-up was 54.1 weeks (range, 5.9-71.1 weeks). Two hemophagocytic lymphohistiocytosis pts discontinued from the study due to rapid early-stage disease progression and subsequently received alternative therapeutic interventions. The best ORR was 88.9% (8/9), with all pts achieving complete remission (CR). The DCR was 100% (9/9), with one pt demonstrating stable disease following vaccination. After vaccinations, we found that the peak proportion of EBV-specific T cells in CD3 + CD8 + cells (average, 4.21%) was significantly increased ( p < 0.05) compared to baseline (average, 0.61%) and the peak number of immune cells also increased, such as activated T cells ( p < 0.05, average increased to 2.61-fold), NK cells ( p < 0.01, average increased to 1.77-fold) and CD8 + T cells ( p < 0.05, average increased to 2.02-fold). We also found that the valley number of T-regs significantly reduced ( p < 0.01, average reduced to 58.14%). Conclusions: AS of now, KSD-101 has demonstrated good safety and efficacy and could activate immune system. Our study highlights its potential as a promising therapeutic agent for the treatment of EBV-LPDs. Larger prospective studies and a longer follow-up period is needed to be conducted. Clinical trial information: NCT05635591 .