Treating hematologic immune dysregulation in inborn errors of immunity: a real-life multicenter study.

In recent years, immune dysregulation has been increasingly recognized as a presenting or leading feature of inborn errors of immunity (IEI). Indeed, immune dysregulation is part of the clinical phenotype of a wide range of IEI and depends on different, and significantly overlapped, molecular mechanisms (, ). The most common manifestations of immune dysregulation are lymphoproliferation (LPD) and autoimmunity, with autoimmune cytopenia (AIC) being the most frequently reported autoimmune feature. LPD is described in up to 40% of patients of the European Society for Immunodeficiencies (ESID) registry (), while the frequency of AIC is reported to be 120-fold higher in IEI when compared to the general population (, ). Also, hemophagocytic lymphohistiocytosis (HLH) can be part of the clinical spectrum of several IEIs (). Collectively, LPD, AIC, and HLH represent the main components of the phenotypic spectrum of hematologic immune dysregulation (H-ID). Several studies have addressed therapeutic strategies that directly target the underlying molecular defects in selected IEI with immune dysregulation. These options include JAK inhibitors for JAK/STAT-related disorders (e.g., STAT1 and STAT3 gain of function [GOF]), abatacept for CTLA-4 haploinsufficiency and LRBA deficiency, and leniolisib for the activated phosphoinositide 3-kinase delta syndrome (APDS) (–). Additionally, for a few monogenic conditions, it is possible to adopt therapies that target disease-specific overactivated molecular pathways. This is the case of sirolimus for autoimmune lymphoproliferative syndrome (ALPS) caused by mutations (ALPS-FAS, ALPS-somatic FAS, or ALPS-sFAS) and for APDS (, ), and for the use of etanercept in patients with deficiency of adenosine deaminase 2 (DADA2) (). Together, targeted therapeutic approaches opened new opportunities for the treatment of H-ID. However, a molecular diagnosis is available only for a subset of patients presenting with H-ID, thus significantly limiting a broader adoption of targeted therapies in clinical practice. Therefore, most patients are treated with immunomodulatory agents based on a phenotypic-directed approach and, in selected cases, undergo hematopoietic stem cell transplantation (HSCT) (). Given the heterogeneity of IEI and the variable clinical presentation and combinations of dysregulatory features, there is no uniform consensus on the optimal therapeutic approach in this subset of patients. In this study, we aimed to analyze the response rates and occurrence of adverse events (AEs) associated with individual therapeutic agents used in H-ID, with a specific focus on comparing targeted versus non-targeted (phenotypic-directed) therapies.