Characteristics and recognition of early infections in patients treated with commercial anti‐CD19 CAR‐T cells

Abstract

The characteristics of infections following chimeric antigen receptor T (CAR-T) cells targeting CD19 in real-word population are obscure. We analyzed infections' characteristics in the first month among consecutive patients with diffuse large B-cell lymphoma (DLBCL) (n = 60, median age, 69.3 years), treated with commercial CAR-T cells. ECOG performance status (PS) was 2-3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n = 5; periodontal infection, n = 1; and cellulitis, n = 1) and microbiology documented infection (MDI) in 9 patients (Gram-negative rod, n = 5; Gram-positive cocci, n = 3, bacteremia; polymicrobial, n = 1). The most common viral infection was cytomegalovirus (CMV) reactivation (n = 10, 17%) leading to initiation of anti-CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell-associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P = .018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P = .074). Age or PS was not associated with increased risk of bacterial infection. Increase in C-reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR-T-cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome.

Cytomegalovirus reactivation after CD19 CAR T-cell therapy is clinically significant

“…CMV viremia (n=14) and end organ disease (pneumonitis [n=2], enteritis [n=1], encephalitis [n=2], and retinitis [n=1)) have been reported after CAR T therapy. 4-12 Another study reported that ten of 60 (17%) CMV-seropositive and -seronegative patients receiving CAR T therapy developed CMV reactivation based upon a single test performed from day+14 to +21 after CAR T infusion, 13 none of these patients developed CMV organ disease. Interpretation of these studies with regard to CMV reactivation incidence is limited by the unknown or low frequency of testing.…”

Comparison of Droplet Digital PCR and Metagenomic Next-Generation Sequencing Methods for the Detection of Human Herpesvirus 6B Infection Using Cell-Free DNA from Patients Receiving CAR-T and Hematopoietic Stem Cell Transplantation

“…Viral infections are particularly common in late infections in CAR T recipients. 13 , 30 , 31 HHV-6B infection is a common type of viral infection after HSCT. 7 However, evidence regarding HHV-6 infection in CAR T recipients is limited to case reports and lacks sufficient clinical data.…”

“…CAR T recipients are highly susceptible to infections due to the immunodeficiency caused by prior chemotherapy treatment. 13 Two major toxicities resulting from CAR T-cell therapy are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). 14 Patients undergoing CAR T-cell therapy may also be at risk for HHV-6B-associated encephalitis, which can be difficult to distinguish from ICANS.…”

How I treat refractory/relapsed diffuse large B‐cell lymphomas with CD19‐directed chimeric antigen receptor T cells

“…Infections are the most frequent cause of non-relapse mortality. 35,54,110,114,[116][117][118][119] Risk factors for severe infections include severe CRS/ICANS, cytopenia prior to lymphodepletion, and prior allo-HSCT. 107,[109][110][111][112][113]115 Moreover, the severity of cytopenias correlates with the degree of CRS.…”

“…107 Other prognostic risk factors for infections after CAR T-cell therapy include age and immune reconstitution. 35,54,110,[116][117][118][119] A secondary myeloid neoplasm should always be considered in a patient developing pancytopenia of unknown significance after CAR T-cell therapy. Pathogenesis of myelodysplastic syndrome (MDS)/AML may be complex in these cases, with the most likely cause being the previous chemo-RT.…”