Effect of Prior Treatment With Fingolimod on Early and Late Response to Rituximab/Ocrelizumab in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Real-life studies noted that the risk of disease activity in multiple sclerosis (MS) after switching to rituximab (RTX) or ocrelizumab (OCR) may be unequal depending on prior disease-modifying therapy (DMT), with a higher risk associated with fingolimod (FING). METHODS: We performed a retrospective analysis of a structured prospective data collection including all consecutive patients with relapsing MS who were prescribed RTX/OCR in the MS center of Marseille. Cox proportional hazards models were applied to clinical and MRI outcomes. RESULTS: We included 321 patients with a median (interquartile range [IQR]) follow-up of 3.5 years (1.5-5) after RTX/OCR initiation. At the first RTX/OCR infusion, the mean (SD) age of patients was 37 (10) years, and the median (IQR) disease duration was 8 years (3-15): 68 patients did not receive treatment before RTX/OCR and 108 switched from FING, 47 from low efficacy therapy, and 98 from natalizumab. For statistical analysis, the group "FING" was divided into "short-FING" and "long-FING" groups according to the median value of the group's washout period (27 days). On Cox proportional hazards analysis, for only the "long-FING" group, the risk of relapse within the first 6 months of RTX/OCR was increased as compared with patients without previous DMT (hazard ratio [HR]: 8.78; 95% CI 1.72-44.86; p < 0.01). Previous DMT and washout period duration of FING had no effect on B-cell levels at 6 months. Beyond the first 6 months of RTX/OCR, age <40 years was associated with increased risk of relapse (HR: 3.93; 95% CI 1.30-11.89; p = 0.01), male sex with increased risk of new T2 lesions (HR: 2.26; 95% CI 1.08-4.74; p = 0.03), and EDSS ≥2 with increased risk of disability accumulation (HR: 3.01; 95% CI 1.34-6.74; p < 0.01). Previous DMT had no effect on the effectiveness of RTX/OCR beyond 6 months after initiation. DISCUSSION: For patients switching from FING to RTX/OCR, the risk of disease reactivation within the first 6 months of treatment was increased as compared with patients with other DMT or no previous DMT only when the washout period exceeded 26 days. Neither FING nor other previous DMT reduced the effectiveness of RTX/OCR beyond the first 6 months of treatment.

Effectiveness and safety of mycophenolate mofetil and rituximab combination therapy for immune idiopathic myopathies.

INTRODUCTION: Idiopathic inflammatory myopathies (IIM) represent a rare and heterogenous group diseases, and their treatment is not fully defined yet. According to previous small case series, the combination of mycophenolate mofetil (MMF) and rituximab (RTX) may be effective in controlling difficult-to-treat patients. Our aim was to further explore the efficacy and safety of this combined approach in patients with IIM. METHODS: Patients with IIM treated with the RTX/MMF combination in our Center were retrospectively identified. After the start of combination therapy, the efficacy was evaluated at 12 months (T12) according the 2016 ACR/EULAR response criteria for IIM. Cardiac imaging and pulmonary function tests were used to monitor disease activity in patients with myocarditis and interstitial lung disease, respectively. Adverse events were recorded over the follow-up period. RESULTS: Among the 20 patients (median age 61 years; 70% female) included in the study, anti-synthetase syndrome was the most prevalent IIM subgroup (60%). At treatment start, muscle, heart, and lung were the most commonly actively affected organs. After 12 months, a moderate or major response was observed in all patients, and creatine kinase was significantly decreased (p-value = 0.012). Cardiac imaging and enzymes monitoring showed a reduction of heart inflammation, while pulmonary function tests improved in patients with lung involvement. No severe side effects were observed. CONCLUSION: Our data show that combination of RTX and MMF is effective and safe in patients with severe and refractory IIM. Therefore, this combined treatment might represent a feasible approach for difficult-to-treat IIM cases.

Long-term clinical and radiological effectiveness and safety of ultralow doses of rituximab in rheumatoid arthritis: observational extension of the REDO trial.

BACKGROUND: The REDO trial (REtreatment with Rituximab in RhEmatoid arthritis: Disease Outcome after Dose Optimisation) showed similar disease activity for retreatment with ultralow doses (200 mg and 500 mg per 6 months) compared with standard low-dose rituximab (RTX, 1000 mg per 6 months). We performed an observational extension study of the REDO trial to assess long-term effectiveness. METHODS: Patients from the REDO trial were followed from start of the trial to censoring in April 2021. RTX use was at the discretion of patient and rheumatologist using treat to target. The primary outcome was disease activity (disease activity score in 28 joints C-reactive protein (DAS28-CRP)), analysed using a longitudinal mixed model by original randomisation and time-varying RTX dose. The original DAS28-CRP non-inferiority (NI) margin of 0.6 was used. RTX dose and persistence, safety and radiological outcomes were also assessed. FINDINGS: Data from 126 of 142 REDO patients was collected from 15 December 2016, up to 30 April 2021. Drop-outs continued treatment elsewhere (n=3) or did not consent (n=13).Disease activity did not differ by original randomisation group: 1000 mg mean DAS28-CRP (95% CI) of 2.2 (2.0 to 2.5), 500 mg 2.3 (2.1 to 2.4) and 200 mg 2.4 (2.2 to 2.5). Lower time-varying RTX dose was associated with higher DAS28-CRP (0.22 (95% CI 0.05 to 0.40) higher for 200 mg/6 months compared with 1000 mg/6 months), but remained within the NI-margin. RTX persistence was 93%. Median RTX dose was 978 mg (IQR 684-1413) per year, and no association was found between RTX dose and adverse events or radiological damage. INTERPRETATION: Long-term use of ultralow doses of RTX is effective in patients with rheumatoid arthritis responding to standard dose RTX.

[Steroid-Dependent Nephrotic Syndrome Due to Minimal Change Glomerulonephritis Treated with Rituximab].

47-year-old woman suffering from minimal lesion glomerulonephritis previously undergone high-dose steroid therapy and subjected to exacerbations of nephrotic syndrome after therapy discontinuation. It was decided to initiate off-label treatment with Rituximab at a dosage of 375 mg/m2 administred at zero-time, one-month and three months with good therapeutic response and resolution of the clinical laboratory picture. The therapy was well tolerated and had no side effects. This scheme could be an alternative to the conventional therapeutic scheme with steroids or other classes of immunosuppressive drugs, especially in order to avoid problems related to prolonged exposure to steroid therapy.

Multiple Sclerosis, Rituximab, Hypogammaglobulinemia, and Risk of Infections.

BACKGROUND AND OBJECTIVES: B-cell-depleting therapies increase the risk of infections and hypogammaglobulinemia. These relationships are poorly understood. The objectives of these analyses were to estimate how much of this rituximab-associated infection risk is mediated by hypogammaglobulinemia and to identify other modifiable risk factors in persons with multiple sclerosis (pwMS). METHODS: We conducted a retrospective cohort study of rituximab-treated pwMS from January 1, 2008, to December 31, 2020, in Kaiser Permanente Southern California. Cumulative rituximab dose was defined as ≤2, >2 and ≤4, or >4 g. Serious infections were defined as infections requiring or prolonging hospitalizations, and recurrent outpatient infections as seeking care for ≥3 within 12 months. Exposures, outcomes, and covariates were collected from the electronic health record. Adjusted hazard ratios (aHRs) were estimated using Andersen-Gill hazards models, and generalized estimating equations were used to examine correlates of IgG values. Cross-sectional causal mediation analyses of rituximab and hypogammaglobulinemia were conducted. RESULTS: We identified 2,482 pwMS who were treated with rituximab for a median of 2.4 years (interquartile range = 1.3-3.9). The average age at rituximab initiation was 43.0 years, 71.9% were female, 49.7% were White, non-Hispanic patients, and 29.6% had advanced disability (requiring walker or worse). Seven hundred patients (28.2%) developed recurrent outpatient infections, 155 (6.2%) developed serious infections, and only 248 (10.0%) had immunoglobulin G (IgG) < 700 mg/dL. Higher cumulative rituximab dose (>4 g) was correlated with lower IgG levels (Beta = -58.8, p < 0.0001, ref ≤2 g) and, in models mutually adjusted for hypogammaglobulinemia, both were independently associated with an increased risk of serious (>4 g, aHR = 1.56, 95% CI 1.09-2.24; IgG < 500, aHR = 2.98, 95% CI 1.56-5.72) and outpatient infections (>4 g, aHR = 1.73, 95% CI 1.44-2.06; IgG < 500 aHR = 2.06, 95% CI 1.52-2.80; ref = IgG ≥ 700). Hypogammaglobulinemia explained at most 17.9% (95% CI -47.2-119%) of serious infection risk associated with higher cumulative rituximab exposure but was not significant for outpatient infections. Other independent modifiable risk factors were advanced physical disability for serious (aHR = 5.51, 95% CI 3.71-8.18) and outpatient infections (aHR = 1.24, 95% CI 1.06-1.44) and COPD (aHR = 1.68, 95% CI 1.34-2.11) and obesity (aHR = 1.25, 95% CI 1.09-1.45) for outpatient infections. DISCUSSION: Higher cumulative rituximab doses increase the risk of infections even in this population where 90% of patients maintained normal IgG levels. Clinicians should strive to use minimally effective doses of rituximab and other B-cell-depleting therapies and consider important comorbidities to minimize risks of infections.

Alemtuzumab-induced thyroid eye disease successfully treated with a single low dose of rituximab.

Introduction: Secondary thyroid autoimmunity, especially Graves' disease (GD), frequently develops in patients with multiple sclerosis (MS) following alemtuzumab treatment (ALTZ; anti-CD52). Thyroid eye disease (TED) can also develop, and rituximab (RTX; anti-CD20) is a suitable treatment. Case presentation: A 37-year-old woman with MS developed steroid-resistant active moderate-to-severe TED 3 years after ALTZ, that successfully responded to a single 500 mg dose of i.v. RTX. Before RTX peripheral B-cells were low, and were totally depleted immediately after therapy. Follow-up analysis 4 years post ALTZ and 1 year post RTX showed persistent depletion of B cells, and reduction of T regulatory cells in both peripheral blood and thyroid tissue obtained at thyroidectomy. Conclusion: RTX therapy successfully inactivated TED in a patient with low B-cell count derived from previous ALTZ treatment. B-cell depletion in both thyroid and peripheral blood was still present 1 year after RTX, indicating a likely cumulative effect of both treatments.

Drugs Targeting CD20 in Multiple Sclerosis: Pharmacology, Efficacy, Safety, and Tolerability.

Currently, there are four monoclonal antibodies (mAbs) that target the cluster of differentiation (CD) 20 receptor available to treat multiple sclerosis (MS): rituximab, ocrelizumab, ofatumumab, and ublituximab. B-cell depletion therapy has changed the therapeutic landscape of MS through robust efficacy on clinical manifestations and MRI lesion activity, and the currently available anti-CD20 mAb therapies for use in MS are a cornerstone of highly effective disease-modifying treatment. Ocrelizumab is currently the only therapy with regulatory approval for primary progressive MS. There are currently few data regarding the relative efficacy of these therapies, though several clinical trials are ongoing. Safety concerns applicable to this class of therapeutics relate primarily to immunogenicity and mechanism of action, and include infusion-related or injection-related reactions, development of hypogammaglobulinemia (leading to increased infection and malignancy risk), and decreased vaccine response. Exploration of alternative dose/dosing schedules might be an effective strategy for mitigating these risks. Future development of biosimilar medications might make these therapies more readily available. Although anti-CD20 mAb therapies have led to significant improvements in disease outcomes, CNS-penetrant therapies are still needed to more effectively address the compartmentalized inflammation thought to play an important role in disability progression.

Compression therapy using surgical gloves is ineffective for the prevention of vincristine-induced neuropathy in patients with malignant lymphoma.

PURPOSE: Vincristine (VCR) often induces peripheral neuropathy (PN) as an adverse event. Currently, there is no consensus on the prevention of vincristine-induced PN (VIPN). In this study, we aimed to investigate the efficacy of compression therapy using surgical gloves for preventing VIPN. METHODS: Patients with malignant lymphoma (vincristine-naïve) who were receiving chemotherapy with cyclophosphamide, doxorubicin, VCR, and prednisolone, with or without rituximab, every 3 weeks for six cycles were eligible. For every VCR infusion, each patient wore two one-size-smaller gloves on one hand (study hand) for 90 min. The other hand was left bare (control hand). PN was assessed at each treatment using the Common Terminology Criteria for Adverse Events ver. 4.0. RESULTS: Fifty-one patients with malignant lymphoma were enrolled and 44 were evaluated. At 1 month after treatment, the occurrence rates of grade ≥ 2 sensory PN were 13.6 and 13.6% in the study and control hands, respectively (p = 1.0), and those of grade ≥ 2 motor PN were 15.9 and 15.9% in the study and control hands, respectively (p = 1.0). CONCLUSION: Compression therapy using surgical gloves showed no significant effect for the prevention of VIPN. TRIAL REGISTRATION: November 1, 2018, National University Hospital Council of Japan (UMIN 000034145).

Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial.

BACKGROUND: Survival in Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disease following haematopoietic stem-cell transplant (HSCT) or solid organ transplant (SOT) is poor after failure of initial therapy, indicating an urgent need for therapies for this ultra-rare disease. With recent EU marketing authorisation, tabelecleucel is the first off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy to receive approval for treatment of relapsed or refractory EBV-positive post-transplant lymphoproliferative disease. We aimed to determine the clinical benefit of tabelecleucel in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease following HSCT or SOT. METHODS: In this global, multicentre, open-label, phase 3 trial, eligible patients (of any age) had biopsy-proven EBV-positive post-transplant lymphoproliferative disease, disease that was relapsed or refractory to rituximab after HSCT and rituximab with or without chemotherapy after SOT, and partially HLA-matched and appropriately HLA-restricted tabelecleucel available. Patients received tabelecleucel administered intravenously at 2 × 106 cells per kg on days 1, 8, and 15 in 35-day cycles and are assessed for up to 5 years for survival post-treatment initiation. The primary endpoint was objective response rate. All patients who received at least one dose of tabelecleucel were included in safety and efficacy analyses. This trial is registered with ClinicalTrials.gov, NCT03394365, and is ongoing. FINDINGS: From June 27, 2018, to Nov 5, 2021, 63 patients were enrolled, of whom 43 (24 [56%] male and 19 [44%] female) were included, 14 had prior HSCT, 29 had SOT. Seven (50%, 95% CI 23-77) of 14 participants in the HSCT group and 15 (52%, 33-71) of 29 participants in the SOT group had an objective response, with a median follow-up of 14·1 months (IQR 5·7-23·9) and 6·0 months (1·8-18·4), respectively. The most common grade 3 or 4 treatment-emergent adverse events were disease progression (in four [29%] of 14 in HSCT and eight [28%] of 29 in SOT) and decreased neutrophil count (in four [29%] of 14 in HSCT and four [14%] of 29 in SOT). Treatment-emergent serious adverse events were reported in 23 (53%) of 43 patients and fatal treatment-emergent adverse events in five (12%); no fatal treatment-emergent adverse event was treatment-related. There were no reports of tumour flare reaction, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, transmission of infectious diseases, marrow rejection, or infusion reactions. No events of graft-versus-host disease or SOT rejection were reported as related to tabelecleucel. INTERPRETATION: Tabelecleucel provides clinical benefit in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease, for whom there are no other approved therapies, without evidence of safety concerns seen with other adoptive T-cell therapies. These data represent a potentially transformative and accessible treatment advance for patients with relapsed or refractory disease with few treatment options. FUNDING: Atara Biotherapeutics.

Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma.

BACKGROUND: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors. METHODS: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression. RESULTS: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab. CONCLUSION: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.

Infliximab rescue therapy in a case of severe granulomatous colitis associated with rituximab use.

Colitis occurs in about 4% of individuals treated with rituximab. Optimal management of rituximab-induced colitis, which does not improve with cessation of the drug and supportive care alone, is poorly defined due to limited evidence. Severe refractory disease can lead to colectomy. We present a case of suspected rituximab-induced colitis occurring in a woman in her 70s suffering from rheumatoid arthritis. The patient achieved full clinical, endoscopic and histological remission of colitis with infliximab therapy. The use of biological therapy to treat rituximab-induced colitis can be a potentially organ-saving rescue therapy; however, it must be balanced against the increased risks of immunosuppression in patients already exposed to rituximab. While more evidence is required to fully understand the efficacy and risks of antitumour necrosis factor therapy in this scenario, our case provides an example of the successful use of infliximab for rituximab-induced colitis, which likely helped the patient avoid a colectomy.

Optimized rituximab regimen versus recommended regimen for idiopathic membranous nephropathy: A single-center retrospective cohort study.

BACKGROUND: Rituximab (RTX) has become the first-line treatment for idiopathic membranous nephropathy (IMN). Compared with conventional therapy, rituximab therapy has a more favorable safety profile. However, the recommended RTX dose as a flux may have its limitations. The aim of this study was to investigate the clinical efficacy and safety of three regimens, including a cyclic corticosteroid-cyclophosphamide regimen and two different doses of RTX regimens, for the treatment of IMN. METHODS: We recruited 58 patients with IMN confirmed by renal biopsy. 20 patients were treated with a cycle regimen, 22 patients were received RTX with 500 mg per week, totaling a dose of 2000 mg (optimized RTX group), and 16 patients received RTX with 1000 mg at day 1 and day 15 (recommended RTX group). Treatment responses, including complete remission (CR) and partial remission (PR), and outcome adverse events such as steroid diabetes, infections and a drop in white blood cell count, were compared among the three groups after 9 months of follow-up. RESULTS: At 9-month follow-up, the composite remission rates (CR + PR) were 90 %, 72.7 %, and 75 % for the cycle regimen group, optimized RTX group, and recommended RTX group, respectively, with CR of 35 %, 22.7 %, and 25 %, respectively. There was no statistical difference between the three groups on CR and composite remission. Kaplan-Meier survival analyses showed no significant differences in cumulative CR rates and cumulative composite remission rates among the three groups (P = 0.632, P = 0.258). The cycle regimen group had a higher risk of steroid diabetes (35 %). Compared with the recommended RTX regimen, the optimized regimen reduced the incidence of adverse events of infection (9.1 % vs. 37.5 %, P = 0.049), especially in patients older than 60 years of age (P = 0.026). A lower anti-PLA2R at baseline may be associated with a higher risk of infection (P = 0.043). CONCLUSIONS: The efficiency of low-dose and long-course of RTX regiment is not inferior to the recommended treatment regimen, and this regimen can effectively reduce the incidence of infection in patients with IMN. Moreover, we recommend a low-dose, long course of RTX treatment for the elderly.

An international multicenter study comparing COVID-19 omicron outcomes in patients with hematological malignancies treated with obinutuzumab versus rituximab.

OBJECTIVES: Hematological malignancy (HM) patients treated with anti-CD20 monoclonal antibodies are at higher risk for severe COVID-19. A previous single-center study showed worse outcomes in patients treated with obinutuzumab compared to rituximab. We examined this hypothesis in a large international multicenter cohort. METHODS: We included HM patients from 15 centers, from five countries treated with anti-CD20, comparing those treated with obinutuzumab (O-G) to rituximab (R-G) between December 2021 and June 2022, when Omicron lineage was dominant. RESULTS: We collected data on 1048 patients. Within the R-G (n = 762, 73%), 191 (25%) contracted COVID-19 compared to 103 (36%) in the O-G. COVID-19 patients in the O-G were younger (61 ± 11.7 vs. 64 ± 14.5, p = 0.039), had more indolent HM diagnosis (aggressive lymphoma: 3.9% vs. 67.0%, p < 0.001), and most were on maintenance therapy at COVID-19 diagnosis (63.0% vs. 16.8%, p < 0.001). Severe-critical COVID-19 occurred in 31.1% of patients in the O-G and 22.5% in the R-G. In multivariable analysis, O-G had a 2.08-fold increased risk for severe-critical COVID-19 compared to R-G (95% CI 1.13-3.84), adjusted for Charlson comorbidity index, sex, and tixagevimab/cilgavimab (T-C) prophylaxis. Further analysis comparing O-G to R-G demonstrated increased hospitalizations (51.5% vs. 35.6% p = 0.008), ICU admissions (12.6% vs. 5.8%, p = 0.042), but the nonsignificant difference in COVID-19-related mortality (n = 10, 9.7% vs. n = 12, 6.3%, p = 0.293). CONCLUSIONS: Despite younger age and a more indolent HM diagnosis, patients receiving obinutuzumab had more severe COVID-19 outcomes than those receiving rituximab. Our findings underscore the need to evaluate the risk-benefit balance when considering obinutuzumab therapy for HM patients during respiratory viral outbreaks.

Cytomegalovirus Occurrence and Time-to-onset Analysis Under Bendamustine With Anti-CD20 Antibodies Using the JADER Database.

BACKGROUND/AIM: Patients with malignant lymphoma, in a latent state of weakened immune function, are at risk of chemotherapy-induced immunosuppression and cytomegalovirus (CMV) infection. Concomitant therapy with bendamustine and rituximab or obinutuzumab intensifies immunosuppression, potentially affecting CMV onset. This study aimed to assess CMV onset differences between bendamustine monotherapy and combination therapy with rituximab or obinutuzumab using the Japanese Adverse Drug Event Report database (JADER). PATIENTS AND METHODS: A JADER analysis dataset (April 2004 to September 2022) defined CMV infection using 31 preferred term (PT) words from MedDRA 25.1J HLT "Cytomegalovirus infection (10011827)". Reporting odds ratios (ROR) calculated CMV infection signals for bendamustine monotherapy, rituximab, obinutuzumab, bendamustine+rituximab (BR), and bendamustine+obinutuzumab (GB). ROR confidence intervals exceeding 1 indicated a CMV signal. Days of CMV infection were calculated based on adverse event onset and administration start. RESULTS: CMV signals were confirmed for monotherapy and combination therapies. CMV infection durations (median, interquartile range) were 41.0 days (23.5-69.5) for bendamustine monotherapy, 63.5 days (35.2-95.0) for BR, and 61.0 days (33.0-102.5) for GB, with cases exceeding 200 days. CONCLUSION: JADER analysis detected significant CMV signals for rituximab, obinutuzumab, and bendamustine. Caution may be warranted 7-9 months post-bendamustine administration, necessitating further investigation, including cell-mediated immunity suppression assessment.

Efficacy and safety of rituximab in multiple sclerosis and neuromyelitis optica spectrum disorder.

In Thailand, resource limitations lead many multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) patients to use off-label immunosuppressants. This study assesses the efficacy and safety of rituximab (RTX) with a CD19-based reinfusion regimen among Thai MS and NMOSD patients. A retrospective review of patients at the Faculty of Medicine Siriraj Hospital from January 1994 to April 2023 was conducted. The primary outcome assessed was the change in annualized relapse rate (ARR) for patients using RTX for over a year. Secondary outcomes included changes in the Expanded Disability Status Scale (EDSS) scores, time to the first relapse after RTX initiation for patients using RTX for over a year, and an evaluation of the safety of RTX. The study encompassed 36 MS and 39 NMOSD patients. A majority of patients (91.7% of MS and 79.5% of NMOSD) experienced no relapses during a median follow-up of 30 months (Interquartile range [IQR] 20-46) and 31 months (IQR 23-41), respectively. The median ARR significantly decreased in both MS (from 0.77 [IQR 0.42-1.83] to 0 [IQR 0-0], p < 0.001) and NMOSD (from 0.92 [IQR 0.68-1.78] to 0 [IQR 0-0.17], p < 0.001) patients after switching to RTX, with no difference between those following a fixed 6-month time point regimen and a CD19-based reinfusion regimen. Median EDSS scores improved significantly at the last follow-up visit in both groups. The mean time to the first subsequent relapse was 8.3 ± 3.0 months in MS and 6.8 ± 1.7 months in NMOSD. Mild adverse drug reactions occurred in 44% of patients. RTX effectively prevents relapses in Thai MS and NMOSD patients, with no observed serious adverse drug reactions.

Rituximab treatment in pediatric-onset multiple sclerosis.

BACKGROUND AND PURPOSE: Rituximab (RTX) is frequently used off-label in multiple sclerosis. However, studies on the risk-benefit profile of RTX in pediatric-onset multiple sclerosis are scarce. METHODS: In this multicenter retrospective cohort study, patients with pediatric-onset multiple sclerosis from Sweden, Austria and Germany, who received RTX treatment were identified by chart review. Annualized relapse rates, Expanded Disability Status Scale scores and magnetic resonance imaging parameters (new T2 lesions and contrast-enhancing lesions) were assessed before and during RTX treatment. The proportion of patients who remained free from clinical and disease activity (NEDA-3) during RTX treatment was calculated. Side effects such as infusion-related reactions, infections and laboratory abnormalities were assessed. RESULTS: Sixty-one patients received RTX during a median (interquartile range) follow-up period of 20.9 (35.6) months. The annualized relapse rate decreased from 0.6 (95% confidence interval [CI] 0.38-0.92) to 0.03 (95% CI 0.02-0.14). The annual rate of new T2 lesions decreased from 1.25 (95% CI 0.70-2.48) to 0.08 (95% CI 0.03-0.25) and annual rates of new contrast-enhancing lesions decreased from 0.86 (95% CI 0.30-3.96) to 0. Overall, 70% of patients displayed no evidence of disease activity (NEDA-3). Adverse events were observed in 67% of patients. Six patients discontinued treatment due to ongoing disease activity or adverse events. CONCLUSION: Our study provides class IV evidence that RTX reduces clinical and radiological activity in pediatric-onset multiple sclerosis.

Long-term outcomes with HLX01 (HanliKang®), a rituximab biosimilar, in previously untreated patients with diffuse large B-cell lymphoma: 5-year follow-up results of the phase 3 HLX01-NHL03 study.

HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2-76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9-87.5%) and 75.4% (95% CI: 68.9-82.6%)( HR: 0.75, 95% CI 0.47-1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4-84.6%) and 73.0% (95% CI: 66.3-80.3%) (HR: 0.84, 95% CI 0.54-1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.

Maintenance therapy for chronic lymphocytic leukaemia.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the most common lymphoproliferative disease in adults and currently remains incurable. As the progression-free period shortens after each successive treatment, strategies such as maintenance therapy are needed to improve the degree and duration of response to previous therapies. Monoclonal antibodies, immunomodulatory agents, and targeted therapies are among the available options for maintenance therapy. People with CLL who achieve remission after previous therapy may choose to undergo medical observation or maintenance therapy to deepen the response. Even though there is widespread use of therapeutic maintenance agents, the benefits and harms of these treatments are still uncertain. OBJECTIVES: To assess the effects and safety of maintenance therapy, including anti-CD20 monoclonal antibody, immunomodulatory drug therapy, anti-CD52 monoclonal antibody, Bruton tyrosine kinase inhibitor, and B-cell lymphoma-2 tyrosine kinase inhibitor, for individuals with CLL. SEARCH METHODS: We conducted a comprehensive literature search for randomised controlled trials (RCTs) with no language or publication status restrictions. We searched CENTRAL, MEDLINE, Embase, and three trials registers in January 2022 together with reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA: We included RCTs with prospective identification of participants. We excluded cluster-randomised trials, cross-over trial designs, and non-randomised studies. We included studies comparing maintenance therapies with placebo/observation or head-to-head comparisons. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We assessed risk of bias in the included studies using Cochrane's RoB 1 tool for RCTs. We rated the certainty of evidence for the following outcomes using the GRADE approach: overall survival (OS), health-related quality of life (HRQoL), grade 3 and 4 adverse events (AEs), progression-free survival (PFS), treatment-related mortality (TRM), treatment discontinuation (TD), and all adverse events (AEs). MAIN RESULTS: We identified 11 RCTs (2393 participants) that met the inclusion criteria, including seven trials comparing anti-CD20 monoclonal antibodies (mAbs) (rituximab or ofatumumab) with observation in 1679 participants; three trials comparing immunomodulatory drug (lenalidomide) with placebo/observation in 693 participants; and one trial comparing anti-CD 52 mAbs (alemtuzumab) with observation in 21 participants. No comparisons of novel small molecular inhibitors were found. The median age of participants was 54.1 to 71.7 years; 59.5% were males. The type of previous induction treatment, severity of disease, and baseline stage varied among the studies. Five trials included early-stage symptomatic patients, and three trials included advanced-stage patients (Rai stage III/IV or Binet stage B/C). Six trials reported a frequent occurrence of cytogenic aberrations at baseline (69.7% to 80.1%). The median follow-up duration was 12.4 to 73 months. The risk of selection bias in the included studies was unclear. We assessed overall risk of performance bias and detection bias as low risk for objective outcomes and high risk for subjective outcomes. Overall risk of attrition bias, reporting bias, and other bias was low. Anti-CD20 monoclonal antibodies (mAbs): rituximab or ofatumumab maintenance versus observation Anti-CD20 mAbs maintenance likely results in little to no difference in OS (hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.73 to 1.20; 1152 participants; 3 studies; moderate-certainty evidence) and likely increases PFS significantly (HR 0.61, 95% CI 0.50 to 0.73; 1255 participants; 5 studies; moderate-certainty evidence) compared to observation alone. Anti-CD20 mAbs may result in: an increase in grade 3/4 AEs (rate ratio 1.34, 95% CI 1.06 to 1.71; 1284 participants; 5 studies; low-certainty evidence); little to no difference in TRM (risk ratio 0.82, 95% CI 0.39 to 1.71; 1189 participants; 4 studies; low-certainty evidence); a slight reduction to no difference in TD (risk ratio 0.93, 95% CI 0.72 to 1.20; 1321 participants; 6 studies; low-certainty evidence); and an increase in all AEs (rate ratio 1.23, 95% CI 1.03 to 1.47; 1321 participants; 6 studies; low-certainty evidence) compared to the observation group. One RCT reported that there may be no difference in HRQoL between the anti-CD20 mAbs (ofatumumab) maintenance and the observation group (mean difference -1.70, 95% CI -8.59 to 5.19; 480 participants; 1 study; low-certainty evidence). Immunomodulatory drug (IMiD): lenalidomide maintenance versus placebo/observation IMiD maintenance therapy likely results in little to no difference in OS (HR 0.91, 95% CI 0.61 to 1.35; 461 participants; 3 studies; moderate-certainty evidence) and likely results in a large increase in PFS (HR 0.37, 95% CI 0.19 to 0.73; 461 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. Regarding harms, IMiD maintenance therapy may result in an increase in grade 3/4 AEs (rate ratio 1.82, 95% CI 1.38 to 2.38; 400 participants; 2 studies; low-certainty evidence) and may result in a slight increase in TRM (risk ratio 1.22, 95% CI 0.35 to 4.29; 458 participants; 3 studies; low-certainty evidence) compared to placebo/observation. The evidence for the effect on TD compared to placebo is very uncertain (risk ratio 0.71, 95% CI 0.47 to 1.05; 400 participants; 2 studies; very low-certainty evidence). IMiD maintenance therapy probably increases all AEs slightly (rate ratio 1.41, 95% CI 1.28 to 1.54; 458 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. No studies assessed HRQoL. Anti-CD52 monoclonal antibodies (mAbs): alemtuzumab maintenance versus observation Maintenance with alemtuzumab may have little to no effect on PFS, but the evidence is very uncertain (HR 0.55, 95% CI 0.32 to 0.95; 21 participants; 1 study; very low-certainty evidence). We did not identify any study reporting the outcomes OS, HRQoL, grade 3/4 AEs, TRM, TD, or all AEs. AUTHORS' CONCLUSIONS: There is currently moderate- to very low-certainty evidence available regarding the benefits and harms of maintenance therapy in people with CLL. Anti-CD20 mAbs maintenance improved PFS, but also increased grade 3/4 AEs and all AEs. IMiD maintenance had a large effect on PFS, but also increased grade 3/4 AEs. However, none of the above-mentioned maintenance interventions show differences in OS between the maintenance and control groups. The effects of alemtuzumab maintenance are uncertain, coupled with a warning for drug-related infectious toxicity. We found no studies evaluating other novel maintenance interventions, such as B-cell receptor inhibitors, B-cell leukaemia-2/lymphoma-2 inhibitors, or obinutuzumab.