Patterns of leukocyte recovery predict infectious complications after CD19 CAR-T cell therapy in a real-world setting

Abstract

Background: Adoptive immunotherapy using CD19-targeted Chimeric antigen receptor T cells (CAR-T) has revolutionized the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Data is limited on the propensity of infections and lymphohematopoietic reconstitution after Day 30 (D30) following CAR-T cell therapy. In this study, we evaluated the prevalence and nature of infectious complications in an expanded cohort of DLBCL patients treated with CD19 CAR-T therapy and its association with the dynamics of leukocyte subpopulation reconstitution post-CAR-T cell therapy. Methods:We conducted a retrospective study including 19 patients who received axicabtagene ciloleucel and investigated associations between cytopenia and infectious complications after D30.Results: Nineteen patients were included, consisting of 42% Hispanic, 32% Caucasian, 21% African-American, and 5% Asian subjects. Post-D30 of CAR-T infusion, 47% patients (n=9) developed an infection and 53% (n=10) remained infection-free. The most common infection type observed was viral (7 patients) followed by bacterial (5 patients) and fungal (3 patients). Of 25 total infectious events, 56% were grade 1 or 2 and 44% were grade 3 with 10 being viral in etiology. To determine the kinetics of lymphohematopoietic reconstitution and its association with infection risk, we evaluated the relationship between cytopenias and rates of infection after D30. Notably, compared to non-infection group, infection group had a higher median absolute lymphocyte count (ALC) (1,000/µL vs. 600/µL, P<0.05), a lower median absolute neutrophil count (ANC)/ALC ratio (1.6 vs. 3.1, P<0.05) and a lower median AMC/ALC at D30 (0.37 vs. 1.67, P<0.05). In addition, we observed that only 22% of patients had recovered ANC >1,500/µL in the infection group as opposed to 70% in the non-infection group at D90 (P<0.05). Fifty-eight percent of the patients (11/19) with

Effects of B-Cell Lymphoma on the Immune System and Immune Recovery after Treatment: The Paradigm of Targeted Therapy

“…Neutropenia and lymphocytopenia are fairly universal before and after infusion. The duration of severe neutropenia can also be prolonged in 16% of cases, maintaining a high risk of infection over time [ 143 ]. In a retrospective study including 19 patients who received CD19 CAR-T cells, the absolute count of neutrophils and monocytes compared to the absolute lymphocyte count predicted infectious complications [ 144 ].…”

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

“…Grade 3 cytopenias developing >30 days after CAR T-cell infusion are defined as prolonged haematological toxicity, 107,109 occur in about 10%-20% of cases, and may present in two waves with a biphasic temporal course. 107,[110][111][112][113] Haematological toxicity is the most common adverse event after CAR T-cell therapy, with a cumulative 1-year incidence of 58% in the real-world setting. 110 In the ZUMA-1 study, neutropenia, anaemia and thrombocytopenia were observed in 78%, 43% and 38% of patients respectively.…”

“…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.…”

“…Early acute cytopenias occur 3–4 weeks after CAR T‐cell infusion and are usually related to bridging therapy, lymphodepletion, CRS 108 or macrophage activation syndrome. Grade 3 cytopenias developing >30 days after CAR T‐cell infusion are defined as prolonged haematological toxicity, 107,109 occur in about 10%–20% of cases, and may present in two waves with a biphasic temporal course 107,110–113 . Haematological toxicity is the most common adverse event after CAR T‐cell therapy, with a cumulative 1‐year incidence of 58% in the real‐world setting 110 .…”

Disseminated tuberculosis infection in a CAR T‐cell recipient

“…A recent study has proposed certain patterns of leukocyte recovery as potential novel predictors of infection in CAR T recipients. 7 There are recommendations to screen, monitor, and prevent infectious diseases in recipients of this therapy. [8][9][10] It is important to highlight the risk of reactivation of infections that could have remained latent under initial chemotherapy; in some cases, prophylaxis is recommended from the beginning of CAR T, or after close monitoring and detection of an increased risk in initially low-risk patients (as per hepatitis B infection and entecavir therapy, in patients who have antibodies against the surface of hepatitis B-anti-HBs + ), 10 but guidelines vary according to authors.…”