Asymptomatic Survivors of Childhood Acute Lymphoblastic Leukemia Demonstrate a Biological Profile of Inflamm-Aging Early in Life

SIMPLE SUMMARY: The most common malignancy diagnosed in childhood is acute lymphoblastic leukemia (ALL). With significant advances in ALL treatment and excellent supportive care, overall survival is now up to 90%, depending on the risk group. As a result, the survivor population is growing significantly. At the same time, it is observed that survivors experience many health problems that substantially reduce their quality of life. Emerging evidence suggests that the increased susceptibility to multiple disorders related to accelerated aging in CCS may be attributed to chronic inflammation. Therefore, this study aimed to investigate whether asymptomatic survivors of ALL have a biological phenotype of accelerated cellular senescence early in life. For this purpose, a broad panel of 51 cytokines was tested. We show that survivors after ALL treatment have an inflammatory profile associated with premature cellular aging. Factors that increase the risk of immunological alterations include younger age at diagnosis, high-risk protocols, and radiation therapy. ABSTRACT: Childhood acute lymphoblastic leukemia (ALL) survivors are at higher risk of developing many late effects later in life. They experience multiple health problems that have significant public health implications, such as frailty, premature onset of lifestyle diseases, and second tumors. There is some evidence that chronic inflammation causes accelerated aging in childhood cancer survivors; however, the available data are very limited. The aim of the study was to evaluate the broad panel of cytokines among asymptomatic ALL survivors after anticancer treatment. The study included 56 subjects with a mean age of 16.11 ± 3.98 years. The commercially available Bio-Plex Pro Human Cytokine Screening 48-Plex Panel Assay and Bio-Plex TGF-β Assay were used for simultaneous determination of 48 cytokines and 3 isoforms of TGF-β. Among 51 tested cytokines, the levels of 33 were statistically significantly higher in ALL survivors than in the control group (p < 0.05). Increased levels of pro-inflammatory cytokines, including the IL-1 family (IL-1 β, IL-1Ra; p < 0.0001), IL-6 (p < 0.001), IL-17 (p < 0.001), IL-18 (p < 0.05), TNFα (p < 0.01), IFNα2 (p < 0.05), and IFNγ (p < 0.01), were found elevated in the entire study group, compared with the controls. Subjects treated previously according to the high-risk protocol had higher IL-18 levels than low- and intermediate-risk groups (p < 0.05). Elevated levels of IL-1ra, IL-6, IL-12 (p70), IL-17, LIF, M-CSF, CSF, and VEGF were found in ALL survivors treated before the age of 5, compared with subjects treated over 5 years of age (p < 0.05). Moreover, individuals who received radiotherapy presented elevated levels of both IL-18 (p < 0.05) and MIG (p < 0.05). In conclusion, we found that young asymptomatic survivors after ALL treatment demonstrated a biological profile of complex low-grade chronic inflammation.