Respiratory infections predominate after day 100 following B-cell maturation antigen-directed CAR T-cell therapy

Abstract

Infections are an important complication after B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy and risks may differ between the early and late periods. We evaluated infections in 99 adults who received a first BCMA-directed CAR T-cell therapy (commercial and investigational autologous BCMA CAR T-cell products at the recommended phase 2 dose) for relapsed/refractory multiple myeloma between November 2016 and May 2022. Infections were recorded until day 365, if patients experienced symptoms with a microbiologic diagnosis, or for symptomatic site-specific infections treated with antimicrobials. One-year cumulative incidence functions were calculated based on time to first respiratory infection using dates of infection-free death and receipt of additional antineoplastic therapies as competing risks. Secondary analysis evaluated risk factors for late respiratory infections using univariate and multivariable Cox regression models. Thirty-seven patients (37%) experienced 64 infectious events over the first year after BCMA-directed CAR T-cell therapy, with 42 early infectious events (days, 0-100), and 22 late infectious events (days, 101-365). Respiratory infections were the most common site-specific infection and the relative proportion of respiratory infections increased in the late period (31% of early events vs 77% of late events). On multivariable analysis, hypogammaglobulinemia (hazard ratio [HR], 6.06; P = .044) and diagnosis of an early respiratory viral infection (HR, 2.95; P = .048) were independent risk factors for late respiratory infection. Respiratory infections predominate after BCMA CAR T-cell therapy, particularly after day 100. Hypogammaglobulinemia and diagnosis of an early respiratory infection are risk factors for late respiratory infections that may be used to guide targeted preventive strategies.

Graphical abstract

Figure 1.

Early infections from days 0 to 100 after BCMA–directed CAR T-cell therapy.Figure 1 presents early infectious events from day 0 to day 100 (n = 42) by pathogen type and individual infection. Between day 0 and day 100 after cell infusion, 26 patients (26%) experienced 42 infectious events. Bacterial infections were the most frequent infectious event (69%), whereas viral infections were less common (17%) and fungal infections were rare (3%). Overall, 13 of 42 (31%) of early infectious events were respiratory infections involving the lungs, upper respiratory tract, or sinuses. “Pneumonia NOS” represents pneumonia diagnosed via clinical and radiographic criteria and not able to be delineated as bacterial vs viral. Amongst early infections, 3/6 cases of pneumonia were "Pneumonia NOS" and 3 cases had bacterial pathogens identified on microbiologic testing. NOS, Not otherwise specified.

Figure 2.

Late infections from days 101 to 325 after BCMA–directed CAR T-cell therapy. The figure presents late infectious events from days 101 to 365 (n = 22) by pathogen type and individual infection. Between days 101 and 365 after cell infusion, 15 patients (15%) experienced 22 infectious events. Viral infections were the most frequent infectious event after day 100 (41%) and bacterial infections were less common after day 100 (27%). A total of 32% of infections were clinical pneumonia that was not delineated as bacterial or viral. There were no fungal infections identified after day 100. The case of disseminated varicella-zoster virus developed in a patient admitted to an outside facility with a vertebral fracture who was briefly off prophylaxis in that setting, and there was no evidence of acyclovir resistance and he improved on IV acyclovir. Overall, 17 of 22 (77%) of late infectious events were composed of respiratory infections involving the lungs, upper respiratory tract, or sinuses. Pneumonia NOS represents pneumonia diagnosed via clinical and radiographic criteria that could not be delineated as bacterial or viral. Amongst late infections, 7/7 cases of pneumonia were "Pneumonia NOS".

Figure 3.

One-year cumulative incidence of respiratory infections after BCMA–directed CAR T-cell therapy. The 1-year cumulative incidence of respiratory infections accounting for competing risks of infection-free death and disease relapse requiring antineoplastic treatment was 22% (95% CI, 15-32).