CD19 CAR-T-cells(Belarusian Research Center For Pediatric Oncology, Hematology And Immunology)

Lymphoma-associated hemophagocytic lymphohistiocytosis/syndrome (LA-HLH/LAHS) represents the most prevalent form of malignancy-associated HLH and is associated with an exceptionally poor prognosis. Emerging evidence implicates germline mutations as potential contributors to hematologic abnormalities, suggesting a genetic predisposition in affected individuals. We conducted whole-exome sequencing (WES) on a cohort of 12 LA-HLH patients, with detailed analysis of 3 representative cases exhibiting coexisting genetic disorders. These cases were comprehensively evaluated for their clinical management strategies and therapeutic outcomes. Our study revealed that gene mutations were detected in 6 patients (6/12), including 2 had somatic mutations, 3 had germline mutations, and 1 had both somatic and germline mutations. Among the 4 patients harbored germline mutations, 3 were diagnosed with concurrent genetic disease. Most patients (11/12) responded to immunochemotherapy for a short time and then progressed or relapsed, even after autologous hematopoietic stem cell transplantation (ASCT). Interestingly, two patients received CAR-T-cell therapy and achieved extremely good responses. One patient received CD19 CAR-T-cell infusion and had a PFS of 26 months. The other patient received double CAR-T infusions and has remained in complete remission for more than 2 years (until now). This study proposes that LA-HLH may constitute a novel genetic subtype of lymphoma. Systematic genetic sequencing should be prioritized to guide precision treatment approaches in selected cases, including immunotherapies such as CAR-T-cell therapy. These insights redefine our understanding of LA-HLH pathogenesis and clinical intervention strategies.

Fludarabine (FLU) is used for lymphodepletion and improves the persistence and expansion of chimeric antigen receptor (CAR) T cells in vivo. Higher FLU systemic exposure is associated with lower relapse risk and improved leukemia-free survival in pediatric patients with acute lymphoblastic leukemia treated with CD19 CAR T-cell therapy. FLU pharmacokinetics (PKs) is age dependent, with increased clearance in younger children. Here, we used modeling and simulation, including clinical trial simulations, to define age-adjusted FLU dosage regimens that may maintain effective FLU exposures and improve outcomes. The FLU PK and pharmacodynamic relationships with overall survival (OS) and cumulative incidence of relapse (CIR) were derived from published pediatric populations. Four FLU dosages were considered for the simulations: 75 or 120 mg/m2 cumulative fixed dose, age-adjusted dosing, and doses based on therapeutic drug monitoring (TDM). The target FLU cumulative area under the curve range was defined as 13.8 to 25 mg × h/L. Clinical trial simulations showed that across the pediatric age range, the number of individuals in the target range increased from a median of 22% to 61% with fixed dosages, to 72% with age-adjusted dosing and 94% with TDM. Clinical trial simulations also showed that age-adjusted or TDM dosing could increase the median number of individuals with OS at 24 months by 67% and decrease the median number of individuals with CIR at 12 months by 72%, compared with fixed dosages. In conclusion, these simulation studies support using FLU age-adjusted or TDM dosing to increase the number of individuals achieving exposure within the targeted range and, therefore, improve clinical outcomes.