RESUMO
PURPOSE: Infections pose a significant risk during therapy for childhood cancer. However, little is known about the risk of infection in long-term survivors of childhood cancer. METHODS: We performed a retrospective observational study of children and adolescents born in Washington State diagnosed with cancer before age 20 years and who survived at least 5 years after diagnosis. Survivors were categorized as having a hematologic or nonhematologic malignancy and were matched to individuals without cancer in the state birth records by birth year and sex with a comparator:survivor ratio of 10:1. The primary outcome was incidence of any infection associated with a hospitalization using diagnostic codes from state hospital discharge records. Incidence was reported as a rate (IR) per 1,000 person-years. Multivariate Poisson regression was used to calculate incidence rate ratios (IRR) for cancer survivors versus comparators. RESULTS: On the basis of 382 infection events among 3,152 survivors and 771 events among 31,519 comparators, the IR of all hospitalized infections starting 5 years after cancer diagnosis was 12.6 (95% CI, 11.4 to 13.9) and 2.4 (95% CI, 2.3 to 2.6), respectively, with an IRR 5.1 (95% CI, 4.5 to 5.8). The survivor IR during the 5- to 10-year (18.1, 95% CI, 15.9 to 20.5) and > 10-year postcancer diagnosis (8.3, 95% CI, 7.0 to 9.7) periods remained greater than comparison group IRs for the same time periods (2.3, 95% CI, 2.1 to 2.6 and 2.5, 95% CI, 2.3 to 2.8, respectively). When potentially vaccine-preventable infections were evaluated, survivors had a greater risk of infection relative to comparators (IRR, 13.1; 95% CI, 7.2 to 23.9). CONCLUSION: Infectious complications continue to affect survivors of childhood cancer many years after initial diagnosis. Future studies are needed to better understand immune reconstitution to determine specific factors that may mitigate this risk.
Assuntos
Sobreviventes de Câncer , Neoplasias , Adolescente , Humanos , Criança , Adulto Jovem , Adulto , Neoplasias/epidemiologia , Neoplasias/terapia , Sobreviventes , Hospitalização , Estudos Retrospectivos , Fatores de RiscoRESUMO
Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range, <1 to 26), response rate of 86% (n = 131 of 152), 12-month OS of 75.1% (95% confidence interval [CI], 67.6% to 82.6%), and 12-month CIR of 36.4% (95% CI, 27.5% to 45.2%). Optimal fludarabine exposure was determined as AUC ≥13.8 mg × h/L. In multivariable analyses, patients with AUC <13.8 mg × h/L had a 2.5-fold higher CIR (hazard ratio [HR], 2.45; 95% CI, 1.34-4.48; P = .005) and twofold higher risk of relapse or loss of BCA (HR, 1.96; 95% CI, 1.19-3.23; P = .01) compared with those with optimal fludarabine exposure. High preinfusion disease burden was also associated with increased risk of relapse (HR, 2.66; 95% CI, 1.45-4.87; P = .001) and death (HR, 4.77; 95% CI, 2.10-10.9; P < .001). Personalized PK-directed dosing to achieve optimal fludarabine exposure should be tested in prospective trials and, based on this analysis, may reduce disease relapse after CAR T-cell therapy.
Assuntos
Imunoterapia Adotiva , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Lactente , Estudos Prospectivos , Recidiva , Estudos Retrospectivos , Vidarabina/análogos & derivados , Adulto JovemRESUMO
Chimeric antigen receptor (CAR) T cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia. Data for CAR therapy in extramedullary (EM) involvement are limited. Retrospective data were abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (complete response) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both central nervous system (CNS)3 and non-CNS EM) were compared with bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease before CAR therapy (CNS3, n = 40; non-CNS EM, n = 15). The median age at infusion in the CNS cohort was 10 years (range, <1-25 years), and in the non-CNS EM cohort it was 13 years (range, 2-26 years). In patients with CNS disease, 88% (35 of 40) achieved a complete response vs only 66% (10 of 15) with non-CNS EM disease. Patients with CNS disease (both with and without BM involvement) had 24-month OS outcomes comparable to those of non-CNS EM or BM only (P = .41). There was no difference in 12-month RFS between CNS, non-CNS EM, or BM-only patients (P = .92). No increased toxicity was seen with CNS or non-CNS EM disease (P = .3). Active CNS disease at time of infusion did not affect outcomes. Isolated CNS disease trended toward improved OS compared with combined CNS and BM (P = .12). R/R EM disease can be effectively treated with tisagenlecleucel; toxicity, relapse, and survival rates are comparable to those of patients with BM-only disease. Outcomes for isolated CNS relapse are encouraging.