Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4424-4428 ◽  
Author(s):  
Roberto Stasi ◽  
Maurizio Brunetti ◽  
Elisa Stipa ◽  
Sergio Amadori
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Complete Response ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Acquired Hemophilia ◽  
Durable Response ◽  
Fviii Inhibitor ◽  
Fviii Activity ◽  
Anti Cd20

Abstract The activity and safety profile of selective B-cell depletion with rituximab, an anti-CD20 monoclonal antibody, were evaluated in 10 patients with acquired hemophilia. Rituximab was given intravenously at the dose of 375 mg/m2 once weekly for 4 consecutive weeks. Infusion-related side effects were observed in 3 patients but were of mild intensity and did not require discontinuation of treatment. Eight patients with Factor VIII (FVIII) inhibitor titers between 4 and 96 Bethesda units per milliliter (BU/mL) achieved a complete remission, which was defined as a return to normal FVIII activity and undetectable FVIII inhibitor titers. Two more patients with inhibitor levels greater than 100 BU/mL experienced only a partial transient decrease of the inhibitor after rituximab alone, but they achieved a complete response after being challenged with a combination of rituximab plus pulse intravenous cyclophosphamide. With a median follow-up of 28.5 months (range, 12-41 months), 3 patients have thus far relapsed. Retreatment with the monoclonal antibody at the same dose and schedule resulted in a new sustained response in all these patients. In conclusion, rituximab appears an effective and well-tolerated treatment for patients with acquired hemophilia and low inhibitor titers. A reinforcement of therapy with other agents seems to be required to achieve a full and durable response in those patients with high inhibitor levels. (Blood. 2004;103:4424-4428)

scholarly journals A phase 2 multicenter study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing forms of multiple sclerosis

2020 ◽  
pp. 135245852091837 ◽  
Author(s):  
Edward Fox ◽  
Amy E Lovett-Racke ◽  
Matthew Gormley ◽  
Yue Liu ◽  
Maria Petracca ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibody ◽  
B Cell ◽  
Optimal Dose ◽  
Cell Depletion ◽  
Controlled Study ◽  
Lesion Volume ◽  
B Cell Depletion ◽  
Phase 2 ◽  
Anti Cd20

Background: Ublituximab, a novel monoclonal antibody (mAb) targeting a unique epitope on the CD20 antigen, is glycoengineered for enhanced B-cell targeting through antibody-dependent cellular cytotoxicity (ADCC). Greater ADCC may allow lower doses and shorter infusion times versus other anti-CD20 mAbs. Objective: The objective was to determine optimal dose, infusion time, and activity of ublituximab in relapsing multiple sclerosis. Methods: This is a phase 2, placebo-controlled study. Patients received three ublituximab infusions (150 mg over 1–4 hours on day 1 and 450–600 mg over 1–3 hours on day 15 and week 24) in six dosing cohorts. The primary endpoint was B-cell depletion. Results: In all cohorts ( N = 48), median B-cell depletion was >99% by week 4, maintained at weeks 24 and 48. Most common adverse events (AEs) were infusion-related reactions (all grade 1–2), with no apparent increased incidence at shorter infusion times. There were no AE-related discontinuations. At weeks 24 and 48, no T1 gadolinium-enhancing lesions ( p = 0.003) and a 10.6% decrease in T2 lesion volume ( p = 0.002) were detected. The annualized relapse rate was 0.07; 93% remained relapse free on study. Overall, 74% of patients had no evidence of disease activity (NEDA). Conclusion: Ublituximab was safely infused as rapid as 1 hour, producing robust B-cell depletion and profound reductions in magnetic resonance imaging (MRI) activity and relapses.

scholarly journals Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study

2007 ◽  
Vol 156 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Mario Salvi ◽  
Guia Vannucchi ◽  
Irene Campi ◽  
Nicola Currò ◽  
Davide Dazzi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Thyroid Function ◽  
Cell Depletion ◽  
Clinical Activity ◽  
Graves Disease ◽  
B Cell Depletion ◽  
Muscle Involvement ◽  
Inflammatory Phase ◽  
Anti Cd20

Introduction: Hyperthyroid Graves’ disease (GD) is a B-cell-mediated condition caused by TSH receptor antibodies (TRAb), which decline when GD remits. Anti-CD20 monoclonal antibody rituximab (RTX) induces transient B-cell depletion that may potentially modify the active inflammatory phase of thyroid-associated ophthalmopathy (TAO). Methods: Nine patients with GD, (seven with active TAO, two with mild lid signs) were studied. The trial was only approved as an open pilot study; thus we compared the effect of RTX therapy to that of i.v. glucocorticoids (IVGC) in 20 consecutive patients. Patients were treated with RTX (1000 mg i.v. twice at 2-week interval) or with IVGC (500 mg i.v. for 16 weeks). TAO was assessed by the clinical activity score (CAS) and severity was classified using NOSPECS (No signs or symptoms; Only signs (lid); Soft tissue involvement; Proptosis, Extraocular muscle involvement; Corneal involvement; Sight loss). Thyroid function and lymphocyte count were measured by standardized methods. Results: All patients attained peripheral B-cell depletion with the first RTX infusion. Minor side effects were reported in three patients. Thyroid function was not affected by RTX therapy and hyperthyroid patients required therapy with methimazole. After RTX, the changes in the levels of thyroglobulin antibodies, thyroperoxidase antibodies and TRAb were neither significant nor correlated with CD20+ depletion (P = NS). CAS values before RTX were 4.7 ± 0.5 and decreased to 1.8 ± 0.8 at the end of follow-up (P < 0.0001) and more significantly compared with IVGC (P < 0.05). Proptosis decreased significantly after RTX both in patients with active TAO (ANOVA; P < 0.0001) and those with lid signs (ANOVA; P < 0.003). The degree of inflammation (class 2) decreased significantly in response to RTX (ANOVA; P < 0.001). Relapse of active TAO was not observed in patients treated with RTX, but occurred in 10% of those treated with IVGC, who also experienced adverse effects more frequently (45 vs 33% of patients). Conclusions: RTX positively affects the clinical course of TAO, independently of either thyroid function or circulating antithyroid antibodies, including TRAb. If our findings are confirmed in large controlled studies, RTX may represent a useful therapeutic tool in patients with active TAO.

scholarly journals POS1226 THE COURSE OF CORONAVIRUS DISEASE 2019 (COVID-19) IN PATIENTS WITH SJOGREN’S SYNDROME TREATED WITH ANTI-CD20 MONOCLONAL ANTIBODY (RITUXIMAB)

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 896.3-897
Author(s):  
E. Sokol ◽  
A. Torgashina ◽  
B. Chalcev ◽  
J. Khvan ◽  
O. Golovina
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Rheumatic Diseases ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Lung Involvement ◽  
Anti Cd20 ◽  
Sjögren‘S Syndrome

Background:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) raised concern for the outcomes in people with different rheumatic diseases and management of these patients. There was an anxiety that biologic therapies, especially anti-B-cell depletion strategies, could lead to more severe disease course and lack of protective antibodies formation. Information about the course of COVID-19 in patients with certain rheumatic diseases is still lacking.Objectives:To examine clinical course of COVID-19 in patients with Sjogren’s syndrome treated with anti-CD20 monoclonal antibody (rituximab).Methods:Single center observational study. Diagnosis of SjS was based on ECR/EULAR 2016 criteria. COVID-19 diagnosis was based on positive PCR test even without clinical symptoms and/or typical clinical features (CT signs, fever and anosmia). Rituximab was administrated in two 1000 mg infusions 14 days apart for the 1st course, then 500 mg every 6 months.Results:19 patients were included, 18 women and 1 man. Median age was 55 years (29-70 years), and median rituximab treatment duration was 24 months (1-48 months). Five patients had concomitant RA (2 patients), SLAE (1 pt), Systemic sclerosis (2 patients). Patients with RA took baricitinib and methotrexate as well. 3 patients had MALT-lymphoma anamnesis (24, 38 and 24 months before the diagnosis of COVID-19). Only 3 patients had chronic ischemic heart disease and/or arterial hypertension. 12 patients were PCR positive, 6 negative and in 1 the test was not done. 11 patients had full and 4 partial B-cell depletion in peripheral blood. Five patients had <20% lung involvement on CT, 2 patients – 20-40% and 4 patients – 40-60%. Three patients with 40-60% lung involvement required hospitalization due to marked shortness of breath and long febrile period, 2 of them received anti-IL6 treatment and neither of them required mechanical lung ventilation (either non-invasive or invasive). Seventeen patients were treated at home and recovered in 10-24 days. Anti-SARS-CoV-2 IgG were measured in 9 patients, 6 (66.7%) of them were positive.Conclusion:It seems that neither SjS itself nor anti-CD20 therapy predisposes patients to severe course of COVID-19. Presumably risk factors such as age, diabetes or anamnesis of cardiovascular diseases have far more significant impact on COVID-19 severity. Data hints that anti-CD20 therapy might negatively affect the formation of specific anti-SARS-CoV-2 humoral immunity, but further investigation is required to determine that with any degree of certainty.Disclosure of Interests:None declared

scholarly journals Autoantibody Inhibitor Eradication In Acquired Hemophilia Associated with Cancer: a Retrospective Analysis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1418-1418 ◽  
Author(s):  
Khendi T White ◽  
Anita Aggarwal ◽  
Marisanta Napolitano ◽  
Craig M. Kessler
Keyword(s):  
B Cell ◽  
Solid Tumor ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Acquired Hemophilia ◽  
Term Survival ◽  
Fviii Inhibitor ◽  
Underlying Malignancy ◽  
Fviii Activity

Abstract Abstract 1418 Introduction: Acquired hemophilia (AH), a rare autoimmune disorder primarily of adults, is typically characterized by the presence of IgG oligoclonal antibodies to the clotting factor VIII protein (FVIII). About 10–15% of patients with AH have an underlying malignancy, but the etiologic relationship of cancer to formation of FVIII inhibitor is yet to be determined. To date, there have been no published, comprehensive reviews on the efficacy of various treatments for AH in the context of either solid tumor or hematologic malignancies. Therefore, we have systematically reviewed 86 patients with cancer-associated AH from our own cancer center and from the published literature. Methods: The literature search for this systematic review was performed using PubMed MEDLINE, Ovid MEDLINE, CINAHL, SCOPUS, and Embase. The search terms included various combinations of “acquired”, “cancer”, “factor VIII”, “hemophilia A”, “autoantibodies”, and “treatment.” The major criterion for inclusion was a diagnosis of cancer before or within three months after appearance of acquired inhibitor. Both solid and hematologic malignancies were included. Any report that did not document a FVIII inhibitor titer and/or FVIII activity was excluded. Success in inhibitor eradication has been defined as undetectable inhibitor and normalization of FVIII activity. All articles with an abstract in English published in the period from January 1985 to July 2010 were considered. Results: 86 cases of AH were collected and analyzed according to classification of cancer and efficacy of treatments for inhibitor and malignancy. The mean age is 67.8 years. 74% of patients were of Caucasian or European background, 8% were of Asian descent, and 2% were of African descent. AH was associated with solid malignancy in 50 cases (58%) and hematologic malignancy in 36 cases (42%). Among all AH cases, 15% and 14% of patients had lymphoma and CLL, respectively. Of the solid tumors, lung and prostate carcinoma (each 12%) occurred with the greatest frequency followed by colorectal (9%) and bladder (5%). Not all patients had treatment for their underlying cancer, bleeding and/or inhibitor. Complete eradication (CE) of inhibitor was achieved in 48 patients (56%), no eradication (NE) in 22 (26%), and 16 (18%) had unknown status. Of the 73% of patients with CE, 22 were treated with chemotherapy, 10 were treated with surgery, and 1 with both (Table 1). In this series, there was a trend towards successful inhibitor eradication with treatment of B-cell lymphoproliferative malignancies as well as lung and prostate cancer. Long term survival was best achieved when successful CE and treatment of underlying malignancy occurred concurrently. Conclusions: This literature and case series suggests that AH is associated almost equally with hematological and solid tumor malignancies. These retrospective data suggest that treatment of the cancer with chemotherapy or surgery is very likely to induce eradication of the autoantibody inhibitor. There is a trend for increased success in CE in B-cell lymphoproliferative malignancies and selected solid tumors. Long term survival appears dependent on concurrent CE and treatment of the cancer. Disclosures: Kessler: Grifols S.A.: Research Funding; Baxter-Immuno: Research Funding; NovoNordisk: Research Funding.

scholarly journals Vaccine Efficacy after Rituximab Exposure: First Interim Analysis of Virtue Project on Behalf of West Midlands Research Consortium, UK

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 196-196
Author(s):  
Adrian M Shields ◽  
Srinivasan Venkatachalam ◽  
Shankara Paneesha ◽  
Mark Ford ◽  
Tom Sheeran ◽  
...  
Keyword(s):  
B Cell ◽  
Vaccine Efficacy ◽  
Haematological Malignancy ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Spike Glycoprotein ◽  
Secondary Immunodeficiency ◽  
Haematology Patients ◽  
Anti Cd20 ◽  
Kinetics Of

Abstract Background: Anti-CD20 B cell depleting agents are amongst the most commonly used immunotherapeutics employed in the treatment of haematological malignancy and autoimmune diseases. By inducing peripheral B cell aplasia, anti-CD20 depleting agents are hypothesised to significantly impair serological responses to neoantigens, including the SARS-CoV-2 spike glycoprotein within SARS-CoV-2 vaccines. Seropositivity following SARS-CoV-2 is the strongest, measurable correlate of protection from severe COVID-19. Understanding the kinetics of B cell reconstitution and vaccine responsiveness following exposure to B cell depleting agents is essential to maximise vaccine efficacy in patients vulnerable to severe COVID-19. Methods: 80 patients with underlying haematological malignancy and 38 patients with underlying rheumatological disease previously treated with anti-CD20 B cell depleting agents were studied following their second dose of a SARS-CoV-2 vaccine (median time to sampling: 46.5d, IQR: 33.8-63.3). Lymphocyte subset (CD4, CD8, CD19, CD56/16) enumeration was performed using 6 colour flow cytometry (BD Trucount). Total anti-SARS-CoV-2 spike glycoprotein antibodies were measured by enzyme-linked immunosorbent assay (The Binding Site, Human Anti-IgG/A/M SARS-CoV-2-ELISA). The relationship between immune reconstitution following B cell depletion and vaccine responsiveness was explored. Results: In the haematology cohort (median age 70y, IQR 60.3-76.0, 62.5% male), overall seropositivity following vaccination was 60.0%. Individuals on active chemotherapy had significantly lower seroprevalence than those vaccinated following the completion of chemotherapy (22.7% vs 74.1%, p&lt;0.0001). In the rheumatology cohort (median age 65y, IQR 58.3-70.8, 39.9% male), overall seropositivity was 69.4%. In both cohorts, vaccine non-responders had significantly smaller populations of peripheral CD19+ B cells (haematology: 0.20 vs 0.02 x10 9/L, p=0.004, rheumatology: 0.07 vs 0.01 x10 9/L, p=0.03). The magnitude of the antibody response following vaccination did not differ between recipients of Tozinameran and Vaxzeveria in either cohort. Vaccine responsiveness was lower in the first 6 months following B cell depletion therapy; 42.9% in the haematology cohort and 33.3% in the rheumatology cohort, increasing to 100% and 75% respectively in individuals receiving their second dose 6-12 months following B cell depletion (Figure 1). B cell reconstitution in the 7-12 month window following B cell depletion was faster in haematology compared to rheumatology patients (77.8% v 22.2% achieving normal B cell count, p=0.005) and associated with improved vaccine responsiveness. However, persistent immunodeficiency occurred in some haematology patients following completion of treatment: 25% of patients who had completed therapy at least 36 months previously failed to respond to vaccination. In this cohort of vaccine non-responders, 83.3% of individuals had B cell numbers within the normal range. These patients had all previously been treated for follicular lymphoma suggesting a specific mechanism for long-range secondary immunodeficiency in these patients. Conclusions: Serological responsiveness to SARS-CoV-2 vaccines is poor during active chemotherapy for haematological malignancy and in the first 6 months following B cell depletion, regardless of underlying disease. Vaccine responsiveness significantly improves in the 7-12 month window following B cell depletion. Compared to haematology patients, B cell reconstitution is slower in rheumatology patients and associated with reduced vaccine responsiveness, possibly due to the use of additional concurrent disease-modifying anti-rheumatic therapies. Furthermore, long-term secondary immunodeficiency occurs in a minority of haematology patients. To maximise the efficacy from SARS-CoV-2 booster vaccination and optimal utilisation of available vaccine doses, immunisations should be delivered at least 6 months following the administration of anti-CD20 depleting drugs. Figure 1: Kinetics of return of vaccine responsiveness following B cell depletion in haematology and rheumatology patients. Figure 1 Figure 1. Disclosures Paneesha: Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria; Celgene: Honoraria. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company.

scholarly journals B cell depletion with anti-CD20 mAb exacerbates anti-donor CD4+ T cell responses in highly sensitized transplant recipients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Asuka Tanaka ◽  
Kentaro Ide ◽  
Yuka Tanaka ◽  
Masahiro Ohira ◽  
Hiroyuki Tahara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Responses ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Transplant Recipients ◽  
Cell Responses ◽  
Anti Cd20

AbstractPretransplant desensitization with rituximab has been applied to preformed donor-specific anti-human leukocyte antigen antibody (DSA)-positive recipients for elimination of preformed DSA. We investigated the impact of pretransplant desensitization with rituximab on anti-donor T cell responses in DSA-positive transplant recipients. To monitor the patients’ immune status, mixed lymphocyte reaction (MLR) assays were performed before and after desensitization with rituximab. Two weeks after rituximab administration, the stimulation index (SI) of anti-donor CD4+ T cells was significantly higher in the DSA-positive recipients than in the DSA-negative recipients. To investigate the mechanisms of anti-donor hyper responses of CD4+ T cells after B cell depletion, highly sensitized mice models were injected with anti-CD20 mAb to eliminate B cells. Consistent with clinical observations, the SI values of anti-donor CD4+ T cells were significantly increased after anti-CD20 mAb injection in the sensitized mice models. Adding B cells isolated from untreated sensitized mice to MLR significantly inhibited the enhancement of anti-donor CD4+ T cell response. The depletion of the CD5+ B cell subset, which exclusively included IL-10-positive cells, from the additive B cells abrogated such inhibitory effects. These findings demonstrate that IL-10+ CD5+ B cells suppress the excessive response of anti-donor CD4+ T cells responses in sensitized recipients.

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