Fungal infections following chimeric antigen receptor T-cell (CAR-T) cell therapy: A retrospective case-control study in the south-central US

Abstract Background: Patients receiving chimeric antigen receptor T-cell (CAR-T) therapy are at increased risk for infections due to profound and prolonged immunosuppression. Fungal infections, though relatively rare, can result in significant morbidity and mortality. However, data regarding the incidence, outcomes, and antifungal prophylaxis strategies in this population remain limited. Methods: We conducted a retrospective case-control study of adult patients who received CAR-T therapy at the OU Health Stephenson Cancer Center in Oklahoma City, OK between September 2019 and July 2024. Clinical, laboratory, and prophylactic data were collected and compared between groups, focusing on outcomes and prophylaxis practices. The primary outcome was invasive fungal infection within the first year after CAR-T therapy. Results: Among 94 patients who received CAR-T therapy, 7 (7.4%) developed a fungal infection within a year. All patients had received antifungal and Pneumocystis prophylaxis. Five patients (71.4%) had B-ALL. Two patients had bloodstream infections (BSI) breaking through micafungin, one with Cryptococcus neoformans, and one with Candida krusei. Another three patients broke through fluconazole, one with Candida glabrata BSI, one with Candida krusei BSI and one with Aspergillus pneumonia. The last two patients broke through posaconazole, one with invasive aspergillosis and one with Trichoderma pneumonia. Five infections occurred in the first 35 days after infusion, and two occurred past 180 days in the setting of relapsed disease. Four patients (57.1%) died due to the fungal infection. On univariate logistic regression, patients with fungal infections were less likely to have lymphoma (OR 0.03, 95% CI 0.003-0.25, p=0.026) or myeloma (OR 0.10, 95% CI 0.01-1.01, p=0.051), more likely to have had a prior allogeneic HCT (OR 64.5, 95% CI 5.43-766, p < 0.001), have a lower ANC at the time of CAR T (OR 0.04 per each 1k/µL increase, 95% 0.003-0.47, p=0.011), have prolonged neutropenia > 14 days after infusion (OR 15.6, 95% CI 2.72-89.9, p=0.002), or CMV reactivation at any time after CAR-T (OR 6.5, 95% CI 1.25-33.8, p=0.026). A multivariate logistic analysis could not be conducted due to the low event rate. Conclusions: While uncommon, invasive fungal infections tend to occur early after CAR-T therapy and are associated with markedly increased mortality despite antifungal prophylaxis. Patients with B-ALL, particularly those with a prior allogeneic HCT, patients with prolonged neutropenia or CMV reactivation after CAR T, seem to be at the highest risk. Larger prospective studies are needed to identify the subset of CAR-T recipients to target for individualized antifungal prophylactic strategies.