Chimeric anti-CD20 Monoclonal Antibody Research Articles

E018 Prophylactic co-trimoxazole prescribing practice in patients who received rituximab therapy: comparison across indications and specialties

Abstract Background/Aims Rituximab is a chimeric anti-CD20 monoclonal antibody targeting B-cells used as part of treatment algorithms for malignancy and autoimmune diseases. As is the case of other immunosuppressive agents, rituximab increases the risk of infections. Primary prophylaxis with co-trimoxazole may be considered in high-risk cohort of patients to prevent opportunistic infection, particuarly Pneumocystis jerovecii pneumonia (PJP). To investigate the prescribing practice for prophylactic co-trimoxazole in patients who received rituximab infusion in a large tertiary referral centre. To compare practices between rheumatology and nephrology department. To compare the incidence of hospitalisation for infection (particularly PJP) between those prescribed prophylactic co-trimoxazole and those who did not. Methods This was a single centre retrospective observational study over a 3 year period assessing prophylactic co-trimoxazole prescribing practice in 185 patients attending rheumatology or renal services in Cork University Hospital (CUH) and receiving rituximab. Co-trimoxazole prophylactic treatment was defined as prophylaxis dose of co-trimoxazole (either 480mg daily or 960mg three times per week) received during rituximab treatment and at least 6 months post completion of treatment. Results 185 patients’ medical charts were reviewed. Only 28 patients received prophylaxis with co-trimoxazole. The majority of patients (n = 24, 85%) who received prophylaxis with co-trimoxazole had an underlying diagnosis of small vessel vasculitis (SVV). Co-trimoxazole was more commonly prescribed by nephrologists (n = 17, 71% primarily for SVV) as compared to rheumatologist (n = 7, 29% primarily for SVV). 156 patients were not prescribed prophylactic co-trimoxazole. The primary indication for rituximab in these patients was inflammatory arthropathy (IA) (n = 72,46%), SVV (n = 26, 16%), systemic lupus erythematosus (n = 19, 12%), with the remainder accounted for by scleroderma, undifferentiated connective tissue disease, membranous nephropathy (MN), myositis, focal segmental glomerulosclerosis and amyloid renal disease. No patient was admitted over the course of the study period with PJP. 59 patients required hospital admissions due to other infections, most commonly patients with SVV. The most common infections were respiratory tract and urinary tract infections. Overall infections requiring hospitalization were more common in the group receiving prophylaxis, perhaps highlighting the vulnerable nature and greater prednisolone prescribing in the SVV cohort. No difference was seen between groups in the prevalence of UTIs. Conclusion In this cohort co-trimoxazole prophylaxis was more commonly prescribed for patient with small vessel vasculitis and differences in prescribing patterns were seen between nephrologists and rheumatologists. With greater awareness of the heightened risk of PJP in patents receiving rituximab consideration should be given to use of antibiotic prophylaxis for other indications. Disclosure S. Tio: None. J. Morrow: None. S. Cowley: None. M. Clarkson: None. G. Murphy: None.

Rituximab – An effective first line treatment in pemphigus vulgaris patients

: Rituximab is a humanized chimeric anti-CD20 monoclonal antibody that quickly lowers blood serum levels of anti-desmoglein autoantibodies, causing pemphigus lesions to heal. To evaluate the efficacy of Rituximab in treating pemphigus vulgaris. : We identified and included 14 patients (3 males and 11 females), in the age group of 14 years to 67 years, of severe pemphigus vulgaris from 2016 to 2022 treated at our institution with rituximab infusion in our retrospective case study. Baseline anti-desmoglein antibodies 1 and 3 levels were elevated in all the patients. 12 of these patients received rituximab infusion as first-line treatment. 11(out of 14) patients received two doses of rituximab (1 gram in each) as intravenous infusions, as per the rheumatoid arthritis protocol; whereas, 3 (out of 14) received a single dose of intravenous rituximab infusion (1 gram). These patients were kept on maintenance dose of prednisolone/ mycophenolate mofetil post rituximab infusion. : 14 patients of pemphigus vulgaris were enrolled in the study. The follow-up period ranged from 2 months to 6 years. All 14 patients responded well to therapy. No serious adverse events were observed. 10 (71.4%) of the 14 patients exhibited complete remission; whereas, 4 (28.6%) showed partial remission. Those with partial remission experienced relapse but the subsequent episode was less severe than the first episode. However, 2 patients who were non-responders to high doses of systemic steroids expired. : For treating patients with pemphigus vulgaris, rituximab infusion was found to be safe and effective. Hence, it should be considered as first-line for management of pemphigus vulgaris.

A Phase Ib Open-Label Study of MRG001 in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL)

Background: Patients with R/R DLBCL who fail multi-agent chemoimmunotherapy have a poor prognosis and a need for more treatment options. MRG001 is an antibody drug conjugate (ADC), which is composed of a chimeric anti-CD20 monoclonal antibody conjugated via a valine citrulline linker to monomethyl auristatin E (MMAE). MRG001 has been evaluated in a first-in-human phase Ia study and determined 1.8 mg/kg Q3W as RP2D. Here we present results from phase Ib study of MRG001 in patients with R/R DLBCL who had failed established therapies for the safety and preliminary antitumor activity evaluation. Methods: Patients aged ≥18 years with ECOG PS 0-1, histologically diagnosed R/R DLBCL who had failed ≥ 2 prior therapies (a prior anti-CD20 antibody treatment was necessary) were enrolled in this single-arm, open-label phase Ib study. All patients received MRG001 1.8 mg/kg IV Q3W until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was overall response rate (ORR) assessed by investigators according to the Lugano response criteria, duration of response (DoR) and safety. Results: At data cutoff (Jul 28, 2023), 35 patients were enrolled and received ≥1 dose of MRG001; 29 (82.9%) had discontinued the treatment and 6 (17.1%) were ongoing. Median age was 62 years (34-76), 24 (68.6%) patients were male, 24 (68.6%) had an ECOG PS of 1. The median antitumor systemic prior lines was 3 (2-7), and most patients (62.9%) had ≥3 prior lines of therapy. 3 patients received prior ASCT, and 7 patients received prior CAR-T. Median follow-up (range) was 6.8 months (0.7-18.0) for all patients. Among the 34 evaluable patients, ORR by investigator review was 38.2% (95% CI, 22.2-56.4), with 6 patients (17.6%) having a CR and 7 (20.6%) having a PR; 10 patients (29.4%) had SD, and disease control rate (DCR) was 67.7% (95% CI, 49.5-82.6). Median DoR for the 13 responders was 10.5 months (95% CI, 6.5-NE). For patients with a CR, mDoR was 13.7 months (95% CI, 10.5-NE). Treatment related adverse events (TRAEs) occurred in 33 (94.3%) pts, most commonly reported were leukopenia (68.6%), neutropenia (65.7%), anemia (45.7%), AST increased (40.0%), and lymphopenia (31.4%). Grade 3/4 TRAEs occurred in 20 (57.1%) pts, most commonly reported were neutropenia (40.0%), leukopenia (17.1%), and lymphopenia (11.4%). Discontinuation due to a TRAE occurred in 2 (5.7%) patients. Patients all successfully recoverd from these TRAEs through the implementation of clinical supportive care. Grade 1/2 treatment-related peripheral neuropathy occurred in 22 (5.7%) patients; no grade 3/4 AEs occurred. No dose reduction occurred due to TRAE. No infusion reaction or tumor lysis syndrome due to treatment occurred and no pts died because of TRAEs. Conclusion: Phase Ib results show that MRG001 had clinically meaningful antitumor activity in patients with R/R DLBCL who progressed after multiple lines of therapy. Additionally, the safety profile was manageable and patients tolerated treatment well. Clinical trial information: NCT05155839.

Hypokalemia after rituximab administration in nephrotic syndrome: two case reports

Rituximab, a chimeric anti-CD20 monoclonal antibody, is an effective treatment for nephrotic syndrome. Hypokalemia is a rare adverse reaction among patients treated with rituximab although there have been extensive reports of acute and chronic adverse events with the administration of rituximab. We herein report two cases of symptomatic hypokalemia after intravenous rituximab administration in our center, to help health professionals consider the possibility of acute hypokalemia after rituximab administration, monitor potassium timely and develop an appropriate treatment plan.

Update on theApplication of Monoclonal Antibody Therapy in Primary Membranous Nephropathy.

When first introduced, rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, brought about an alternative therapeutic paradigm for primary membranous nephropathy (PMN). Rituximab was shown to be effective and safe in PMN patients with kidney dysfunction, with. patients receiving second-line rituximab therapy achievingremission as effectively as those patients who had not previously received immunotherapy. No safety issues were reported. TheB cell-driven protocol seems to be as efficient asthe 375 mg/m2 × 4 regimen or 1 g × 2 regimen in achieving B cell depletion and remission, but patients with high M-type phospholipase A2 receptor(PLA2R) antibody levels may benefit from a higher dose of rituximab. While rituximab added another therapeutic option to the treatment regimen, it does have limitations as 20 to 40% of patients do not respond. Not all patients respond to RTX therapy for lymphoproliferative disorders either, therefore further novel anti-CD20 monoclonal antibodies have been developed and these may provide alternative therapeutic options for PMN. Ofatumumab, a fully human monoclonal antibody, specifically recognizes an epitope encompassing both the small and large extracellular loops of the CD20 molecule, resulting in increased complement-dependent cytotoxic activity. Ocrelizumab binds an alternative but overlapping epitope region to rituximab and displays enhanced antibody-dependent cellular cytotoxic (ADCC) activities. Obinutuzumab is designed to have a modified elbow-hinge amino acid sequence, leading to increased direct cell death induction and ADCC activities. In PMN clinical studies, ocrelizumab and obinutuzumab showed promising results, while ofatumumab displayed mixed results. However, there is a lack of randomized controlled trials with large samples, especially direct head-to-head comparisons. Alternative molecular mechanisms have been suggested in this context to explore novel therapeutic strategies. B cell activator-targeted, plasma cell-targeted and complement-directed treatments may lead to novel therapy paradigms for PMN. Exploratory strategies for the use of drugs with different mechanisms, such as a combinationof rituximab and cyclophosphamide and a steroid, a combination of rituximab anda calcineurin inhibitor, may provide more rapid and efficient remission, but the combination of standard immunosuppression with rituximab could increase infection risk.

Flashback Foreword: Chimeric Anti-CD20 Monoclonal Antibody Therapy

Flashback Foreword: Chimeric Anti-CD20 Monoclonal Antibody Therapy

Phase 1 trial of HS006, a recombinant human-mouse chimeric anti-CD20 monoclonal antibody to treat CD20 positive B-cell non-Hodgkin's lymphoma in China

Phase 1 trial of HS006, a recombinant human-mouse chimeric anti-CD20 monoclonal antibody to treat CD20 positive B-cell non-Hodgkin's lymphoma in China

Rituximab use in the treatment of children with nephrotic syndrome

Background. High recurrence rates of nephrotic syndrome in children and consequences in the form of steroid dependence and a high risk of side effects from corticosteroids as a result involve immunosuppressive steroid-preserving agents that would increase long-term remission. Rituximab, a chimeric anti-CD20 monoclonal antibody that inhibits CD20-mediated B-cell proliferation and differentiation, has been identified as a possible alternative treatment. The purpose of the study — to estimate the efficacy and safety of treatment recurrence of nephrotic syndrome in children using rituximab like we did it on three clinical cases. Materials and methods. The experience of rituximab in children was analyzed according to the databases of Scopus, Web of Science, MedLine, The Cochrane Library, EMBASE, Global Health and our own study of the treatment of three children with steroid-sensitive nephrotic syndrome was presented. Results. Treatment of nephrotic syndrome in three children who are 5 to 7 years with rituximab was conducted. One child had a second recurrence, two children had a first recurrence. The previous episode of nephrotic syndrome in all children was treated according to the recommendations of KDIGO 2021. All patients received rituximab (two intravenous injections two weeks apart) at a dose of 15 mg/kg for 5–6 hours with prior administration of methylprednisolone at a dose of 7–10 mg/kg. One child had side effects to the first administration of rituximab in the form of hypotension 70/40 and tachycardia 116–118. Reducing the speed of administration helped to eliminate side effects. The next injection in two weeks the child endured well. The other two children had no side effects to both rituximab injections. Moreover after 1 month of rituximab administration was without side effects or hematological changes. The next administration of rituximab is scheduled in 6 months after the last administration with prior control of CD20 level. Conclusions. In general a review of studies of rituximab confirms the high efficacy of the medication in nephrotic syndrome in children and the requirement for long-term evaluation. Rituximab can be considered as a first-line treatment for recurrence of nephrotic syndrome, including in resource-limited settings. Our own experience with rituximab in recurrent nephrotic syndrome has revealed slight short-term side effects.

P241 Efficacy of obinutuzumab in systemic lupus erythematosus patients with secondary non response to rituximab

Abstract Background/Aims Rituximab is a chimeric type-1 anti-CD20 monoclonal antibody approved by NHS England for refractory SLE. Secondary inefficacy with infusion reactions and anti-rituximab-antibodies occurs in 14% of re-treated patients. Obinutuzumab is a next-generation humanised type-2 anti-CD20 antibody licensed for the treatment of haematological malignancies. Methods We collated data from nine SLE patients receiving off-label obinutuzumab for secondary non-response to rituximab with infusion reactions across six centres (Leeds, Bradford, York, UCL, Birmingham and Nottingham). Disease activity was assessed using BILAG-2004 and SLEDAI-2K and serology in local diagnostic laboratories before, and 6 months after, obinutuzumab 2x1000mg infusions 2 weeks apart alongside methylprednisolone 100mg. Results All patients received concomitant oral immunosuppression and prednisolone. 6/9 received hydroxychloroquine. The median number of rituximab cycles before obinutuzumab therapy was 2.5. Before obinutuzumab 6/9 patients had BILAG A/B mucocutaneous, 6/9 had BILAG A/B musculoskeletal and 4/9 had BILAG A/B renal. 6 months after obinutuzumab 1/9 patients had BILAG B mucocutaneous, no patients had BILAG A/B musculoskeletal and 2/9 patients had BILAG A/B renal. Median dsDNA reduced from 118 to 83 IU/mL, C3 increased from 0.53 to 1.02g/L and C4 increased from 0.095 to 0.23g/L. Prednisolone dose was reduced in 5/9 patients; before obinutuzumab all patients received 10mg or more. After obinutuzumab, 4/9 patients received 5mg and were in Lupus Low Disease Activity State (LLDAS). Patient 5 did not respond and required further methylprednisolone and cyclophosphamide at 4 months. Patient 6 had a partial renal response but required renal transplantation, which was successful. Patient 8 responded well to obinutuzumab but died from severe COVID-19 infection (unvaccinated). After obinutuzumab 6 patients with B-cell data all achieved complete depletion including 4/4 assessed with highly sensitive assays. Conclusion These results demonstrate obinutuzumab’s efficacy in patients with secondary non-response to rituximab. These patients have severe disease with few treatment options, but previous responsiveness to B-cell depletion. Therefore, switching to another therapy in this class is mechanistically logical. Obinutuzumab appeared effective in renal and non-renal SLE as well as steroid-sparing. Immunological markers also improved. Obinutuzumab was generally well tolerated and will be further investigated for treatment-refractory lupus in the REGENCY and ALLEGORY trials. Disclosure J.E. Arnold: None. S. Dass: Consultancies; Received consultancy fees from Roche, Abbvie, UCB & Chugai. Honoraria; Received honoraria from Roche, Abbvie, UCB & Chugai. S. Twigg: None. C.H. Jones: None. B. Rhodes: None. P. Hewins: None. M. Chakravorty: None. P. Courtney: None. M. Ehrenstein: Honoraria; Received honoraria from GSK. Grants/research support; Received funding from GSK. M. Md Yusof: None. E. Vital: Consultancies; Received consulting fees from Roche, GSK, Eli Lilly and AstraZeneca. Honoraria; Received honoraria from Roche, GSK, Eli Lilly and AstraZenec. Grants/research support; Received research support from Roche and AstraZeneca (Paid to the University of Leeds).

Refractory pemphigus vulgaris with extrapulmonary tuberculosis: A challenging case management with rituximab

Pemphigus vulgaris is an autoimmune acantholytic blistering disease that affects the skin and mucous membranes and that is due to IgG autoantibodies targeted against adhesion molecules such as desmoglein 1 and 3 in the epidermis. It follows a chronic course with remissions and exacerbations affecting the patient’s quality of life. Since the advent of immunosuppressants, the prognosis of pemphigus has improved but mortality still persists. Long-term use of high-dose corticosteroids and immunosuppressants leads to serious adverse events. Recently, rituximab, a chimeric anti-CD20 monoclonal antibody, which causes B-cell depletion, has been shown to improve disease remission rates with faster tapering of steroids compared to the conventional treatment. Herein, we present a case of refractory pemphigus vulgaris with extrapulmonary tuberculosis and myelosuppression, focusing on unmet challenges due to high-dose systemic steroids, azathioprine, and successful management of the case with rituximab.

Expert consensus on the application of rituximab in the treatment of membranous nephropathy

Membranous nephropathy is a histopathological type of renal disease, characterized by the thickening of glomerular basement membrane caused by an accumulation of immune deposits on the outer aspect of the glomerular basement membrane. Its main clinical manifestations are nephrotic syndrome or asymptomatic proteinuria. Rituximab is a murine/human chimeric anti-CD20 monoclonal antibody that depletes B cells. In recent years, rituximab has been applied to the treatment of membranous nephropathy and achieved good effects. The nephrology expert panel of the Peking University Health Science Center formed this consensus by searching PubMed, China National Knowledge Infrastructure database, Wanfang database, VIP database and other relevant literature, and combining the current situation in China, so as to standardize the clinical application of rituximab in the treatment of membranous nephropathy and provide practical guidance for clinicians.

New and Old Anti-CD20 Monoclonal Antibodies for Nephrotic Syndrome. Where We Are?

Nephrotic proteinuria is the hallmark of several glomerulonephritis determined by different pathogenetic mechanisms, including autoimmune, degenerative and inflammatory. Some conditions such as Minimal Change Nephropathy (MCN) and Focal Segmental Glomerulosclerosis (FSGS) are of uncertain pathogenesis. Chimeric anti-CD20 monoclonal antibodies have been used with success in a part of proteinuric conditions while some are resistant. New human and humanized monoclonal anti-CD 20 antibodies offer some advantages based on stronger effects on CD20 cell subtypes and have been already administered in hematology and oncology areas as substitutes of chimeric molecules. Here, we revised the literature on the use of human and humanized anti-CD 20 monoclonal antibodies in different proteinuric conditions, resulting effective in those conditions resistant to rituximab. Literature on the use of human anti-CD 20 monoclonal antibodies in different proteinuric diseases is mainly limited to ofatumumab, with several protocols and doses. Studies already performed with ofatumumab given in standard doses of 1,500 mg 1.73m2 suggest no superiority compared to rituximab in children and young adults with steroid dependent nephrotic syndrome. Ofatumumab given in very high doses (300 mg/1.73m2 followed by five infusion 2,000 mg/1.73 m2) seems more effective in patients who are not responsive to common therapies. The question of dose remains unresolved and the literature is not concordant on positive effects of high dose ofatumumab in patients with FSGS prior and after renal transplantation. Obinutuzumab may offer some advantages. In the unique study performed in patients with multidrug dependent nephrotic syndrome reporting positive effects, obinutuzumab was associated with the anti-CD38 monoclonal antibody daratumumab proposing the unexplored frontier of combined therapies. Obinutuzumab represent an evolution also in the treatment of autoimmune glomerulonephritis, such as membranous nephrotahy and lupus nephritis. Results of randomized trials, now in progress, are awaited to add new possibilities in those cases that are resistant to other drugs. The aim of the present review is to open a discussion among nephrologists, with the hope to achieve shared approaches in terms of type of antibodies and doses in the different proteinuric renal conditions.

Pemphigus Vulgaris: Present and Future Therapeutic Strategies.

Pemphigus vulgaris (PV) belongs to the group of autoimmune blistering diseases. PV can affect not only mucous membranes, but also the skin and it is characterized by serum IgG autoantibodies against desmoglein 1 and 3, two major components of desmosomes. The introduction of glucocorticoids improved dramatically the prognosis of patients affected by PV. However, long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants can lead to several adverse events. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been recently approved as in-label therapy for PV, leading to an improvement of the prognosis and higher remission rate. Furthermore, other anti B-cell therapies and several anti-CD20 biosimilars have been introduced in the clinical practice. We focused on present and future therapeutic approaches in PV.

Impact of rituximab in Mexican patients with Multiple Sclerosis–A single-center retrospective study

BackgroundMultiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). B cells have an essential role in the disease pathogenesis and therefore selective B-cell depletion are commonly used to treat the disease. Rituximab (RTX), a chimeric anti-CD20 monoclonal antibody had demonstrated reduced inflammatory activity and radiological activity in MS patients. Due to economic constrains and treatment access limitations, RTX is often used as a treatment alternative in these patients. Here, we described our center experience in RTX -treated MS patients. MethodsA single-center observational retrospective study was conducted in a Mexican cohort MS during 2010 to 2020. All patients had a confirmed MS diagnosis.All patients received fixed scheme involving induction with 1 g on day one and day 15, followed by 500 mg-1 g every six months for maintenance. Annual Relapse Rate (ARR), Progression index (PI), Expanded Disability Status Scale (EDSS) and MRI activity of the disease were evaluated. Comparison between naïve and non-naïve patients was also conducted. ResultsA total of 85 patients were included. The mean age at diagnosis was 33.13 (±8.90) years with 73 (85.9%) being RRMS. 39 (34.1%) were treatment-naïve. While treated with RTX, 62(72.9%) patients reached a free-of-relapse status, with statistically significant decrease in the mean ARR from 0.82 to 0.36 [0.14 (95%CI: 0.09–0.20), p = 0.0001 and EDSS [0.25 CI 0–0.5 (p = 0.034)] and a decrease in their T1 Gd-enhancing MRI lesions (1.64 vs. 0.12 CI 0.70–2.30, p = 0.004. 29 (29.4%) patients achieved NEDA-3. Among all patients, only 2 (2.4%) experienced infusion-related mild adverse events. No serious adverse events were reported. ConclusionWe found significant clinical and radiological improvement in naïve and non-naïve MS patients treated with RTX.

Rituximab for the Treatment of Multiple Sclerosis: A Retrospective Observational Cohort in Morocco

Background: RITUXIMAB (RTX) is a chimeric anti-CD20 monoclonal antibody that has initially demonstrated efficacy in patients with B-cell lymphoma. Then, over time, it has demonstrated its efficacy in systemic inflammatory diseases and recently in neurological diseases such as multiple sclerosis (MS). Here we describe our experience with rituximab from one MS center from MOROCCO. Objectives: To investigate the safety and efficacy of Rituximab in MS in a Moroccan population. Methods: A retrospective uncontrolled observational single-center study from January 2017 to July 2020, was including all off-label Rituximab-treated patients with MS with at least 6 months of follow-up. Outcome data were collected and evaluated relapse rate, EDSS score, and adverse events (AEs) from the medical charts. Adverse events grade according to the Common Terminology Criteria for Adverse Events. Results: A total of 63 MS patients were treated with RTX, 47 patients were included, while 12 cases had just initiated treatment and 4 cases were lost to follow-up. The mean age of the patients was 39 ± 12 years with a female predominance (F/M: 1.6). All forms of MS were included, 83% of whom had relapsing-remitting MS. The duration of disease progression was 8 ± 5 years. Median EDSS before RTX initiation was 5.5 (0 - 7). 51% of patients were treated with RTX as second-line therapy after failure of other disease-modifying therapies, whereas 34% received it as first-line therapy. The annualized relapse rates decreased from 0.8 to 0.2 after RTX treatment. The Median EDSS remained unchanged at 71%. Radiological stability was noted in 83.7%, while 13.5% had a single new T2 lesion. Infusion-related AEs occurred during 27.6% of infusions and most were mild. Simple infection grades ≤ 2 were noted in 19%. Abortion occurred in only one patient. Conclusion: Our study confirms the usability of rituximab treatment for MS in the MOROCCO healthcare environment.

Rituximab in Pemphigus - An Observational Study from a Tertiary Care Center of North India.

Background:Pemphigus is a group of potentially fatal autoimmune mucocutaneous blistering diseases. Rituximab (RTX) is a chimeric anti-CD20 (anti-cluster of differentiate 20) monoclonal antibody being increasingly used and becoming the first-line therapy in the management of pemphigus.Aims and Objectives:This was an observational study to evaluate the efficacy and safety of rituximab in patients of pemphigus vulgaris (PV) who either did not respond or relapsed after conventional therapeutic regimens and in treatment naive pemphigus patients.Materials and Methods:The study included pemphigus patients coming to our immunobullous clinic who did not respond to conventional therapy or relapsed after receiving conventional therapy as well as fresh cases between January 2019 and October 2021. All enrolled patients received two doses of rituximab (1 gram in each) as intravenous infusions two weeks apart as per the rheumatoid arthritis protocol. The efficacy and safety were evaluated by assessing pemphigus area and activity score (PAAS) before and after the therapy, clinical response, and any adverse events during follow-up.Results:Sixteen (ten males and six females) patients were included in the study. The age of these patients ranged from 27 to 60 years, with a mean of 43.8 ± 9.8 years. There were 15 (93.75%) patients with PV (14 mucocutaneous type and 01 mucosal) and one (6.25%) with pemphigus foliaceus. Among these patients, nine (56.25%) were relapse cases, four (25%) were non-responders, and three (18.75%) were fresh cases who received rituximab as first-line therapy. Fourteen (87.5%) patients reached complete remission off therapy over a median time of 6.36 months (ranging from 18 weeks to 35 weeks). Rituximab was well-tolerated by our patients, and no serious adverse events were observed. The main limitation of our study was the small sample size and the lack of a comparison group.Conclusion:Rituximab is a safe and effective treatment for pemphigus.

Rituximab Therapy for Adults with Nephrotic Syndromes: Standard Schedules or B Cell-Targeted Therapy?

Rituximab is a chimeric anti-CD20 monoclonal antibody. It acts mainly through complement-dependent cytotoxicity on B cells expressing the CD20 marker. In this review, we analyse the efficacy and possible pitfalls of rituximab to treat nephrotic syndromes by taking into account pharmacological considerations and CD19 marker testing utility. Despite the fact that the drug has been in use for years, efficacy and treatment schedules in adults with nephrotic syndrome are still a matter of debate. Clinical trials have proven the efficacy and safety of rituximab in idiopathic membranous nephropathy. Data from observational studies also showed the efficacy of rituximab in minimal change disease and focal segmental glomerulosclerosis. Rituximab use is now widely recommended by new Kidney Disease Improved Outcome (KDIGO) guidelines in membranous nephropathy and in frequent-relapsing, steroid-dependent minimal change disease or focal segmental glomerulosclerosis. However, rituximab response has a large interindividual variability. One reason could be that rituximab is lost in the urine at a higher extent in patients with nonselective nephrotic proteinuria, exposing patients to different rituximab plasma levels. Moreover, the association between CD19+ levels and clinical response or relapses is not always present, making the use of this marker in clinical practice complex. High resolution flow cytometry has increased the capability of detecting residual CD19+ B cells. Moreover, it can identify specific B-cell subsets (including IgG-switched memory B cells), which can repopulate at different rates. Its wider use could become a useful tool for better understanding reasons of rituximab failure or avoiding unnecessary retreatments.

Efficacy and Safety of Recombinant Human-Mouse Chimeric Anti-CD20 Monoclonal Antibody (SCT400) Combined with CHOP in Patients with Treatment-Naïve Diffuse Large B-Cell Lymphoma: A Multicenter, Randomized, Single-Blind, Parallel Active-Controlled, Phase III Study

Background:SCT400 is a recombinant, human-mouse chimeric anti-CD20 IgG1 monoclonal antibody and has the same variable regions and antigen-binding site as rituximab. SCT400 has the heavy and κ light chain constant regions of human IgG1 allotype G1m (1,17), which is common in Asians. There is only one amino acid difference between SCT400 and rituximab (V219A in the CH1 domain of the heavy chain). The phase Ⅱ study showed that pharmacokinetics, pharmacodynamics and safety of SCT400 are equivalent to rituximab in patients with CD20-positive non-Hodgkin lymphoma.Objectives:This phase III study aimed to evaluate the safety and efficacy of SCT400 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) compared with rituximab plus CHOP in patients with treatment-naïve diffuse large B-cell lymphoma (DLBCL) (ClinicalTrials.gov, identifier: NCT02772822).Methods:In this multicenter, randomized, single-blind, parallel active-controlled, non-inferiority, phase III study, patients were enrolled from 37 centers in China. Eligible patients were aged 18～75 years with histologically confirmed CD20-positive, treatment-naïve DLBCL; international prognostic index (IPI) 0～2; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0～2. Patients were randomly assigned in a 2:1 ratio to receive either SCT400 plus CHOP (S-CHOP) or rituximab plus CHOP (R-CHOP) every 21 days cycle treatment for six cycles.The primary endpoint was objective response rate (ORR) after six cycles of therapy, assessed by an independent review committee, with a non-inferiority margin of -12%. The secondary endpoints were complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and safety.Results:Between October 19, 2016 and July 13, 2018, 534 patients were screened and 364 eligible patients were randomized to either the S-CHOP group (n=243) or R-CHOP group (n=121). Patient demographics and disease characteristics at baseline were well balanced between the two treatment groups.In the per protocol set (PPS), the best ORRs within six cycles of treatment were 94.5% (95% confidence interval [CI], 90.8% to 97.0%) and 94.1% (95%CI, 88.2% to 97.6%) in the S-CHOP and R-CHOP groups respectively, with an intergroup difference of 0.4% (95%CI, -4.7% to 5.6%, P=0.6569) (Figure 1A). The 95%CI lay on the positive side of the prespecified non-inferiority margin of -12%, meeting the criterion for non-inferiority. The results of using the full analysis set (FAS) were consistent with the primary efficacy analysis in the PPS. No significant differences were observed in the secondary efficacy endpoints, in either the PPS or the FAS (Figure 1B and Figure 2).There were no significant differences were observed in ≥1 adverse event (AE, 97.9% vs. 99.2%), grade≥3 AE (85.2% vs. 86.0%), serious AE (35.4% vs. 38.8%), treatment discontinuation due to AE (7.8% vs.12.4%) between S-CHOP and R-CHOP groups, respectively (Table 1).AEs of special interest occurred in 63.8% of patients in the S-CHOP group and in 59.5% of patients in R-CHOP group, including infection (46.5% vs. 46.3%), infusion-related reaction (20.2% vs. 17.4%), cardiotoxicity (17.7% vs. 11.6%), hepatitis B virus reactivation (1.2% vs. 3.3%), ileus and enterobrosis (1.2% vs. 0.8%), tumor lysis syndrome (0.0% vs. 0.8%) (Table 1).A total of 51 deaths were reported in the S-CHOP group (n=35, 14.4%) and R-CHOP group (n=16, 13.2%), and 10 deaths were due to AE (S-CHOP group: n=7, 2.9%; R-CHOP group: n=3, 2.5%) (Table 1).After treatment, study-drug related anti-drug antibodies (ADAs) were detected in 11(10.9%) patients in S-CHOP group and in 8(16.0%) patients in R-CHOP group (Table 1).Conclusion:SCT400 plus CHOP showed non-inferiority of efficacy to rituximab plus CHOP in patients with treatment-naïve DLBCL. The safety and immunogenicity profiles of SCT400 were comparable with rituximab, with no new treatment-related AE occurred. SCT400 could be a therapeutic option for DLBCL.Funding source:This study was supported by the sponsor, Sinocelltech Ltd., and by grants from the China National Major Project for New Drug Innovation (No. 2018ZX09736002 and No. 2017ZX09304015).Conflicts of interest:Liangzhi Xie is an employee of Sinocelltech Ltd. and has ownership interests in the company. All other authors declare no conflicts of interest. [Display omitted] DisclosuresHu: Astellas Pharma, Inc.: Research Funding. Xie: Sinocelltech Ltd.: Current Employment, Current equity holder in publicly-traded company.

A Dose Escalation Phase Ia Study of Anti-CD20 Antibody Drug Conjugate, MRG001 in Relapsed/Refractory Advanced Non-Hodgkin Lymphom

Background: MRG001 is an antibody drug conjugate (ADC), which is composed of a chimeric anti-CD20 monoclonal antibody conjugated via a valine citrulline linker to monomethyl auristatin E (MMAE), an anti-microtubulin agent. In preclinical studies, MRG001 demonstrated significant tumor growth inhibition in rituximab-resistant non-Hodgkin's lymphoma (NHL) models. MRG001 is being evaluated in a first-in-human, open-label, multicenter Phase I study for the safety, tolerability, pharmacokinetics (PK) and preliminary antitumor activity in patients with CD20-positive relapsed or refractory (R/R) B-cell NHL.Methods: MRG001 was evaluated as a monotherapy for the treatment of patients with confirmed CD20-positive R/R B-cell NHL. The study consists of Phase Ia dose escalation and Ib dose expansion. In the Phase Ia dose-escalation study utilizing a “3+3” design, patients with pathologically confirmed R/R NHL received single agent MRG001 intravenously once every 3 weeks (Q3W) for a maximum of 6 treatment cycles. Six dose levels ranging from 0.15 to 2.5 mg/kg were evaluated for safety, PK and preliminary antitumor activity to determine the MTD/RP2D.Results: From June 25, 2019 to May 31, 2021, a total of 21 subjects with DLBCL (n=8), FL (n=12), and MZL (n=1) who met the eligibility criteria had received at least two cycles of MRG001. As of May 31, 2021, 18 subjects were off treatment and 3 subjects were still on treatment. There were 3 subjects enrolled into the 0.15, 0.3 , 0.6, 1.2 and 2.5 mg/kg cohort respectively, and 6 subjects enrolled into the 1.8 mg/kg cohort. Of the 21 subjects enrolled, 12 subjects were male and 9 subjects were female, with age ranging from 27 to 75 years old.Among the 18 subjects who were off treatment, 5 had completed 6 cycles of treatment, and 13 had drug discontinuation (12 due to progression of disease and 1 subject due to withdrawal of the informed consent for personal reasons).Commonly observed drug-related TEAEs were decreased white blood cell/neutrophil/lymphocyte counts, ALT/AST elevation, pyrexia, hypertension, increased LDH, QT prolongation, and thrombocytopenia.TEAEs (29 cases) ≥ Grade 3 were reported in 9 subjects, including 23 drug-related TEAEs in 8 subjects. The most commonly reported Grade 3 or above TRAEs were leukopenia/neutropenia, lymphopenia, hypertension, and ALT elevation. In the 2.5 mg/kg cohort, two subjects experienced drug-related toxicities that met the DLT definition per protocol, including 1 subject with Grade 3 hyperlipidemia and 1 subject with Grade 4 neutropenia that lasted 5 days. There was no death due to AEs.PK samples of total antibody, MRG001 and MMAE were measured at predefined time points and the results showed that the C max and AUC of total antibody, MRG001 and MMAE increased with dose level increase. The T max of MMAE was non-linear to dose level increase, similar trends could be observed in two other parameters including C max and AUC 0-t, which suggested that MMAE was continuously released from MRG001.Among 21 pts who had at least one tumor assessment, 1 CR (5%), 4 PR (19%), 9 SD (43%), and 7 PD (33%). The investigator assessed ORR was 24% and the DCR was 67%. In the starting dose 0.15 mg/kg cohort, one subject with FL acheived PR. Among six subjects (4 with DLBCL and 2 with FL) enrolled in the 1.8 mg/kg cohort, one DLBCL subject achieved CR and another subject with DLBCL achieved PR, ORR was 33.33% (2 out of 6). Three subjects were enrolled in the 2.5 mg/kg cohort, two subjects with FL had PR, both of them had DLT on cycle 1 and had dose reduction to 1.8 mg/kg from cycle 2, ORR was 66.7% (2 out of 3).Conclusion: The dose escalation study of MRG001 has shown manageable safety profiles and encouraging preliminary antitumor activity in patients with NHL. Based on the safety, tolerability, and pharmacokinetic parameters of MRG001, 1.8 mg/kg was determined to be the RP2D and further investigation of MRG001 in patients with NHL is warranted. DisclosuresPeng: Lepu Biopharma Co., Ltd.: Current Employment. Sun: Shanghai Miracogen Inc.: Current Employment. Sun: Shanghai Miracogen Inc.: Current Employment. Li: Shanghai Miracogen Inc.: Current Employment.

M180 PERSISTENT HYPOGAMMAGLOBULINEMIA IN A PEDIATRIC PATIENT FOLLOWING RITUXIMAB TREATMENT FOR AUTOIMMUNE ENCEPHALITIS

Rituximab, a chimeric anti-CD20 monoclonal antibody that depletes pre-plasma B-cells, is used for the treatment of autoimmune disease. While proven effective in disease management, anti-CD20 therapies are also associated with prolonged (>6-9 months) hypogammaglobulinemia and subsequent infectious risk. We describe an adolescent patient with autoimmune encephalitis who experienced prolonged B-cell depletion and persistent hypogammaglobulinemia following Ritixumab, with eventual B-cell recovery but persistent hypogammaglobulinemia and absence of isotype-switched memory B cells(CD19+CD27+IGD-IgM-).