Hypogammaglobulinemia at Leukapheresis Predicts Delayed Humoral Immune Reconstitution and Increased Risk of Infections After CD19 CAR-T for B-Cell Lymphoma.

[BACKGROUND] Infectious complications account for approximately half of non-relapse mortality after chimeric antigen receptor T cell (CAR-T) therapy, yet the impact of pre-infusion humoral immunity on postinfusion immune reconstitution and infection risk remains controversial, particularly in CD19 CAR-T for B-cell lymphoma.

[OBJECTIVE] We aimed to analyze whether hypogammaglobulinemia at leukapheresis was associated with postinfusion infection rates, as well as its impact on blood counts and IgG recovery, with the ultimate goal of contributing to strategies that reduce infection incidence.

[STUDY DESIGN] We retrospectively analyzed 104 patients with relapse or refractory B-cell lymphoma who underwent apheresis for lisocabtagene maraleucel (liso-cel) or axicabtagene ciloleucel (axi-cel) therapy at our institution between September 2021 and September 2025. Patients were stratified based on hypogammaglobulinemia (IgG < 600 mg/dL) at leukapheresis. Postinfusion infection rates, blood count and IgG kinetics, and treatment outcomes were compared between the groups.

[RESULTS] Patients with hypogammaglobulinemia at leukapheresis had higher cumulative incidences of any-grade infections (69.5% vs 36.7% at 1 year, p < .01) and grade ≥3 infections (45.9% vs 11.1%, p = .04). At 1-year, the incidence of treatment-related mortality was higher in the hypogammaglobulinemia group (19.4% vs. 1.6%, p = .02), attributable to the higher estimated infection-related mortality rate (23.6% vs. 0%, p < .01). After adjustment for ECOG performance status, CAR-HEMATOTOX score and prior hematopoietic stem cell transplantation (autologous and/or allogenic), and corticosteroids exposure after CAR T-cell infusion, hypogammaglobulinemia at leukapheresis remained a significant risk factor of any-grade infections (HR 2.39, p = .05) and severe infections (HR 3.42, p = .03). Neutrophil and lymphocyte recovery at days 28, 90, 180, 365, 540 and 730 did not differ significantly between groups. However, in the hypogammaglobulinemia group, the median IgG level dropped below 400 mg/dL by day 90 (369 mg/dL) and remained below this threshold thereafter, whereas in the other group, the median IgG reached its lowest point on day 180 (472 mg/dL) and subsequently showed a recovery trend.

[CONCLUSION] Hypogammaglobulinemia at leukapheresis is a simple yet informative biomarker that predicts delayed humoral immune recovery, increased infectious events, and treatment-related mortality after CD19 CAR-T therapy in B-cell lymphoma. Moreover, it represents an independent risk factor for post-CD19 CAR-T infections, separate from neutrophil and lymphocyte recovery.