Persistent Cytopenia After Cancer Treatment Reveals Underlying Inborn Errors of Immunity in Childhood Cancer Survivors: A Monocentric Italian Case Series

Background Inborn errors of immunity (IEI) are often associated with higher cancer risks, especially lymphoma, and genetic predispositions underlie many hematologic malignancies. Cytopenias following cancer treatment may occur sporadically or persist due to incomplete immune reconstitution. Recent findings suggest these abnormalities may indicate a previously undiagnosed IEI. Data on the prevalence and long-term follow-up of cytopenias in childhood cancer survivors (CCSs) remain limited. Aim To evaluate the prevalence of persistent cytopenias (PCs) in a cohort of CCSs followed at our late effects clinic (IRCCS Giannina Gaslini) and describe their clinical, immunologic, and genetic characteristics. Materials and Methods PCs were defined as those lasting over 12 months post-treatment or starting 6-12 months post-treatment and lasting over a year. CNS tumor survivors and those treated with allogenic marrow transplantation were excluded. Immunological and genetic analysis (NGS of 162 IEI genes or WES) were performed in patients with PC. Results Twenty (2.7%) out of 751 eligible CCSs (including 304 hematologic malignancies) showed PC, which was more common in patients with hematologic malignancies history (p < 0.00001). Patient characteristics and PC type are shown in Figure 1A. During follow-up, 6/20 patients developed autoimmune signs (10% incidence at 5 years, Figure 1B) at a median of 6.0 years post-treatment, 3/20 showed concomitant benign lymphoproliferation (EBV related in 1 case). Peripheral lymphocyte subsets revealed decreased B-memory and T-regulatory cells, increased activated δγ/HLADR+ T cells and B-naïve cells, and a shift to memory T cells (Figure 1C). Figure 1. Features of 20 CCSs with persistent cytopenia (A), cumulative incidence of autoimmune phenomena (B), and lymphocyte subpopulations (C). 12/20 patients were screened by genetic analysis, which in 6/12 (50%) of them showed pathogenic variants in TNFRSF13B, MAGT1, ITK, CEBPA, AIRE, and SAMD9 genes, related to auto/dysimmunity. 3/6 further developed subsequent neoplasms (SNs) (lymphomas, sarcoma, and giant-cell carcinoma). Conclusions In our cohort, the prevalence of PC following cancer treatment is overall low but higher in CCSs treated for hematologic malignancies, a finding consistent with the literature. PC may suggest underlying IEI, especially when associated with features like autoimmunity, peculiar immunophenotype, and lymphoproliferation. Careful and prolonged follow-up is necessary for the potential development of autoimmunity and SNs. Further studies are needed to confirm these findings and broaden their application to all CCSs with post-treatment immunologic abnormalities.