Long-Term Risk of Infections After Treatment of Childhood Leukemia: A Population-Based Cohort Study Using Administrative Health Data

Abstract

PURPOSE Infections are a frequent complication during childhood leukemia treatment. Little is known about the infectious risk in survivors. We compared the relative rate (RR) of infections after treatment completion between pediatric leukemia survivors and the general population. METHODS We performed a retrospective, population-based cohort study of children diagnosed with leukemia between 1992 and 2015 in Ontario, Canada, who were alive and relapse free 30 days after treatment completion (index date). Leukemia survivors were matched 5:1 with the general population by year of birth, sex, and rural status and stratified by initial treatment, including and excluding hematopoietic stem-cell transplantation (HSCT). The primary outcome was time to infections, as identified using validated diagnostic codes from administrative databases. Individuals were censored at the earliest of death, first relapse, loss to follow-up, or end of study. RESULTS A total of 2,204 leukemia survivors were included and matched with 11,020 controls. The rate of infections was elevated after treatment completion compared with controls (RR, 1.51; 95% CI, 1.45 to 1.57) and at less than 1 year (RR, 1.77; 95% CI, 1.69 to 1.86); 1 to 4.99 years (RR, 1.66; 95% CI, 1.62 to 1.71), and 5 or more years (RR, 1.29; 95% CI, 1.22 to 1.36) from the index date. Among those whose initial treatment excluded HSCT, the rate remained elevated more than 5 years from the index date (RR, 1.29; 95% CI, 1.23 to 1.35). Infection-related death was significantly increased in leukemia survivors both among the entire cohort (hazard ratio, 149.3; 95% CI, 20.4 to 1,091.9) and among those without HSCT (hazard ratio, 92.7; 95% CI, 12.4 to 690.7). CONCLUSION A significant association was found between a history of leukemia therapy and an increased risk of infections. Additional study is needed to establish which exposures in patients with leukemia lead to late infections.

Multi-omic profiling of the leukemic microenvironment shows bone marrow interstitial fluid is distinct from peripheral blood plasma

“…While the cellular immune response is reinforced by increased hematopoiesis following induction chemotherapy our data confirms substantial reduction in the humoral innate immune response in line with increased susceptibility to infection [36,37]. Importantly, elements of this post-apoptotic immunosuppressed humoral microenvironment, such as elevated adenosine, may play an essential role in the regeneration of the hematopoietic progenitor cell pool [38].…”

Risks of late mortality and morbidity among survivors of childhood acute leukemia with Down syndrome: A population‐based cohort study

“…Similarly, DS is associated with immunodeficiency and a high susceptibility to infections, both at baseline and during leukemia treatment 6,30 . Interestingly, survivors of childhood cancer have recently been noted to be at increased risk of infection‐related death well after the completion of cancer treatment 31 . For both pulmonary and infectious complications, it is possible that baseline DS‐associated risks of infectious and pulmonary events are further increased among DS survivors, resulting in increased late mortality compared to both non‐DS survivors and DS controls.…”

The Microbiome in Childhood Acute Lymphoblastic Leukemia

“…Furthermore, in these individuals, increased T-cell activation and chronic inflammation was observed, suggesting a correlation between dysregulated microbial taxa and immune dysregulation [ 41 ]. The increased infection risk in survivors [ 73 ], a high prevalence of chronic health conditions [ 74 , 75 ] and an elevated risk of mortality and morbidity have been investigated [ 76 ]. Thus, microbial dysregulation due to the influences of chemotherapy and antibiotics during ALL treatment may have long-term effects on the development of other diseases, such as obesity or diabetes, in adult survivors of pediatric ALL [ 41 , 42 ].…”