Case Report: Persistent Hypogammaglobulinemia More Than 10 Years After Rituximab Given Post-HSCT

Abstract

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.

Common Variable Immunodeficiency and Neurodevelopmental Delay Due to a 13Mb Deletion on Chromosome 4 Including the NFKB1 Gene: A Case Report

“…Once the patient received rituximab, low B cells and hypogammaglobulinemia persisted thus making difficult to establish an appropriate diagnosis of CVID. It is well described that rituximab may cause long term immunological effects undistinguishable from CVID in susceptible individuals specially with low IgG and IgA levels before therapy (23,24). Therefore, the role of NFKB1 as either causative or predisposing gene in this patient remains to be clarified.…”

Predictors for Persistent Hypogammaglobulinemia After Rituximab Therapy in Pediatric Patients

“…[43] We also identi ed a total of 4 patients with a post-RTX class-switch recombination-de ciency, a phenomenon that has only recently emerged in literature and been described as profoundly rare. [11,35,38,44,45] A recent study by De Bruin et al showed that an impaired IgG + memory B cell maturation post-RTX could not be attributed to intrinsic B cell defects, as in vitro stimulation led to normal maturation and class-switch recombination abilities [42].…”

Secondary rituximab‐associated versus primary immunodeficiencies: The enigmatic border

“…While hypogammaglobulinemia following biologic B-cell targeting therapies might be regarded as an uncommon but expected iatrogenic effect, it is significantly more challenging to establish the pathogenetic role of B-cell perturbation in patients that present a prolonged persistence of B-cell aplasia and low Ig values [8,9,11,17,23,29]. The lack of proper pretreatment assessment contributes to this confusion when hypogammaglobulinemia persists for years after treatment and selective B-cell targeting might not be sufficient to explain the lack of immune recovery.…”

“…Also, post-RTX PH has been observed in patients with HIV-associated lymphomas [23] and in patients after high-dose chemotherapy [24,25] as well as after stem cell transplant [14,[26][27][28]. Specifically, post-transplant EBV-associated lymphoproliferative disorder seems to be a high-risk condition for prolonged post-RTX hypogammaglobulinemia [29,30]. A higher number of doses have been significantly associated with PH in patients with NHL [24,31] by different groups, although data remain scarce and mainly retrospective.…”