Persistent hypogammaglobulinemia due to immunoglobulin class switch impairment by peri-transplant rituximab therapy

Mizuhara, Kentaro; Fujii, Nobuharu; Meguri, Yusuke; Takahashi, Takahide; M, Aoe; Nakamura, Makoto; Seike, Keisuke; Sando, Yasuhisa; Fujii, Keiko; Abe, Masaya; Sumii, Yuichi; Urata, Tomohiro; Fujiwara, Yuki; Saeki, Kyosuke; Asada, Noboru; Ennishi, Daisuke; Nishimori, Hisakazu; Matsuoka, Ken; Maeda, Yoshinobu

doi:10.1007/s12185-020-02886-x

Cited by 3 publications

(1 citation statement)

References 21 publications

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“…Nonetheless, the risk of hypogammaglobulinemia increases with time on B-cell–depleting maintenance therapy. 12 Importantly, the reversibility of hypogammaglobulinemia after B-cell–depleting therapy withdrawal could be related to the kinetics of CD27 + memory B-cell repopulation, 13 , 14 which highly depends on the time of maintenance therapy. Thus, one way to reduce the risk of hypogammaglobulinemia and subsequent infections could be to increase the dosing interval to lead to substantial CD27 + memory B-cell repopulation.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Rituximab Outlasts B-Cell Repopulation in Multiple Sclerosis

Claverie,

Perriguey,

Rico

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesPatients with multiple sclerosis (PwMS) receiving extended dosing of rituximab (RTX) have exhibited no return of disease activity, which suggests that maintenance of deep depletion of circulating B cells is not necessary to maintain the efficacy of RTX in MS.MethodsThis was a prospective monocentric observational study including all consecutive PwMS who started or continued RTX after 2019, when the medical staff decided to extend the dosing interval up to 24 months for all patients. Circulating B-cell subsets were monitored regularly and systematically in case of relapse. The first extended interval was analyzed.ResultsWe included 236 PwMS (81% with relapsing-remitting MS; mean [SD] age 43 [12] years; median [range] EDSS score 4 [0–8]; mean relapse rate during the year before RTX start 1.09 [0.99]; 41.5% with MRI activity). The median number of RTX infusions before extension was 4 (1–13). At the time of the analysis, the median delay in dosing was 17 months (8–39); the median proportion of circulating CD19+B cells was 7% (0–25) of total lymphocytes and that of CD27+memory B cells was 4% (0–16) of total B cells. The mean annual relapse rate did not differ before and after the extension: 0.03 (0.5) and 0.04 (0.15) (p= 0.51). Similarly, annual relapse rates did not differ before and after extension in patients with EDSS score ≤3 (n = 79) or disease duration ≤5 years (n = 71) at RTX onset. During the “extended dosing” period, MRI demonstrated no lesion accrual in 228 of the 236 patients (97%). Five patients experienced clinical relapse, which was confirmed by MRI. In these patients, the level of B-cell subset reconstitution at the time of the relapse did not differ from that for patients with the same extension window.DiscussionThe efficacy of RTX outlasted substantial reconstitution of circulating B cells in PwMS, which suggests that renewal of the immune system underlies the prolonged effect of RTX in MS. These findings suggest that extended interval dosing of RTX that leads to a significant reconstitution of circulating B cells is safe in PwMS, could reduce the risk of infection, and could improve vaccine efficacy.

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Section: Introductionmentioning

confidence: 99%

Efficacy of Rituximab Outlasts B-Cell Repopulation in Multiple Sclerosis

Claverie,

Perriguey,

Rico

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Rituximab

2020

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Predictors for Persistent Hypogammaglobulinemia After Rituximab Therapy in Pediatric Patients

Höppener,

Veldkamp,

Groot

et al. 2024

Preprint

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Hypogammaglobulinemia (HG) is a recognized consequence of rituximab (RTX) therapy, extensively studied in adults but minimally explored in children. We conducted a retrospective cohort study at a tertiary care center to determine prevalence, predictors and clinical outcomes of HG in children after RTX therapy. Patients aged ≤ 18 years treated with RTX for various indications between 2000 and 2020 were included. Patients were classified as having HG when (1) IgG levels were <-2SD below reference for age, or (2) they received immunoglobulin replacement therapy (IGRT). HG after the last RTX dose was observed in 100/141 patients (71%). Persistent HG (>6 months) was observed in 61/95 patients (64%), of whom 10 patients remained in HG for more than 5 years. Low baseline IgG levels and HSCT treatment were significantly associated with persistent HG. Median reconstitution time for CD19+ B cells was 11 months (IQR=[7.3-18.1]). Median reconstitution time for CD19+CD27+IgG+ switched memory B cells was 1.8 years (IQR=[0.87-2.8]) and for every additional 6 months of IgG+ memory B cell depletion, chances of recovering from HG fell by 11% (HR=0.89, 95% CI=[0.81-0.98], p=0.02). Four patients developed a class-switch recombination-deficiency. Recurrent infections, of which 2 fatal, were observed in 18 patients with HG. In conclusion, over 70% of children had low IgG levels and/or required IGRT following RTX therapy. Predictors for persistent HG were low pre-RTX IgG levels and/or patients post-HSCT. Children with HG were often IGRT-dependent, may suffer from (lethal) recurrent infections and can occasionally develop secondary Ig class-switch defects.

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Persistent hypogammaglobulinemia due to immunoglobulin class switch impairment by peri-transplant rituximab therapy

Cited by 3 publications

References 21 publications

Efficacy of Rituximab Outlasts B-Cell Repopulation in Multiple Sclerosis

Efficacy of Rituximab Outlasts B-Cell Repopulation in Multiple Sclerosis

Rituximab

Predictors for Persistent Hypogammaglobulinemia After Rituximab Therapy in Pediatric Patients

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