Rituximab-induced B-cell Depletion Research Articles

Rituximab-to-vaccine interval on SARS-CoV-2 immunogenicity in children: The potential role of prior natural infection.

Treatment with anti-CD20 antibodies (rituximab) is used in both adults and children to treat various autoimmune and oncological diseases. Rituximab depletes B CD20+ cells and, thereby, antibody response to vaccines. This study aimed to examine the antibody response to mRNA-based COVID-19 vaccines in children aged 5-18 years undergoing rituximab treatment compared to healthy matched children. Between 31 January and 18 July 2022, we conducted a prospective observational study at the Geneva University Hospitals, enrolling children aged 5-18 years under rituximab treatment who had received two mRNA-based SARS-CoV-2 vaccine doses. Controls were healthy volunteers with no significant medical conditions. Exclusion criteria included a recent SARS-CoV-2 infection. Blood samples were collected at day 60 (±30) and day 270 (±90) after the second vaccination. The rituximab-treated group exhibited significantly lower levels of antibodies specific to the anti-receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein than healthy controls at 60 (±30) days after the second vaccine dose (geometric mean concentration: 868.3 IU/mL in patients and 11,393 IU/mL in controls; p = .008). However, patients with a rituximab-to-vaccine interval shorter than 6 months and with evidence of a past infection (based on positive anti-N antibody levels) had a high level of anti-RBD antibodies. A past infection with SARS-CoV-2 may induce anti-RBD-specific memory B cells that can be re-activated by SARS-CoV-2 vaccination, even after rituximab-induced B-cell depletion. This suggests that it is possible to vaccinate earlier than 6 months after rituximab to develop a good antibody response, especially in the case of past SARS-CoV-2 infection.

Antiviral treatment with fluoxetine for rituximab-associated chronic echovirus 13 meningoencephalitis and myofasciitis.

Enterovirus infections pose a serious threat for patients with humoral deficiencies and may be lethal, whilst the efficacy of proposed treatment options such as corticosteroids, intravenous immunoglobulins and fluoxetine remains debated. Viral clearance was investigated in a patient with rituximab-induced B-cell depletion and chronic echovirus 13 (E13) meningoencephalitis/myofasciitis in response to intravenous immunoglobulins and fluoxetine using sequential semi-quantitative E13 viral load measurements by real-time reverse transcription polymerase chain reaction. Fluoxetine concentrations in plasma and cerebrospinal fluid were determined by liquid chromatography mass spectrometry. Intravenous immunoglobulins appeared ineffective in this case of E13 infection, whereas virus clearance in cerebrospinal fluid was obtained after 167 days of oral fluoxetine. Since treatment with corticosteroids resulted in a flare of symptoms, rechallenge with viral load measurements was not attempted. In this report of a patient with rituximab-associated chronic echovirus 13 meningoencephalitis, viral clearance in response to single treatment options is assessed for the first time. Our observations further support the in vivo efficacy of fluoxetine against enteroviral infections. More research is needed to establish its efficacy in different enterovirus strains.

Immunological changes in diffuse large B-cell lymphomas after Rituximab-CHOP treatment: Own data and review of the literature

Rituximab treatment may induce a long-term B-cell depletion, which can be accompanied with an increased infection risk. To examine the changes of the white blood cell, CD19+ B-cell and CD4+ T-cell counts and the levels of immunoglobulin G, A, M after rituximab containing chemotherapy and to explore the infectious complications in our patients and review of the literature. Thirty-five diffuse large B-cell lymphoma patients were examined, who were treated with rituximab-cyclophosphamide-vincristine-doxoribicine-prednisolone (R-CHOP). The B- and T-cell populations were analyzed with flow-cytometry while the immunoglobulin levels were measured by nephelometry. CD19+ B-lymphocytes were undetectable after the treatment and their count only increased from the post-therapeutic 12th month. Infection did not occur in this group of patients. Rituximab induced B-cell depletion was appreciable also in this group of patients, while serious or unexpected infection did not occur. Increased infectious risk primarily can be observed after long-term, maintenance rituximab treatment.

A Prospective Study of the Factors Shaping Antibody Responses to the AS03-Adjuvanted Influenza A/H1N1 Vaccine in Cancer Outpatients

To identify the determinants of antibody responses to adjuvanted influenza A/H1N1/09 vaccines in a cohort of cancer outpatients. Patients with cancer and controls were enrolled in a prospective single-center field study. Two doses of AS03-adjuvanted pandemic influenza vaccine were administered to patients and one dose was administered to controls. Antibody responses were measured using hemagglutination inhibition and confirmed by microneutralization. Geometric mean titers (GMTs) and seroprotection rates (defined as GMTs ≥40) were compared. Immunizations were safe and well tolerated in 197 cancer patients (lymphoma, 57; glioma, 26; lung or head and neck, 37; gastrointestinal, 41; breast, 36) and 138 controls. Similar seroprotection rates (82.3% versus 87%) and GMTs (336.9 versus 329.9) were achieved after two doses of adjuvanted vaccine in cancer patients and one dose in controls. Univariate analyses identified older age, prior immunization against seasonal influenza, lymphoma, CD4 count, active chemotherapy, and rituximab and steroid treatments as being associated with weaker antibody responses. However, only age and chemotherapy plus rituximab remained independent determinants of vaccine responses in multivariate analyses. Two doses of AS03-adjuvanted influenza vaccine elicited potent antibody responses in most cancer patients despite ongoing chemotherapy, with the exception of rituximab-induced B-cell depletion. Oncology patients treated in an outpatient setting benefit from preventive vaccination against influenza with adjuvanted vaccines.

Chemokine/cytokine profiling after rituximab: Reciprocal expression of BCA-1/CXCL13 and BAFF in childhood OMS

The aim of the study was to test the hypothesis that B-cell repopulation following rituximab (anti-CD20) therapy is orchestrated by chemokines and non-chemokine cytokines. Twenty-five children with opsoclonus–myoclonus syndrome (OMS) received rituximab with or without conventional agents. A comprehensive panel of 40 chemokines and other cytokines were measured in serum by ELISA and multiplexed fluorescent bead-based immunoassay. Serum BAFF concentration changed dramatically (even after first infusion) and inversely with B-cell depletion/repopulation and CXCL13 concentration at 1, 3, and 6 months. Negative correlations were found for BAFF concentration vs blood B cell percentage and serum CXCL13 concentration; positive correlations with serum rituximab concentrations. Six months after initiation of therapy, no significant difference in the levels of APRIL, CXCL10, IL-6, or 17 other cytokines/chemokines were detected. These data reveal a major role for BAFF in peripheral B cell repopulation following rituximab-induced B-cell depletion, and novel changes in CXCL13. ClinicalTrials.gov NCT0024436.

Rituximab is an effective and safe therapeutic alternative in adults with refractory and severe autoimmune hemolytic anemia

Rituximab-induced B-cell depletion has been proven to be a useful therapy for autoimmune hemolytic anemia (AIHA). The aim of this retrospective study was to evaluate the effectiveness of rituximab in the treatment of 36 patients with AIHA refractory to several treatments. These patients had received a median of four (one to eight) previous treatments, and 13 patients had undergone splenectomy. Rituximab was administered by intravenous infusion at a dose of 375 mg/m(2) once weekly for four doses in 29 patients, and 7 patients received one to six doses. Overall, 28 (77%) of 36 patients achieved response. Twenty-two patients (61%) reached a complete response (CR), and 6 patients (16%) obtained a partial response. All patients that reached CR (61%) were able to maintain the response during more than 6 months, with a median follow-up of 14 months (1-86 months). Sixteen patients maintained response for more than 1 year. The predictors of maintained response were achievement of CR and negative Coombs test result. Splenectomized patients showed a better response rate than those nonsplenectomized. Rituximab was well tolerated, and only one patient presented a transitory rash during infusion. Rituximab induced clinical responses in multitreated severe refractory both warm and cold AIHA patients with little toxicity, and consequently, this therapy should be considered as an early therapeutic option in this setting.

Bilateral retinal vasculitis in a patient with systemic lupus erythematosus and its remission with rituximab therapy

Severe retinal vasculitis is a rare, but potentially blinding, complication of patients with systemic lupus erythematosus (SLE). We describe here the first reported case of treating severe bilateral SLE-associated retinal vasculitis with the anti-CD20 monoclonal antibody rituximab, a drug which has established its role in rheumatoid arthritis and has shown promise in case series for the treatment of severe SLE that is unresponsive to other therapies. This case suggests that rituximab-induced B-cell depletion may provide an important new therapeutic option for refractory cases of this devastating ocular complication.

Effect of Prior Rituximab on Residence Time of I131 Tositumomab Consolidation Therapy in Patients (pts) with Non Hodgkin's Lymphoma (NHL): Analysis of SWOG Clinical Trials.

Backround: Anti CD-20 radioimmunotherapy (RIT) is effective therapy for indolent B-cell NHL, and under investigation in more aggressive histologies. Most data on safety and efficacy of RIT is from the pre-rituximab era, and the effect of rituximab exposure on RIT in pts with NHL is unknown. Gopal et al recently demonstrated that exposure to rituximab correlated with inferior tumor response and alteration in tumor: organ dosimetry ratio both in vitro and in mouse models following therapy with iodine-131 tositumomab (Blood 112:830). Two ongoing SWOG trials evaluating RIT consolidation therapy provide a unique opportunity to evaluate the impact of prior rituximab on pharmacodynamics of iodine-131 tositumomab in humans. S0016 enrolls previously untreated pts with follicular NHL, and iodine-131 tositumomab consolidation is administered after 6 cycles of CHOP. S0433 enrolls previously untreated pts with DLBCL, and iodine-131 tositumomab is administered after 6 cycles of CHOP with rituximab, and 2 additional cycles of CHOP alone. As rituximab leads to B-cell depletion for 6 months or more, we hypothesized the residence time of iodine-131 tositumomab would differ in pts exposed recently to rituximab compared to no prior rituximab.Methods: Prospective pts at the University of Rochester enrolled in S0016 and S0433 were analyzed. Residence times of iodine-131 tositumomab were calculated using serial imaging on a Picker XP 2000 gamma camera. Rituximab levels were performed within one week prior to dosimetric iodine-131 tositumomab administration using ELISA. Medians were used to summarize the data, and the 2-tailed Mann-Whitney-Wilcoxon test was used for hypothesis testing.Results: 16 pts (6 female) on S0016 and 12 pts (6 female) on S0433, were identified, with median ages of 54.5 and 69.5 respectively. All pts had advanced stage disease, and median BMI and creatinine were similar for both groups. Pts on S0433 had a median time from rituximab to RIT of 78.6 days (range 58–98 days). Despite this, rituximab levels were present at time of iodine-131 tositumomab in all pts measured (N=9; median rituximab level 37.2 ug/ml, range 15.6–61.69). Median absolute lymphocyte count appeared lower in the S0433 group compared to the S0016 group (600 vs 1050 /ul), but this difference was not significant (p=0.12). Pts on S0433 (all had received rituximab prior to iodine-131 tositumomab consolidation) had significantly longer RIT residence times when compared to those on S0016, (not treated with prior rituximab): 115 hours vs. 107 hours; p=0.02. Therapeutic doses of iodine-131 tositumomab were not significantly different between the two studies (S0433: 72 mCi vs. S00016: 78 mCi p=0.59).Conclusions: Our results indicate that prior therapy with rituximab results in a longer residence time of iodine-131 tositumomab when used as consolidation after chemotherapy. Measurable rituximab levels at time of RIT suggest that rituximab-induced B-cell depletion decreases clearance of RIT, possibly allowing for longer exposure times. The significance of this longer residence time is unknown but it could be associated with greater toxicity to normal organs, and could be indicative of decreased tumor binding. If confirmed in larger studies, these findings could have profound implications on RIT administration in the context of rituximab. Rituximab-induced B-cell depletion could obligate the need for unlabeled antibody dosing prior to RIT, and may affect dosimetry of RIT. Prospective studies of RIT in the rituximab era should evaluate the impact of prior rituximab and RIT residence time on toxicities and outcomes in pts treated with RIT.

F.36. Increased Baff Levels After Rituximab-Induced B-Cell Depletion in Sle Patients

F.36. Increased Baff Levels After Rituximab-Induced B-Cell Depletion in Sle Patients

Cytomegalovirus-associated meningoradiculoneuritis after treatment of mantle cell lymphoma with a combination of chemotherapy and rituximab

Rituximab is a chimeric human/mouse monoclonal antibody directed against the CD20 antigen. It has become part of the standard therapy for non-Hodgkin’s lymphoma (NHL). Rituximab effectively kills lymphoma B cells and rapidly leads to the sustained depletion of peripheral blood B cells. Mantle cell lymphoma (MCL) is incurable with standard therapy. The median survival time is short (43 months). Rituximab has been shown to trigger a response in between 20 and 38% of patients with MCL [1]. Sustained rituximab-induced B-cell depletion may compromise the immune system. Accordingly, some viral infections have already been reported in patients with NHL receiving chemotherapy in conjunction with rituximab. Here, we describe an unusual case of cytomegalovirus reactivation in one patient with MCL who had previously been treated with chemotherapy plus rituximab. A57-year-oldmanwasdiagnosedwithcyclinD1-positive inguinal bilateral MCL, Ann Arbor stage II, in March 2003. Before the start of chemotherapy, gammaglobulinemia was normal (10 g/l). He was treated with VAD (vincristine 0.4 mg/day on days 1–4, doxorubicin 9 mg/m/day on days 1–4, dexamethasone 40 mg/day on days 1–4) plus chlorambucil (6 mg/day on days 20–29) and rituximab (375 mg/m on day 28) (5 cycles) for 6 months. This chemotherapy corresponds to the GroupeOuest Est d’etude des Leucemies et Autres Maladies du Sang (GOELAMS) MCL 2001 clinical research protocol, which includes six cycles of VAD– chlorambucil–rituximab followed by therapeutic intensification with total-body irradiation (TBI) plus busulfan before autologous peripheral stem cell reinjection. Before the beginning of the treatment, hypercellularity associated with elevated protein levels in cerebrospinal fluid (CSF) let us suppose neuromeningeal localisation. Thus, intrathecal infusions (nine cycles) with methylprednisolone (40 mg), cytarabine (40mg) and methotrexate (15 mg) were administered. In October 2003, he was referred for accentuated neuromuscular weakness and diffuse chest pain associated with a persistent headache (10 days) resistant to usual painkillers. Clinical examination revealed neurological deficit affecting the psoas territory and the foot and finger elevators. Osteotendinous reflexeswere abolished.Nopulmonary, cardiac or abdominal manifestations were observed. Whole-body computed tomography (CT) found an interstitial syndrome without adenopathy. Electromyography and nerve conduction analysis did not find any acute signs but revealed chronic anterior horn cell lesions. Bone marrow aspirate was normal. Peripheral blood contained atypical basophilic lymphocytes, suggestive of lymphocyte activation. C-reactive protein concentration was moderately elevated (33 g/l). Hypogammaglobulinemia (5 g/l) without monoclonal secretion was found. Blood and bone marrow were negative for cyclin D1. Fluorescent in situ hybridisation (FISH) analysis failed to detect t(11;14) translocation in the CSF. Hepatic and kidney functions were normal. Blood cultures were negative for bacteria. Serum was positive for cytomegalovirus (CMV) IgG with a high avidity, showing prior immunity. Electroencephalography (EEG) showed a focal lesion in the frontal and temporal regions, but no associated clinical phenotype was observed. CSF contained an abnormally high amount of protein (0.63 g/l) and normal glucose and chloride levels. The CSF contained 38 leukocytes/mm (65% lymphocytes, 9% monocytes and 25% polynuclear S. Vallet (*) . A. Tran . M. C. Legrand-Quillien . V. Narbonne Department of Microbiology (E.A. Biodiversity and Microbial Ecology no. 3882), University Hospital Morvan, 2 avenue Foch, 29609 Brest Cedex, France e-mail: sophie.vallet@chu-brest.fr Tel.: +33-2-98223308 Fax: +33-2-98223987