Efficacy Of Rituximab Research Articles

Impact of Maintenance Rituximab Following First-Line Systemic Therapy on Outcomes in Patients with Marginal Zone Lymphoma: Real-World Evidence from 10 US Centers

Introduction First-line treatment options for patients (pts) with marginal zone lymphoma (MZL) include rituximab monotherapy (R) and immunochemotherapy (IC), such as bendamustine with rituximab (BR) or RCHOP/RCVP. The efficacy of maintenance rituximab (M-R) has been studied in splenic (SMZL) and nodal (NMZL) MZL, showing a benefit in progression-free survival (PFS) when M-R is administered after BR (Rummel et al., ASCO 2018). However, the role of M-R in pts with extranodal MZL (EMZL) of the mucosa-associated lymphatic tissue (MALT), or those receiving R or RCHOP/RCVP, remains uncertain. In this study, we analyzed the outcomes of pts with MZL who received M-R after their first-line systemic therapy (R or IC) using data from a large multi-institutional retrospective cohort. Methods Adult pts with MZL (SMZL, NMZL, or EMZL) who were treated at 10 US medical centers from 2010 onwards were included. Pts who had received first-line treatment with either R or IC and achieved a partial (PR) or complete (CR) response to the initial therapy were divided into groups based on whether they subsequently received M-R or not. To avoid immortal-time bias, we required a minimum follow-up of 6 months from diagnosis. Outcomes included PFS, overall survival (OS) and cumulative incidence of histologic transformation (HT). Because of non-proportional hazards, Wilcoxon test was used to compare survival curves, and Cox models (augmented by multiple imputation to account for missing data) were bounded by 6 years of follow up. Multivariable models adjusted for prognostic factors including age, sex, performance status, stage, baseline hemoglobin, albumin, LDH, type of IC and CR/PR status at the end of therapy. Results The study included 427 pts with a median age of 63 years. Of these pts, 53% were women, and 49% had EMZL, 27% had NMZL, and 23% had SMZL. The first-line therapies received were R (54%), BR (36%), RCHOP (7%), or RCVP (3%). A CR was achieved by 70% (n=298) of pts after the initial therapy. Overall, 33% (n=140) received M-R with a median of 8 cycles. Among pts who initially had PR, 39% converted to a CR during M-R therapy. The median follow-up period was 5 years. Factors associated with a higher likelihood of receiving M-R included achieving a PR instead of a CR after the first-line therapy (41% vs 29% receiving M-R, respectively; p=0.02) and having the SMZL subtype (p=0.03, Fig 1A). Pts treated with RCHOP were less likely to receive M-R compared to those receiving other regimens (p=0.049). There was also evidence of hospital-level preference to either prescribe M-R or not. We analyzed survival outcomes separately for pts who received first-line IC or R monotherapy, stratified further by MZL subtype and the type of IC regimen. Among pts who received IC (n=197), M-R was associated with longer PFS (median of 9.0 vs. 6.8 years, p=0.008, Fig 1B). However, the statistical significance was lost in the multivariable model (adjusted HR=0.52, 95%CI=0.25-1.10). When evaluated by MZL subtype, pts with EMZL had a significantly longer PFS with M-R (p=0.01), while those with NMZL and SMZL did not (p=0.41 and 0.10, respectively). When examining the type of first-line IC, pts receiving RCHOP/RCVP had a prolonged PFS with M-R (p=0.03), whereas the difference was not statistically significant after BR (p=0.12). There was no difference in OS overall (p=0.09; adjusted HR=0.55, 95%CI=0.12-2.60) or in any subgroup. Among pts who received first-line R, there were no statistically significant differences in PFS (p=0.70; adjusted HR=0.99, 95%CI=0.59-1.66) or OS (p=0.17) based on the receipt of M-R, either in the entire cohort or any subset. A total of 14 transformation events occurred during the study, including 3 in the M-R group. The cumulative incidence of HT did not significantly differ between the two groups (sub-HR=0.76, 95%CI=0.21-2.82, p=0.68). Discussion In this large retrospective cohort study, the use of M-R in MZL was primarily influenced by local preferences, the quality of response after initial treatment, and the type of IC regimen. Receipt of M-R was associated with a longer PFS for pts receiving first-line IC, especially for those with EMZL and those receiving RCHOP/RCVP. These findings suggest a PFS advantage of M-R in EMZL, which is a novel observation. However, this advantage was not observed in terms of OS or the rate of HT. M-R after initial R did not show any significant differences in outcomes for MZL.

The Final Results of a Phase I Study Using Bortezomib (Velcade), Cladribine, and Rituximab (VCR) in Treating Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium sized B cell lymphoma. No standardized treatment exists for this disease. Cladribine is a hypomethylating agent that indirectly down-regulate DNA methylation to suppress tumorigenesis. Combination of Cladribine and Rituximab showed a synergetic effect in treating B cell lymphomas. Bortezomib (Velcade) is an FDA approved proteasome inhibitor to treat relapsed/refractory MCL. In this study, we evaluated the safety and efficacy of Valcade, Cladribine, and Rituximab (VCR) combination treatment in newly diagnosed and relapsed/refractory MCL. Patients and Methods: This is a single arm open label phase I trial. This study employed a standard 3+3 dose escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. Briefly, the treatment scheme was consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m 2 infusion started on day 5 of the first week and then given weekly for 3 weeks; in the next 5 cycles Rituximab was given on day 5 of each cycle, and then every 2 months as the maintenance therapy. Cladribine 3 to 5 mg/m 2 (3 mg/m 2 for level 1, 4 mg/m 2 for level 2, and 5 mg/m 2 for level 3) infusion was given on days 1 to 5 for 6 cycles. For patient older than 70 years old, Cladribine was only given on days 1 to 3 of each cycle. Velcade 1.6 mg/m 2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1 to 3, Days 5 and 19 for Cycles 4 to 6, then once per month as maintenance therapy. The primary endpoint of this study was the dose limiting toxicity (DLT), safety, and efficacy of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression free survival (PFS) and overall survival (OS) (Figure 1). The analysis was done by intent to treat. Differentially methylated region (DMR) analysis and cytokine assay were performed to explore biomarkers differentiating good-responders from poor-responders. Results: This study recruited 13 patients, with a median age of 64 years old (range from 55 to 83) and including 11 males and 2 females. Ten patients were never previously treated, other 3 either relapsed or failed from previous treatments. Most patients tolerated this regimen well. No patient experienced DLT at either level 1 or 2, one possible DLT (infectious colitis) was observed during 2nd cycle at level 3. Two relapsed patients experienced disease progression after received two cycles of treatment and died in 5 and 7 months. Another patient died in 15 months after receiving treatment. The overall remission (OR) rate was 85% (11/13) and complete remission (CR) rate was 77% (10/13). In newly diagnosed patient cohort, CR rate was 100% (10/10), OS rates were 90% (9/10), and PFS was 80% (8/10), of which 3 patients have been followed for more than 4 years, 3 other patients for more than 3 years, and 3 others for over 2 years (Fig.1). In relapsed/refractory patient cohort, 1 achieved CR for 7 months but then relapsed, 2 had no response. There were 2 blastoid patients, 1 of these 2 patients was newly diagnosed and achieved CR. Bone marrow suppression caused prolonged anemia and thrombocytopenia were the most common toxicity (3/13 with ≤grade 2). Low grade peripheral neuropathies (≤grade 2) were observed in 15% (2/13). Mild fatigue was a frequent complaint. Cytokine assay showed decreased CXCL12 level in the good responders. Though global methylation pattern showed no difference, DMRs were identified in the good responders and the poor responders. DMRs-related genes involved in CXCL2 pathways were further extracted and enriched biological process analysis revealed the pathway profile difference between good responders and poor responders. Good responders exhibited alternation of apoptotic and Wnt signaling pathways (Fig.2). Conclusions: The VCR combination is a well-tolerated, low toxicity and effective regimen for MCL, especially for untreated MCL. Cladribine 5 mg/m 2 is a tolerable dose with manageable toxicity. Individual patient methylation profile may affect response to VCR therapy.

Rituximab in combination with cyclosporine and steroid pulse therapy for childhood-onset multidrug-resistant nephrotic syndrome: a multicenter single-arm clinical trial (JSKDC11 trial)

BackgroundOnly 80% of children with idiopathic nephrotic syndrome respond well to glucocorticoid therapy. Multidrug-resistant nephrotic syndrome (MRNS) is associated with a poor kidney prognosis. Several retrospective studies have identified rituximab as an effective treatment for MRNS; however, prospective studies are required to assess its efficacy and safety.MethodsWe conducted a multicenter, non-blinded, single-arm trial to investigate the efficacy and safety of rituximab in patients with childhood-onset MRNS who were resistant to cyclosporine and more than three courses of steroid pulse therapy. The enrolled patients received four 375 mg/m2 doses of rituximab in combination with baseline cyclosporine and steroid pulse therapy. The primary endpoint was a > 50% reduction in the urinary protein/creatinine ratio from baseline on day 169. Complete and partial remissions were also evaluated.ResultsSix patients with childhood-onset MRNS were enrolled. All patients were negative for pathogenic variants of podocyte-related genes. On day 169, five patients (83.3%) showed a > 50% reduction in the urinary protein/creatinine ratio, two patients showed partial remission, and two patients showed complete remission. No deaths occurred and severe adverse events occurred in two patients (infection in one patient and acute kidney injury in one patient). Three patients needed treatment for moderate-to-severe infection.ConclusionsThe study treatment effectively reduced the urinary protein/creatinine ratio in patients with childhood-onset MRNS. The adverse events in this study were within the expected range; however, attention should be paid to the occurrence of infections.

Pre-Treatment Serum Complement 3 Levels And Rituximab Response In Idiopathic Membranous Nephropathy

Objective: The efficacy of rituximab has been reported in patients with idiopathic membranous nephropathy (MN). We aimed to evaluate the relationship between biochemical tests at diagnosis, immunohistochemical profile, and rituximab response in patients with idiopathic MN unresponsive to other therapies in our center. Material and Methods: In this study, nine patients with idiopathic MN who received other immunosuppressive therapies between 2017-2022 and who underwent renal biopsy in our center were evaluated. Pre-treatment phospholipase A2 antibody levels were positive in 6 patients, and antibodies could not be analyzed in 3 patients. All patients received rituximab ≥2 grams after renin-angiotensin-aldosterone system (RAAS) blocker, cyclophosphamide, steroid, and calcineurin inhibitors. Results: Of the nine patients included in the study, 7 (78.2%) were male, and the mean age was 39.713.2 years. Four patients had complete remission (CR) with rituximab treatment, and five had partial remission (PR). Sclerotic glomeruli count, IgG, A, M, C1q, C3, C4d, fibrinogen, kappa and lambda staining, tubular atrophy, and interstitial fibrosis findings on renal biopsy were similar. However, the serum complement 3 (C3) level was significantly lower within normal limits (1.22  0.26 vs 1.560  0.56 p=0.016). The mean arterial pressure was significantly higher (96.22.5 mmHg vs 84.754.27 mmHg, p=0.018) in patients with partial remission compared to those with complete remission. Conclusion: A low baseline serum C3 level within normal limits before treatment in patients with idiopathic membranous nephropathy may help predicting unresponsiveness to other immunosuppressive therapies and partial response to rituximab treatment.

Promising efficacy of Low-Dose rituximab in Muscle specific kinase antibody positive Myasthenia Gravis

AimsThe study aims to evaluate the efficacy of low dose rituximab (RTX) in patients with muscle-specific kinase antibody positive myasthenia gravis (MuSK-MG). MethodsThis is a single-center, retrospective study. A total of 10 patients with MuSK-MG were admitted to the Department of Neurology, First Hospital, Shanxi Medical University, between April 2021 to April 2023. Of them, 9 patients had been treated with low dose RTX (500 mg every 6 month) and recruited in this study. The clinical information, including the severity before and after RTX treatment, were collected from the medical records. Clinical effectiveness was assessed by Myasthenia Gravis Foundation of America (MGFA)-postintervention status (PIS), MG-related activities of daily living (MG-ADL), Quantitative Myasthenia Gravis (QMG) scores, Myasthenia Gravis Quality of Life 15-item revised (MG-QOL15r), dosage of steroid at the end of follow up. ResultsAll nine patients showed clinical improvement at the final follow-up after low-dose RTX treatment. The mean dose of prednisolone decreased significantly from 50 mg at baseline to 18.33 mg at the last follow-up (z = -3.417, p = 0.001). The administration of low-dose RTX treatment led to significant improvements in ADL levels (Z = -2.675, P < 0.01), QMG score levels (Z = -2.371, P < 0.05) and QOL-15r levels (Z = -2.547, P < 0.01) at last visit. ConclusionLow-dose RTX is effective for treating MuSK-MG patients. Longer-term follow-up and larger-scale studies are needed to provide further evidence.

Clinical, biological, electrophysiological and therapeutic profile of patients with anti-MAG neuropathy according to MYD88L265P and CXCR4 mutations and underlying haemopathy.

Anti-MAG neuropathies are associated with an IgM monoclonal gammopathy of undetermined significance (MGUS) or with a malignant haemopathy. Our objective was to determine whether the presence of a haemopathy or somatic mutations of MYD88 and CXCR4 genes influences disease presentation and response to rituximab (RTX). We included 79 patients (mean age 74years, disease duration 9.68years) who had a bone marrow aspiration with morphologic and immunophenotypic analysis. MYD88L265P and CXCR4 mutations were analysed in peripheral B cells. Information collected included: inflammatory neuropathy cause and treatment sensory sum score (ISS), MRC testing, overall neuropathy limitation scale (ONLS), Rash-built Overall Disability Score (RODS), ataxia score, anti-MAG titres, peak IgM dosage, neurofilament light chain levels, motor and sensory amplitudes, motor unit index (MUNIX) and motor unit size index (MUSIX) sum scores. Efficacy of RTX was evaluated at 12months in 26 patients. Malignant haematological disorders were discovered in 17 patients (22%): 13 Waldenstrom macroglobulinemia, 3 marginal zone lymphoma and one mantle cell lymphoma. MYD88L265P mutation was detected in 29/60 (48%) patients and CXCR4 in 1 single patient. Disease severity, biological and electrophysiological data and response to RTX were comparable in patients with MGUS/lymphoma and patients with/without MYD88L265P mutation. ISS was lower and MUSIX higher in patients improved by RTX. MYD88L265P mutation and underlying haemopathies are not predictive of a more severe disease. However, in cases of resistant and progressive neuropathy, they provide an opportunity to prescribe newly available drugs such as Bruton tyrosine kinase inhibitors.

The Immunobiological Agents for Treatment of Antiglomerular Basement Membrane Disease.

Combination therapy with glucocorticoids, cyclophosphamide, and plasmapheresis is recommended as the standard treatment for anti-glomerular basement membrane (anti-GBM) disease, but the prognosis of this disease remains poor. Several immunobiological agents have been administered or are expected to be useful for anti-GBM disease in light of refractory disease or the standard treatments' tolerability. Many data regarding the use of biologic agents for anti-GBM disease have accumulated, verifying the effectiveness and potential of biologic agents as a new treatment option for anti-GBM disease. Tumor necrosis factor (TNF) inhibitors were shown to be useful in animal studies, but these agents have no clinical use and were even shown to induce anti-GBM disease in several cases. Although the efficacy of the TNF-receptor antagonist has been observed in animal models, there are no published case reports of its clinical use. There are also no published reports of animal or clinical studies of anti-B-cell-activating factor, which is a member of the TNF family of agents. Anti-interleukin (IL)-6 antibodies have been demonstrated to have no effect on or to exacerbate nephritis in animal models. Anti-C5 inhibitor was observed to be useful in a few anti-GBM disease cases. Among the several immunobiological agents, only rituximab has been demonstrated to be useful in refractory or poor-tolerance patients or small uncontrolled studies. Rituximab is usually used in combination with steroids and plasma exchange and is used primarily as an alternative to cyclophosphamide, but there is insufficient evidence regarding the efficacy of rituximab for anti-GBM disease, and thus, randomized controlled studies are required.

Efficacy of Rituximab for Minimal Change Disease and Focal Segmental Glomerulosclerosis with Frequently Relapsing or Steroid-Dependent Nephrotic Syndrome in Adults: A Chinese Multicenter Retrospective Study

Introduction: Rituximab has been proven effective and safe in pediatric patients with frequently relapsing or steroid-dependent nephrotic syndrome (FR/SDNS). We aimed to analyze the efficacy and safety of rituximab in adult FR/SDNS patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). Methods: A retrospective cohort study at three nephrology centers in China included adult FR/SDNS patients with biopsy-proven MCD or FSGS. Primary outcomes were relapse frequency and first relapse-free survival time. Adverse events were well recorded, and logistic regression analyses were used to investigate the risk factors of relapse. Results: Eighty-one patients (age, 25.0 years; interquartile range, 20.0–40.5; 67% males; 82.7% MCD) received an average rituximab dose of 1,393.8 ± 618.7 mg/2 years during the 2-year follow-up period. The relapse frequency, calculated as the ratio of relapse times to follow-up years, significantly decreased after rituximab treatment (0.04 [0.00, 0.08] vs. 1.71 [1.00, 2.45], p < 0.001). The first relapse-free survival time was 16.7 ± 8.0 months. Fifty-seven patients (70.4%) achieved cessation of corticosteroids and immunosuppressants within 3 months after the first rituximab infusion. Adverse events were mostly mild, and no severe treatment-related adverse events were observed. Low serum albumin level before rituximab and high CD56⁺CD16⁺ natural killer cell count after rituximab were independent risk factors of relapse within 2 years after rituximab treatment. Conclusion: Rituximab was proven an effective and safe treatment option for adult FR/SDNS patients with MCD or FSGS in maintaining disease remission and minimizing corticosteroid exposure.

Low-dose rituximab in steroid-refractory chronic graft-versus-host disease

BackgroundChronic graft-versus-host disease (cGvHD) is a major complication that puts patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at risk of death or infection. Currently, there is no gold standard for the first-line treatment of patients who do not respond to steroids, and there are several therapeutic options being evaluated in clinical trials for this disease to be used even in the first-line treatment for GvHD. There is evidence of the benefit of rituximab, an anti-CD20 antibody, at a standard dose of 375 mg/m2 weekly in the treatment of steroid-refractory chronic graft-versus disease (SR-cGvHD). ObjectiveTo demonstrate the safety and efficacy of low-dose rituximab in a middle-income center in northeastern Mexico Study designWe report the experience of 26 patients with chronic graft-versus-graft disease who received low-dose rituximab (100 mg weekly for 4 weeks). We utilized the advances in the National Institutes of Health (NIH) criteria for diagnosis, scoring, trial design, and assessment of treatment response. ResultsWe obtained a 5-year overall survival of 23.6%, including four patients with complete response. The 1-year event-free survival was 70% for patients with rituximab. During the treatment, there were 3 hospitalizations, and the causes were: immune thrombocytopenia, a parapneumonic effusion, and a cerebral vascular event. The median length of hospital stay was twelve days. ConclusionA low dose of rituximab is an available and cost-effective option for patients with steroid-refractory cGvHD.

Retrospective Review of Patients Treated with Intrathecal Rituximab for Primary and Secondary CNS Lymphoma and Leukemia

Background: Rituximab has been studied and incorporated into the treatment of primary and secondary CNS lymphoma (Grommes 2017; Bobillo 2023). Systemic rituximab, a CD20-targeting monoclonal antibody, is widely used in the treatment of various B-cell malignancies (Klein 2021); however penetration into the central nervous system (CNS) is limited (Petereit 2009; Harjunpää 2001). Although there are conflicting data regarding the efficacy of IV rituximab in primary CNS lymphoma (Schmitt 2019; Ferrari 2022; Bromberg 2019), its role in other B-cell malignancies with CNS involvement has not been adequately described. In particular, its role in treating the cerebrospinal fluid (CSF) space is unclear. The rationale for direct administration of rituximab into the CSF via lumbar puncture or Ommaya reservoir is to allow for consistent treatment of this compartment in order to effectively clear the CSF of lymphoma cells (Kadoch 2014). Limited data exist regarding the efficacy and safety of intrathecal rituximab (Bonney 2011 Aslan 2022; van de Fling 2008; Santiago 2021; Soares 2019). Current intrathecal armamentarium for leptomeningeal lymphoma is very limited and more data on the efficacy and safety of intrathecal rituximab is needed in these patients. Methods: This is a retrospective, single center study of adult patients with a diagnosis of leukemia or lymphoma who received intrathecal (IT) rituximab between 1/1/2016 and 12/31/2022 at Hackensack Meridian Health. Rituximab 25 mg IT was administered weekly either via lumbar puncture or into an Ommaya reservoir. The primary objective of this study was to evaluate the efficacy and safety of IT rituximab. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan Meier method. Descriptive statistics were used to summarize data for categorical and continuous variables. Results: Twelve patients were identified to have received IT rituximab at our institution between 1/1/2016 and 12/31/2022. Median age was 60 years (range 45-81), 54% were male, and 69% white. Disease types included primary CNS lymphoma (67%), diffuse large B-cell lymphoma (17%), PTLD of the CNS (8%), and chronic lymphocytic leukemia (8%). In regards to CNS disease involvement, 58% of patients presented with parenchymal and leptomeningeal disease, 33% with leptomeningeal disease only, and 8% with parenchymal disease only. There were 12 patients who received IT rituximab for the treatment of malignant CNS disease with characteristics and outcomes as shown in Table 1. The median number of IT rituximab treatments administered were 8 (range 2-9). Of the 10 patients evaluable for response, 92% of patients achieved complete response in the CSF following treatment with IT rituximab as evaluated by flow cytometry, cytology, cell count and protein levels in CSF. One patient that did not achieve CSF remission has an unusual case of relapsing/remitting CLL and leukemic meningitis. There were 2 patients unevaluable for response to IT rituximab: one patient received only 2 treatments prior to switching to hospice care; and the other patient had a severe adverse reaction (tightening of throat, flushing, toe numbness) after IT rituximab and was not continued on treatment. At a median follow-up of 19.7 months, median PFS was not reached (NR) (95% CI, 0.5-NR) ( Figure 1). Median OS was 70.1 months (95% CI, 1.2-NR). Six (50%) patients experienced adverse reactions from IT rituximab treatment, including perioral numbness, headache, nausea, and flushing ( Table 1). No treatment-related deaths occurred. One (8%) patient experienced a severe adverse reaction following administration of IT rituximab. This patient developed tightening of the throat, flushing, and toe numbness after the first IT rituximab and symptoms resolved with administration of hydrocortisone and diphenhydramine. No further IT rituximab doses were administered. Another patient experienced a mild reaction consisting of headache, fatigue, nausea, diaphoresis, hypotension, and bradycardia following the fourth dose of IT rituximab in combination with IV rituximab, but was able to complete his treatment course. Conclusions: The use of IT rituximab appears safe and showed promising activity in B cell malignancies, specifically as part of induction in patients with leptomeningeal disease and PCNSL as those patients achieved cytologic response.

Efficacy and Safety of Reduced-Dose Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) in Patients over 80 with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)

Background: The standard treatment for newly diagnosed DLBCL has been R-CHOP for many years. Recently, Pola-R-CHP using polatuzumab vedotin has been reported to have superior efficacy to R-CHOP and is available as first-line treatment for DLBCL. However, the patients in the phase 3 POLARIX trial were under 80, and the efficacy and safety for patients over 80 are not established. To investigate the efficacy and safety of Pola-R-CHP in the elderly, we conducted this study. Patients and Methods: From September 2022 to March 2023, we retrospectively analyzed patients with newly diagnosed DLBCL treated with Pola-R-CHP at Anjo Kosei Hospital. Patients previously treated for hematologic malignancies were excluded. The dosages of polatuzumab vedotin and rituximab were not reduced, and the dosages of cyclophosphamide, doxorubicin, and prednisone or treatment schedules were determined by the treating physician. The primary endpoint was the rate of treatment continuation without early termination, and secondary endpoints were efficacy, progression free survival (PFS), and safety. Results: A total of 29 patients (younger group: under 80, n = 21; elderly group: over 80, n = 8) were consecutively enrolled. The median age in the younger group was 64 (range 42-78) and in the elderly group was 82.5 (range 80-94). Patient characteristics, including history of malignancy (24% vs 13%, p=0.50), lifestyle diseases (43% vs 50%, P = 0.73), and sanctuary lesions (10% vs 25%, P = 0.28), were comparable in both groups. However, advanced disease was significantly higher in the younger group (76% vs 38%, P = 0.05). The Revised IPI scores were similar in both groups (Very good: 5% vs 0 %, Good: 29% vs 50%, Poor: 67% vs 50%, P = 0.50). Cyclophosphamide, doxorubicin, and prednisone were administered at full dose in 71% of the younger group, but were reduced in all patients in the elderly group (P = 0.001). Peg-GCSF was administered during treatment in all cases in the elderly group. The median days to the 6th cycle were 111 (range 105-126) in the younger group and 114.5 (range 107-124) in the elderly group, with no significant difference (P = 0.37). The rate of treatment continuation until the 6th cycle was 86% in the younger group and 100% in the elderly group, with no significant difference (P = 0.27, Fig A). Three patients in the younger group discontinued treatment due to deterioration of comorbidities (n=1), early death due to infection (n=1), and insufficient treatment effect leading to regimen change (n = 1). In the positron emission tomography (PET) / computer tomography (CT)-based response evaluation after treatment, complete metabolic response was observed in 48% of the younger group and 50% of the elderly group, and partial metabolic response was observed in 19% and 13% respectively (P = 0.90, Fig B). The CT based response were evaluated during the treatment. After 2 cycles of treatment, partial response was achieved 86% of patients in younger group and 75% of those in elderly group (P = 0.50). In the elderly group, complete response was confirmed in 75% of the patients at the end of cycle 6. The 6-month PFS after treatment initiation was 95% in the younger group (95% confidence interval, 71-99%) and 100% in the elderly group (p = 0.54). The incidence of grade 3 or higher non-hematologic toxicity was 28% in the younger group and 48% in the elderly group (P = 0.27). The incidence of febrile neutropenia or grade 3 or higher infection was 76% in the younger group and 75% in the elderly group (P = 0.95), and one case of grade 5 sepsis was observed in the younger group. There were no cases of cytomegalovirus reactivation or infection. Peripheral neuropathy occurred in 3 cases (14%) in the younger group but not in the elderly group. Conclusion: Pola-R-CHP is a feasible and effective treatment in clinical practice for patients over 80 with newly diagnosed DLBCL, with efficacy equivalent to that in younger patients. Further confirmation of long-term treatment effects and safety is necessary, but reduced-dose Pola-R-CHP is a reasonable choice as a standard treatment for newly diagnosed DLBCL in the elderly.

Efficacy and Safety of Polatuzumab-Vedotin Plus Rituximab, Cyclophosphamide, Doxorubicin and Prednisone (Pola-R-CHP) for Diffuse Large B-Cell Lymphoma in the Real-World Setting: A Single Institute Retrospective Study

Background In the POLARIX study, Pola-R-CHP showed significant improvement in progression free survival (PFS) in previously untreated diffuse large B-cell lymphoma (DLBCL) compared to R-CHOP. Pola-R-CHP was approved in September 2022 in Japan ahead of the the world. However, there are still few reports about the safety and efficacy of Pola-R-CHP in real-world setting, leaving some questions about the optimal patient population for Pola-R-CHP. So, we conducted this single institute retrospective observational study in clinical practice. Methods The Pola-R-CHP group included untreated DLBCL patients who received Pola-R-CHP therapy from September 2022 to January 2023 at Kansai Medical University Hospital. The control group included untreated DLBCL patients treated with R-CHOP or R-THP-COP from January 2020 to June 2022 at our hospital. The primary endpoint was the complete remission rate (CRR) at the end of treatment, and secondary endpoints were 6-month PFS, 6-month overall survival (OS) survival, and severity and frequency of adverse events. Results In the Pola-R-CHP group, 30 patients (median age 74 [range;42-88] years) were enrolled. 8 patients over 80 years old were included. 46.7% (14/30) of the cases were Ann Arbor Stage Ⅲ-Ⅳ, and 73.3% (22/30) of the cases had IPI(International Prognostic Index) of 2 or more points. 60.0% (18/30) of patients were GCB (germinal center B-cell) type and 33.3% (10/30) were non-GCB type, and 36.7% (11/30) of patients were DEL (Double expressor lymphoma).In the control group, 100 patients (median age 75 [range;39-88] years) were enrolled. 23 patients over 80 years old were included. 54% (54/100) of the cases were Stage Ⅲ-Ⅳ, and 74%(74/100) of the cases had IPI of 2 or more points. 44%(44/100) of patients were GCB type and 47% (47/100) were non-GCB type (nine were not classified), and 40% (40/100) of patients were DEL. 65% (65/100) of patients were treated with R-CHOP and 35% (35/100) patients were treated with R-THP-COP. There were no significant differences in the patient backgrounds between the respective groups.In Pola-R-CHP cohort, the median follow-up was 282 days (range, 181-348 days). The median number of Pola-R-CHP cycles performed 6 (range; 2-6), with a 6-cycles completion rate of 86.7% (26/30). In patients over 80 years old, the doses of CHP were reduced to 50%. In the Pola-R-CHP group at end of treatment (EOT), the overall response rate was 93.3% (n=28), CRR was 86.7% (n=26), partial response was 6.7% (n=2), and progressive disease was 6.7% (n=2)(Fig.1). In the control group, CRR at EOT was 76.0% but the difference between each group was not significant (p=0.321). The PFS at 6 months was 93.3% (95% confidence interval (CI),75.9%-98.3%) in the Pola-R-CHP group and 80.0% (95%CI,70.7%-86.6%) in the control group, with significantly improvement in the Pola-R-CHP group (p=0.017). Notably, in patients with IPI of 4 to 5, CRR was 88.9 % in the Pola-R-CHP group and 51.5% in the control group (p=0.060), and the PFS at 6 months was significantly higher in the Pola-R-CHP group (88.9% [95%CI,43.4%-98.4%] vs. 60.6%[95%CI,42.0%-74.9%]; p=0.034) In the patients with high metabolic tumor volume (MTV) measured based on PET-CT (cut off value; 166 cm 3 in the top quartile of MTV), PFS at 6 months was significantly higher in the Pola-R-CHP group than the control group (100% vs 73.7% [95% CI,47.9%-88.1%]; p=0.045). OS at 6 months was 89% (95%CI,81%-93.8%) in the control group, while all patients in the Pola-R-CHP group were alive. The most common AE was hematological toxicity: neutropenia, anemia, and thrombocytopenia at grade 3-4 was observed in 43.3%, 16.7%, and 20.0%, respectively (Fig. 2). 14 cases of infection were observed. Peripheral neuropathy was found in 23.3% of the patients, and one of the patients reached grade 3-4. Many cases were complicated with constipation, but only a few cases were grade 3-4. Diarrhea was present in 20%, but all were mild and transient. No deaths due to AE were observed. One patient had to discontinue treatment due to heart failure. Unexpected adverse events were not observed. Conclusion In this study, Pola-R-CHP showed a treatment response and PFS benefit compared to historical control in patients with previously untreated DLBCL in the real-world setting.The incidence of diarrhea and peripheral neuropathy was lower, while AE profiles were similar to POLARIX study. Pola-R-CHP is well tolerated and the efficacy can be promising compared to R-CHOP.

Trial in Progress: Treatment of Newly-Diagnosed Follicular Lymphoma with Celmod BMS-986369, Rituximab +/- Nivolumab: An Umbrella Phase II Investigator-Initiated Study

Background: Follicular lymphoma (FL) outcomes are influenced by tumour microenvironment composition and manipulation. As patients (pts) with FL are predominantely aged over 65 and may require treatment multiple times over their disease course, novel regimens which maintain or enhance efficacy and minimise toxicity are highly desirable. We have previously reported favourable efficacy and safety of nivolumab plus rituximab as a 1 st line treatment in advanced-stage, grade 1-3A treatment naïve FL, (ORR 92%; CR 54%; toxicity grade 3 or higher in 41%) in an investigator-led trial. 1-3 Oral cereblon-modulating (CELMoD) compounds have shown substantial efficacy alone or in combination with rituximab in both treatment naive and relapsed/refractory FL. 4,5 CELMoDs co-opt cereblon to promote degradation of key transcription factors in cell development and homeostasis, including Ikaros and Aiolos, which are upregulated in FL. 6 Additionally, they act as immunomodulatory agents and augment immune host response. The novel CELMoD, BMS-986369 (golcadomide), demonstrated enhanced antiproliferative and apoptotic activity in pre-clinical studies, with ORR of up to 75% following monotherapy doses of 0.4mg or higher in heavily pre-treated FL pts. 7-10 Our follow-on study (‘TOP-FLOR’; NCT05788081) builds on these findings and potential immunomodulatory synergy to explore the efficacy and safety of BMS-986369 with rituximab +/-nivolumab in treatment-naïve advanced stage FL pts. Study Design and methods: This is an open label multicentre umbrella Bayesian Optimal randomised Phase II trial. The study will randomise up to 40 eligible pts 1:1 to receive rituximab, BMS986369 +/- nivolumab (20 per arm) from 5 Australian sites. Eligibility includes pts aged &amp;gt;18 years, with previously-untreated, stage II-IV, grade 1-3A FL with performance status of 0-1 who require systemic therapy. Treatment consists of 8 cycles (28 days each) of BMS-986369 0.4 mg po daily on days 1- 14 plus rituximab 375 mg/m2 IV day 1 in Arm A; BMS-986369, rituximab as above plus nivolumab 480mg IV day 1 in Arm B. All pts in partial or complete response at end of induction receive 12-weekly rituximab maintenance (8 doses). The primary endpoint will be CR rate in the absence of prohibitive toxicity in accordance with CTCAE V5.0 after eight cycles of rituximab, BMS-986369 +/-nivolumab. Secondary endpoints include: Overall toxicity, response rate (according to modified Lugano criteria), time to treatment failure, progression-free survival and overall survival. Exploratory endpoints include: pt reported outcomes as measured by EORTC-QLQ-c30 and FACT-Lym, PET radiomics and tissue, blood and stool immune and genomic biomarkers. Study assessments include: PET/CT, biomarker blood collection and pt reported outcome measures performed at baseline, post cycle 2, 5 and 8, then 6 monthly on maintenance therapy. Response assessment according to modified Lugano criteria. Safety assessments prior to each cycle until 28 days after the final study drug is administered using CTCAEv5.0. Interim assessment of the primary endpoint will be conducted for 11 pts in each arm, arms will be closed for futility if fewer than 7 pts achieve the primary endpoint. Treatment arms will not be formally compared. Survival probabilities will be reported using Kaplan-Meier analysis. Status: This trial received IRB approval on 14 July 2023 (HREC/88597/Austin-2023) at Austin Health, Heidelberg, Australia. Funding: This trial is supported by an investigator-sponsored research grant from Bristol-Myers Squibb. Nivolumab and BMS 989369 supplied by Bristol-Myers Squibb.

Therapeutic Potential of Rituximab in Managing Hepatitis C-Associated Cryoglobulinemic Vasculitis: A Systematic Review

(1) Background. Hepatitis C infection often leads to extrahepatic manifestations, including cryoglobulinemic vasculitis. This systematic review aimed to assess the efficacy and safety of rituximab in treating hepatitis C-associated cryoglobulinemic vasculitis. (2) Methods. Following PRISMA guidelines, databases were searched for relevant studies. Eligibility criteria included studies on hepatitis C-associated cryoglobulinemic vasculitis treated with rituximab. (3) Results. Nine studies met the eligibility criteria and were included in this analysis. Rituximab was commonly administered at 375 mg/m2 weekly for one month. The results consistently demonstrated the efficacy of rituximab, whether as a standalone treatment or as part of a therapeutic regimen. The combination of rituximab with Peg-IFN-α and ribavirin significantly increased the complete response rate compared to Peg-IFN-α and ribavirin alone (54.5% vs. 33.3%, p &lt; 0.05). The 3-year sustained response rate was notably higher in the rituximab combination group (83.3% vs. 40%). In another trial, rituximab achieved remission in 83.3% of patients at 6 months, compared to only 8.3% in the control group. The efficacy of rituximab was supported by long-term experience, with clinical benefits in patients with severe cryoglobulinemic vasculitis, including those resistant to standard therapies. Mild adverse events were generally reported, with rare severe reactions in some studies. (4) Conclusions: In conclusion, rituximab appeared to be effective and safe in managing hepatitis C-associated cryoglobulinemic vasculitis, either alone or with antiviral therapy.

Rituximab bij auto-immune blaarziekten

Rituximab for autoimmune bullous diseases For a long time, the treatment of autoimmune blistering diseases consisted of classical immunosuppressants. Recently, biologicals, including rituximab, directed against the pan B-cell marker CD20, are used. Currently, practical guidelines for the optimal use of rituximab in the treatment of autoimmune blistering diseases are still under discussion. This literature review provides an overview of the efficacy, side effects, indication, optimal dosage and administration interval of rituximab in this population. In total, 37 publications were included, based on a systematic search strategy and selection procedure. The reported efficacy of rituximab in pemphigoid, expressed as complete remission without further therapy, ranges from 20% to 79%. For pemphigus, this amounts to 89% in the RITUX-3 study, which formed the basis for approval as first-line therapy. Side effects occur in 24% to 85% of the cases. The most important are infusion-related reactions and infections. In general, the safety profile corresponds to the known side effects of rituximab in other indications. The evidence for the practical guidelines is mainly built around pemphigus. Currently, the ‘high-dose rheumatoid arthritis protocol’ is preferred, although randomised, comparative studies are lacking. The high relapse rate justifies the need for repeated administrations. Further research should clarify whether repeated administration should be done systematically or based on different parameters. Rituximab is an effective and relatively safe therapy in autoimmune blistering diseases in both first and second line. In terms of practical use, further research is recommended.

Pembrolizumab With R-CHOP in Previously Untreated DLBCL: Sustained, High Efficacy, and Safety With Long-Term Follow-Up

BackgroundWhile generally ineffective in relapsed diffuse large B cell lymphoma (DLBCL), immune checkpoint inhibitors (ICIs) may hold greater promise in untreated, immunocompetent patients. We previously reported safety and early efficacy of pembrolizumab plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (PR-CHOP) in a phase I trial of untreated DLBCL, noting responses in 90% of patients (complete response 77%) and a 2-year progression-free survival (PFS) of 83%. We herein report long-term safety and efficacy at 5-year follow up. Patients and MethodsAdult patients with untreated DLBCL or grade 3b follicular lymphoma, intended to receive 6 cycles of R-CHOP were eligible. Patients (N = 30) were treated with pembrolizumab 200 mg IV and R-CHOP in 21-day cycles for 6 cycles. ResultsAt median follow up of 4.8 years, 5-year PFS was 71% (CI, 54%-94%) and 5-year overall survival was 83% (CI, 71%-98%). Immune-related adverse events (IRAEs) occurred in 7 (23%) patients (10% grade 3/4). Three IRAEs (rash, thyroiditis, rheumatoid arthritis) occurred beyond 3 months of treatment completion. PD-L1 tumor expression was documented in 19 of 23 (83%) tested patients. None of the 19 patients who had any PD-L1 expression have relapsed, whereas 2 out of the 4 patients with no PD-L1 expression have relapsed. ConclusionPR-CHOP has led to durable responses in most patients, with the best outcomes in PD-L1-expressing disease. Furthermore, the safety profile was manageable, with no consistent pattern of late events. These data support ongoing strategies incorporating ICIs in frontline DLBCL therapy and confirmation of predictive biomarkers including tumor PD-L1 expression.

Efficacy and Safety of Rituximab-Based Treatments in Angioedema With Acquired C1-Inhibitor Deficiency

Angioedema (AE) due to acquired C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is related to excessive consumption of C1-INH or to anti-C1-INH antibodies, and is frequently associated with lymphoproliferative syndromes or monoclonal gammopathies. Standard of care for prophylactic treatment in this condition is not established. Rituximab may be effective to prevent attacks, especially if the lymphoid hemopathy is controlled, but data are scarce. To evaluate efficacy of rituximab in AAE-C1-INH. A retrospective multicenter study was carried out in France, including patients with AAE-C1-INH treated with rituximab between April 2005 and July2019. Fifty-five patients with AAE-C1-INH were included in the study, and 23 of them had an anti-C1-INH antibody. A lymphoid malignancy was identified in 39 patients, and a monoclonal gammopathy in 9. There was no associated condition in 7 cases. Thirty patients received rituximab alone or in association with chemotherapy (n= 25). Among 51 patients with available follow-up, 34 patients were in clinical remission and 17 patients had active AE after a median follow-up of 3.9 years (interquartile range, 1.5-7.7). Three patients died. The presence of anti-C1-INH antibodies was associated with a lower probability of AE remission (hazard ratio, 0.29 [95% CI, 0.12-0.67]; P= .004). Relapse was less frequent in patients with lymphoma (risk ratio, 0.27 [95% CI, 0.09-0.80]; P= .019) and in patients treated with rituximab and chemotherapy (risk ratio, 0.31 [95% CI, 0.12-0.79]; P= .014). Rituximab is an efficient and well-tolerated therapeutic option in AE, especially in lymphoid malignancies and in the absence of detectable anti-C1-INH antibodies.

Meta-analysis on the efficacy and safety of rituximab versus tacrolimus for nephrotic syndrome in the paediatric age group.

Meta-analysis on the efficacy and safety of rituximab versus tacrolimus for nephrotic syndrome in the paediatric age group.

Inebilizumab reduces neuromyelitis optica spectrum disorder risk independent of FCGR3A polymorphism.

Inebilizumab, a humanized, glycoengineered, IgG1 monoclonal antibody that depletes CD19+ B-cells, is approved to treat aquaporin 4 (AQP4) IgG-seropositive neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab is afucosylated and engineered for enhanced affinity to Fc receptor III-A (FCGR3A) receptors on natural killer cells to maximize antibody-dependent cellular cytotoxicity. Previously, the F allele polymorphism at amino acid 158 of the FCGR3A gene (F158) was shown to decrease IgG-binding affinity and reduce rituximab (anti-CD20) efficacy for NMOSD attack prevention. In contrast, our current findings from inebilizumab-treated NMOSD patients indicate similar clinical outcomes between those with F158 and V158 allele genotypes.

Retracted: Efficacy and Safety of Rituximab in the Treatment of Idiopathic Membranous Nephropathy: A Meta-Analysis.

[This retracts the article DOI: 10.1155/2022/5393797.].