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Rituximab (RTX) is an anti-CD20 monoclonal antibody that targets B cells—from the immature pre-B-cell stage in the bone marrow to mature circulating B cells—while preserving stem cells and plasma cells. It is used to treat autoimmune diseases, hematological malignancies, or complications after hematopoietic stem cell transplantation (HSCT). Its safety profile is acceptable; however, a subset of patients can develop persistent hypogammaglobulinemia and associated severe complications, especially in pediatric populations. We report the unrelated cases of two young men aged 17 and 22, presenting with persistent hypogammaglobulinemia more than 7 and 10 years after treatment with RTX, respectively, and administered after HSCT for hemolytic anemia and Epstein–Barr virus reactivation, respectively. Both patients’ immunological workups showed low levels of total immunoglobulin, vaccine antibodies, and class switched-memory B cells but an increase in naive B cells, which can also be observed in primary immunodeficiencies such as those making up common variable immunodeficiency. Whole exome sequencing for one of the patients failed to detect a pathogenic variant causing a Mendelian immunological disorder. Annual assessments involving interruption of immunoglobulin replacement therapy each summer failed to demonstrate the recovery of endogenous immunoglobulin production or normal numbers of class switched-memory B cells 7 and 10 years after the patients’ respective treatments with RTX. Although the factors that may lead to prolonged hypogammaglobulinemia after rituximab treatment (if necessary) remain unclear, a comprehensive immunological workup before treatment and long-term follow-up are mandatory to assess long-term complications, especially in children.

Most children with a SARS-CoV-2 infection are asymptomatic or exhibit mild symptoms. However, a small number of children develop features of substantial inflammation temporarily related to the COVID-19 also called multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), clinically similar to Kawasaki disease, toxic shock syndrome and hemophagocytic lymphohistiocytosis (HLH). It is well-known that genetic pre-disposition plays an important role in virally-triggered diseases such as Epstein-Barr virus (EBV)-associated HLH, while this has not yet been established for patients with MIS-C. Here we describe a male patient fulfilling the diagnostic criteria of MIS-C, who was initially treated according to current consensus guidelines. Presence of hypofibrinogenemia, normal lymphocyte counts and C-reactive protein, but substantial hyperferritinemia distinguish this patient from others with MIS-C. The clinical course following initial presentation with acute respiratory distress syndrome was marked by fatal liver failure in the context of EBV-associated HLH despite treatment with steroids, intravenous immunoglobulins, interleukin (IL)-1 receptor blockade and eventually HLH-directed treatment. X-linked lymphoproliferative disease type 1 (XLP1), a subtype of primary HLH was diagnosed in this patient post-mortem. This case report highlights the importance of including HLH in the differential diagnosis in MIS-C with severe disease course to allow specific, risk-adapted treatment and genetic counseling.

Abstract Development of novel therapies is critical for T‐cell acute leukaemia (T‐ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T‐ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T‐ALL cell samples cultured on stromal cells independently of NOTCH activation and maintained their ability to propagate in vivo. Similar results were obtained when T‐ALL cells were cultured with ERK1/2‐knockdown stromal cells or with conditioned medium from MEKi‐treated stromal cells. Microarray analysis identified interleukin 18 (IL‐18) as transcriptionally up‐regulated in MEKi‐treated MS5 cells. Recombinant IL‐18 promoted T‐ALL growth in vitro, whereas the loss of function of IL‐18 receptor in T‐ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL‐18R was activated by IL‐18 in blast cells. IL‐18 circulating levels were increased in T‐ALL‐xenografted mice and also in T‐ALL patients in comparison with controls. This study uncovers a novel role of the pro‐inflammatory cytokine IL‐18 and outlines the microenvironment involvement in human T‐ALL development.