Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma

Abstract

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed large B-cell lymphoma (LBCL). We evaluated the long-term course of hematologic recovery, immune reconstitution, and infectious complications in 41 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) at a single center. Grade 3+ cytopenias occurred in 97.6% of patients within the first 28 days postinfusion, with most resolved by 6 months. Overall, 63.4% of patients received a red blood cell transfusion, 34.1% of patients received a platelet transfusion, 36.6% of patients received IV immunoglobulin, and 51.2% of patients received growth factor (granulocyte colony-stimulating factor) injections beyond the first 28 days postinfusion. Only 40% of patients had recovered detectable CD19+ B cells by 1 year, and 50% of patients had a CD4+ T-cell count <200 cells per μL by 18 months postinfusion. Patients with durable responses to axi-cel had significantly longer durations of B-cell aplasia, and this duration correlated strongly with the recovery of CD4+ T-cell counts. There were significantly more infections within the first 28 days compared with any other period of follow-up, with the majority being mild-moderate in severity. Receipt of corticosteroids was the only factor that predicted risk of infection in a multivariate analysis (hazard ratio, 3.69; 95% confidence interval, 1.18-16.5). Opportunistic infections due to Pneumocystis jirovecii and varicella-zoster virus occurred up to 18 months postinfusion in patients who prematurely discontinued prophylaxis. These results support the use of comprehensive supportive care, including long-term monitoring and antimicrobial prophylaxis, beyond 12 months after axi-cel treatment.

Clinical and Product Features Associated with Outcome of DLBCL Patients to CD19-Targeted CAR T-Cell Therapy

“…As regards infections as a CAR T-cell-related toxicity, five patients in our cohort developed invasive fungal infections (candidemia and aspergillosis) and five exhibited CMV reactivations. This level could be associated with tocilizumab and corticosteroids treatments [ 37 ].…”

Infectious complications of CAR T-cell therapy: a clinical update

“…Overall, the most common late infectious aetiology in this cohort appears to be viral respiratory tract infection. 37 Indeed, the majority of late infections (>28 days postinfusion) were respiratory viruses in a number of studied cohorts. 35 , 37 , 42 This was confirmed in another small study where the majority of viral infections occurred after 30 days, and included one death due to influenza A.…”

“… 37 Indeed, the majority of late infections (>28 days postinfusion) were respiratory viruses in a number of studied cohorts. 35 , 37 , 42 This was confirmed in another small study where the majority of viral infections occurred after 30 days, and included one death due to influenza A. 22 A high incidence of respiratory viral infection during the late phase may be explained by patients who received CAR T-cell therapy swiftly responding to therapy and transitioning back into the community while still at risk.…”

“…Indeed, there appears to be a high rate of C. difficile infection among this group with cohort infection rates ranging from 12.5% to 20%. 22 , 30 , 35 – 37 Bacterial infection occurred infrequently after 30 days. In another study, bacterial infection occurred in 17% of patients within the first 28 days after infusion: half of these infection episodes were bloodstream infections including a small minority from multidrug-resistant Gram-negative pathogens.…”

Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy

“…[1][2][3] These individuals are profoundly immunocompromised from their underlying malignancy and prior anti-tumor treatments, in addition to CAR-T-cell therapy related factors including lymphodepleting chemotherapy and cytokine release syndrome (CRS). 4 Severe and often persistent cytopenias occur in part due to "on-target/off-tumor" depletion of nonmalignant B-lineage cells expressing the CAR-T-cell targets. [1][2][3][4][5][6][7] Strategies to prevent infections after CAR-T-cell therapy are not well established.…”