Over-expression of BCL-2 defines follicular lymphoma (FL). Venetoclax (VEN), a selective BCL-2 inhibitor, has previously been evaluated with bendamustine-based chemoimmunotherapy. VEN was given continuously, resulting in promising efficacy but unacceptable toxicity. The Phase II PrE0403 study was designed to evaluate intermittent dosing of VEN (10 days per cycle) combined with obinutuzumab and bendamustine (VEN-OB) in untreated FL subjects with high-risk features defined as a FLIPI-1 score of ≥3 and/or high tumor burden by GELF criteria. A total of 56 subjects were planned to be accrued with a goal of having 51 subjects eligible to improve the historical 50% CR rate to 65% with an 85% power and 15% type I error rate. Immunohistochemistry (IHC) expression of 3 antiapoptotic proteins (BCL-xL, MCL-1, and BCL-2) was performed and correlated with clinical outcomes. All 56 subjects were eligible and treated. CR rate was 41/56 (73.2%) and ORR was 52/56 (92.5%) meeting the primary endpoint. 2-year estimated PFS was 87.5% (90% CI: 75.3,93.9%) and 2-year estimated OS was 94.6% (90% CI: 86.7, 97.9%). However, the incidence of treatment-related adverse events ≥ grade 3 was 83.9% and serious adverse events were seen in 57.1%. After induction, atypical infections, including Grade 5 events, occurred. Anti-apoptotic protein expression by IHC was not correlated with clinical outcomes. Thus, while meeting the primary efficacy end point, VEN-OB is considered overly toxic in high-risk FL.

Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, provided significantly better renal responses than placebo in a phase 2 trial involving patients with lupus nephritis receiving standard therapy.

In a phase 3, randomized, controlled trial, we assigned adults with biopsy-proven active lupus nephritis in a 1:1 ratio to receive obinutuzumab in one of two dose schedules (1000 mg on day 1 and at weeks 2, 24, 26, and 52, with or without a dose at week 50) or placebo. All patients received standard therapy with mycophenolate mofetil, along with oral prednisone at a target dose of 7.5 mg per day by week 12 and 5 mg per day by week 24. The primary end point was a complete renal response at week 76, defined by a urinary protein-to-creatinine ratio of less than 0.5 (with protein and creatinine both measured in milligrams), an estimated glomerular filtration rate of at least 85% of the baseline value, and no intercurrent event (i.e., rescue therapy, treatment failure, death, or early trial withdrawal). Key secondary end points at week 76 included a complete renal response with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 and a urinary protein-to-creatinine ratio lower than 0.8 without an intercurrent event.

A total of 271 patients underwent randomization; 135 were assigned to the obinutuzumab group (combined dose schedules) and 136 to the placebo group. A complete renal response at week 76 was observed in 46.4% of the patients in the obinutuzumab group and 33.1% of those in the placebo group (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 2.0 to 24.8; P = 0.02). A complete renal response at week 76 with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 was observed in more patients in the obinutuzumab group than in the placebo group (42.7% vs. 30.9%; adjusted difference, 11.9 percentage points; 95% CI, 0.6 to 23.2; P = 0.04), and a urinary protein-to-creatinine ratio lower than 0.8 without an intercurrent event was more common with obinutuzumab than with placebo (55.5% vs. 41.9%; adjusted difference, 13.7 percentage points; 95% CI, 2.0 to 25.4; P = 0.02). No unexpected safety signals were identified. More serious adverse events, mainly infections and events related to coronavirus disease 2019, occurred with obinutuzumab than with placebo.

Among adults with active lupus nephritis, obinutuzumab plus standard therapy was more efficacious than standard therapy alone in providing a complete renal response. (Funded by F. Hoffmann-La Roche; REGENCY ClinicalTrials.gov number, NCT04221477.).

The blood-brain barrier (BBB) presents a major challenge for the development of monoclonal antibody (mAb)-based therapies for brain disorders. To improve the likelihood of success of such therapies, Roche Brainshuttle technology utilizes a single anti-transferrin receptor 1 (TfR1)-antigen-binding antibody fragment linked to a therapeutic antibody, allowing engagement with TfR1 to transport the therapeutic antibody into the brain via receptor-mediated transcytosis.

We compared Fc-silenced and Fc-competent variants of the Brainshuttle and the parental (non-shuttled) type II CD20 mAb, obinutuzumab in in vitro and in vivo (mouse and cynomolgus macaque) models. Endpoints assessed included B cell binding, B cell killing, tolerability, and ability to cross the BBB.

The Fc-silenced Brainshuttle construct showed a superior safety profile compared with the Fc-competent construct while maintaining the ability to cross the BBB and to deplete B cells in head-to-head comparisons in human and mouse in vitro and in mouse and cynomolgus macaque in vivo models.

Together, our data provide a path forward for the future development of safe and efficacious brain-targeted B-cell-depleting therapies.

The BBB hinders mAb-based brain disorder therapies A brain-targeted B-cell-depleting mAb for MS that efficiently crosses the BBB via hTfR1 was developed using Brainshuttle™ technology (1a and 1b) The Brainshuttle™-CD20 mAb was well tolerated (2a and 2b) and displayed B-cell-killing properties (1c), paving the way for future development and clinical translation of TfR1-targetingtherapies for increased brain penetration.

Membranous nephropathy (MN) is a kidney disease characterized by thickening of the glomerular basement membrane due to immune complex deposition, often leading to nephrotic syndrome and potentially progressing to end-stage renal disease. Traditional treatments, including corticosteroids and immunosuppressive agents, have significant side-effects and variable efficacy. Recently, obinutuzumab, a fully humanized monoclonal antibody targeting CD20, has emerged as a promising therapeutic option for MN. Herein, we review the pathophysiology of MN, the mechanism of action of obinutuzumab, clinical data supporting its use and highlight its potential as a game changer in MN treatment.

Obinutuzumab was approved in China in June 2021 used in combination with chemotherapy (followed by obinutuzumab maintenance) for the treatment of adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma (FL). The clinical application of obinutuzumab has recently begun in China, but there is a lack of evidence to determine under which circumstances it should be considered the treatment of choice. A comprehensive assessment is necessary to evaluate the efficacy, safety, and cost-effectiveness of obinutuzumab in adult patients with FL.

To summarize the evidence on the efficacy, safety, and cost-effectiveness of obinutuzumab in adult patients with FL, aiming to provide medical professionals with evidence for informed choices in clinical practice.

The approach to this evidence synthesis was a rapid review of systematic reviews/meta-analyses (SR/meta-analyses), health technology assessment (HTA) reports, and pharmacoeconomic studies that brings together and summarizes the efficacy, safety, and cost-effectiveness of obinutuzumab in adult patients with FL. A literature search was conducted across multiple databases, including PubMed, Embase, Wanfang, CNKI, Weipu database, the Cochrane Library, the Centre for Reviews and Dissemination (CRD) database, International Network of Agencies for Health Technology Assessment (INAHTA) and Canada's Drug Agency (CDA-AMC), International Society for Pharmacoeconomics and Outcomes Research (ISPOR), National Institute For Health and Care Excellence (NICE), Institute For Clinical And Economic Review (ICER), Grey Literature Database and Grey Net International. The studies on obinutuzumab for FL were searched in full text with obinutuzumab, systematic review, meta-analysis, economics, cost, and health technology assessment as keywords, with a search time frame from the date of database creation to 29 November 2024. The literature was screened based on predefined inclusion and exclusion criteria, and data were meticulously extracted and synthesized by two authors. Simultaneously, the quality of the literature was thoroughly assessed.

Obinutuzumab based chemotherapy (the chemotherapy regimen-cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); cyclophosphamide, vincristine, and prednisone (CVP); or bendamustine) significantly prolonged progression free survival (PFS) compared to other chemotherapy regimen at primary and updated analyses. The incidence of grade 3-5 AEs, infusion-related reactions (IRRs), and infection were higher in the obinutuzumab based chemotherapy group compared to other chemotherapies. The economic researches conducted in China, United States, Japan, Italy and Norway had demonstrated that obinutuzumab-based chemothrepy was cost-effective compared to other chemothrepies. Although obinutuzumab significantly prolonged PFS and was cost-effective, its safety profile was considered lower.

Compared with other chemothrapy regimen, obinutuzumab based chemotherapy significantly prolonged PFS and was cost-effective, while its safety profile was considered lower. Therefore, medical professionals should be caution when using or introducing obinutuzumab treatment for FL patients.

Despite the great advancements in treatment strategies for hematological malignancies (HMs) over the years, their effective treatment remains challenging. Conventional treatment strategies are burdened with several serious drawbacks limiting their effectiveness and safety. Improved understanding of tumor immunobiology has provided novel anti-cancer strategies targeting selected immune response components. Currently, immunotherapy is counted as the fourth pillar of oncological treatment (together with surgery, chemo- and radiotherapy) and is becoming standard in the treatment regimen, alone or in combination therapy. Several categories of immunotherapies have been developed and are currently being assessed in clinical trials for the treatment of blood cancers, including immune checkpoint inhibitors, antigen-targeted antibodies, antibody-drug conjugates, tumor vaccines, and adoptive cell therapies. However, monoclonal antibodies (mAbs) and their derivatives have achieved the most notable clinical outcome so far. Since the approval of rituximab for treating B-cell malignancies, the availability of mAbs against tumor-specific surface molecules for clinical use has flourished. Antibody-based therapy has become one of the most successful strategies for immunotherapeutic cancer treatment in the last few decades, and many mAbs have already been introduced into standard treatment protocols for some hematologic malignancies. To further increase the efficacy of mAbs, they can be conjugated to radioisotopes or cytostatic drugs, so-called antibody-drug conjugates. Moreover, with the growing recognition of T-cell immunity's role in cancer development, strategies aimed at enhancing T cell activation and inhibiting mechanisms that suppress T cell function are actively being developed. This review provides a comprehensive overview of the current status of immunotherapeutic strategies based on monoclonal antibodies and their derivatives, including antibody-drug conjugates, bispecific T-cell engagers, and checkpoint inhibitors, approved for the treatment of various HMs.

Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against factor VIII, with a high mortality risk. It should be suspected in subjects with abnormal bleedings, especially subcutaneous bleed associated with prolonged activated partial thromboplastin time (aPTT). AHA is often idiopathic but is associated with autoimmune diseases, malignancies, pregnancy and postpartum period or drugs. Treatment is based on haemostatic agents as by-passants agents such as factor VIIa and activated prothrombine concentrate complex or recombinant porcine factor VIII for severe bleeding. Eradication of inhibitor should be established as soon as the diagnosis is confirmed with steroid alone often associated with cytotoxic agents or rituximab, depending on FVIII activity and inhibitor titer. The purpose of this review is to summarize the epidemiology, etiopathogenesis, diagnosis, treatment of AHA and discuss current recommendations.

A 68-year-old woman with follicular lymphoma was treated with chemotherapy, including the anti-CD20 monoclonal antibody obinutuzumab, and achieved remission. A month after the administration of obinutuzumab, the patient contracted coronavirus disease 2019 (COVID-19), and various antiviral drugs were administered. However, the infection had not been eliminated. One year and three months after chemotherapy, peripheral B cell recovery was achieved, and the infection had resolved. This report provides insight into the course of COVID-19 in patients with impaired humoral immunity.

Obinutuzumab is a type II anti-CD20 monoclonal antibody associated with a higher rate of toxicity when compared to rituximab. Gastrointestinal side-effects have been reported but data is still sparse.

A 47-year-old female with medical history of stage IV follicular non-Hodgkin lymphoma under chemotherapy presented with chronic bloody diarrhea and iron deficiency anemia. Endoscopic and histologic features resembled inflammatory bowel disease (IBD), imposing a thorough differential diagnosis. The diagnosis of obinutuzumab-induced pancolitis was made and the drug was suspended with subsequent clinical improvement.

This is the first case report of obinutuzumab-induced pancolitis. The challenging differential diagnosis of IBD required a multidisciplinary approach with subsequent outcome and management implications.

Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody approved in Europe and the United States for relapsed/refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior therapies.

We present interim safety data from the mosunetuzumab GO29781 (NCT02500407) phase I/II dose-escalation study in R/R non-Hodgkin lymphoma (NHL), focusing on FL.

Overall, 218 patients with R/R NHL, including 90 with R/R FL, received a median of eight 21-day cycles of intravenous mosunetuzumab with step-up dosing in Cycle (C) 1 (C1 Day [D] 1, 1 mg; C1D8, 2 mg; C1D15/C2D1, 60 mg; C3D1 and onwards, 30 mg). Cytokine release syndrome (CRS) was the most common adverse event (AE), occurring in 39.4% (NHL) and 44.4% (FL) of patients. Events occurred predominantly during C1 at the first loading dose; the majority were grade 1/2. CRS events were managed at the investigator's discretion with supportive care, steroids, and tocilizumab, based on protocol management guidelines. Immune effector cell-associated neurotoxicity syndrome was uncommon, reported in 0.9% (NHL) and 1.1% (FL) of patients. Neutropenia occurred in 27.5% (NHL) and 28.9% (FL) of patients (mostly grade 3/4) and could be effectively managed using granulocyte colony-stimulating factor. Tumor lysis syndrome occurred in 0.9% (NHL) and 1.1% (FL) of patients (all grade 3/4 with CRS; all resolved).

Mosunetuzumab monotherapy as treatment for R/R B-cell NHL, including FL, was associated with low rates of severe AEs (including CRS) and is suitable for outpatient administration in the community setting. Adapted protocol guidance for the management of select AEs during mosunetuzumab treatment is included.

To determine whether adding obinutuzumab to standard-of-care lupus nephritis (LN) therapy could improve the likelihood of long-term preservation of kidney function and do so with less glucocorticoids.

Post hoc analyses of the phase II NOBILITY trial were performed. Time to unfavorable kidney outcome (a composite of treatment failure, doubling of serum creatinine, or death), LN flare, first 30% and 40% declines in estimated glomerular filtration rate (eGFR) from baseline, and chronic eGFR slope during the trial were compared between patients with active LN who were randomized to take obinutuzumab (n = 63) or placebo (n = 62) in combination with mycophenolate mofetil and glucocorticoids. The number of patients who achieved complete renal response (CRR) on 7.5 mg or less per day of prednisone was also determined.

Obinutuzumab reduced the risk of developing the composite kidney outcome by 60%, LN flare by 57%, and first eGFR decline of 30% or 40% by 80% and 91%, respectively. Patients receiving obinutuzumab had a significantly slower decline in eGFR than patients receiving placebo, with an annualized eGFR slope advantage of 4.1 ml/min/1.73 m2 /year (95% confidence interval 0.14-8.08). Overall, 38% of patients receiving obinutuzumab compared with 16% of patients receiving placebo achieved CRR at week 76 while receiving 7.5 mg or less per day of prednisone (P < 0.01); at week 104, the difference did not achieve significance (38% vs 22%; P = 0.06).

Post hoc analyses of NOBILITY demonstrated that compared with standard-of-care therapy, obinutuzumab treatment resulted in superior preservation of kidney function and prevention of LN flares. More patients achieved CRR at week 76 with less glucocorticoid use in the obinutuzumab group.

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma (BCL) globally. Recently, its incidence has increased in Europe, the United States, and Asia, with the number of gastrointestinal FL cases expected to increase. Genetic abnormalities related to t(14;18) translocation, BCL2 overexpression, NF-κB pathway-related factors, histone acetylases, and histone methyltransferases cause FL and enhance its proliferation. Meanwhile, microRNAs are commonly used in diagnosing FL and predicting patient prognosis. Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted, resulting in a marked improvement in therapeutic outcomes for FL. Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options, FL treatment has become more complex, requiring combinatorial therapeutic regimens. However, optimal treatment combinations have not yet been achieved, highlighting the importance of a complete under-standing regarding the pathogenesis of gastrointestinal FL. Accordingly, this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations. Moreover, the results of clinical trials are summarized, with a particular focus on treating nodal and gastrointestinal FLs.

A decision analytic model was constructed to assess the cost-effectiveness of obinutuzumab plus bendamustine followed by obinutuzumab maintenance therapy (O-B-O) in Chinese patients with relapsed and refractory follicular lymphoma (rrFL). O-B-O was associated with a dominant or more favorable cost-effectiveness than the conventional therapies. Survival outcomes, quality of life of progression-free survival, and subsequent treatment costs for progressive disease were the main drivers of the cost-effectiveness of O-B-O. The cost-effectiveness proportions of O-B-O relative to conventional therapies under the recommended cost-effectiveness threshold ranged from 61.0% to 99.9%. Thus, O-B-O was highly cost-effective for treating patients with rrFL in China compared with conventional therapies.

People with hematologic malignancies have a significantly higher risk of developing severe and protracted forms of SARS-CoV-2 infection compared to immunocompetent patients, regardless of vaccination status.

We describe two cases of prolonged SARS-CoV-2 infection with multiple relapses of COVID-19 pneumonia in patients with follicular lymphoma treated with bendamustine and obinutuzumab or rituximab. The aim is to highlight the complexity of SARS-CoV-2 infection in this fragile group of patients and the necessity of evidence-based strategies to treat them properly.

Patients with hematological malignancies treated with bendamustine and anti-CD20 antibodies had a significant risk of prolonged and relapsing course of COVID-19. Specific preventive and therapeutic strategies should be developed for this group of patients.

SARS-CoV-2 infection has been associated with a prolonged course and a poor prognosis in patients who receive anti-CD20 antibodies. However, there are no established treatments for such patients. Serial changes in the SARS-CoV-2 antigen titer during the clinical course and treatment strategies for immunosuppressed patients are discussed.

We report a case of prolonged SARS-CoV-2 infection during obinutuzumab and bendamustine treatment for follicular lymphoma. Four years previously, the patient had been diagnosed with follicular lymphoma (Stage IIIA, Grade 2). She received several chemotherapy regimens, including rituximab and radiation therapy. Although these therapies achieved complete response temporally, they did not continue and recurred at 8 months before. Obinutuzumab and bendamustine therapy was selected, and she received five courses of obinutuzumab and bendamustine. She also received a SARS-CoV-2 mRNA vaccine two times. Although she did not have any symptoms, a routine check-up just before the 6th course of obinutuzumab and bendamustine revealed SARS-CoV-2 infection. Because she was immunosuppressed and was considered to be at high risk for the exacerbation of her disease, molnupiravir was immediately administered, and her SARS-CoV-2 antigen decreased. However, it was not completely cleared and flared-up at 6 weeks, with symptoms of COVID-19 appearing. Despite intensive treatment for SARS-CoV-2 infection, including remdesivir, baricitinib, tocilizumab and intravenous immunoglobulin, her SARS-CoV-2 antigen titer never became negative, and she finally died of respiratory failure caused by prolonged SARS-CoV-2 infection. Serial changes in the SARS-CoV-2 antigen titer during the clinical course and treatment strategies for immunosuppressed patients are discussed.

Among all glomerular diseases, membranous nephropathy (MN) is perhaps the one in which major progress has been made in recent decades, in both the understanding of the pathogenesis and treatment. Despite the overall significant response rates to these therapies-particularly rituximab and cyclical regimen based on corticosteroids and cyclophosphamide-cumulative experience over the years has shown, however, that 20%-30% of cases may confront resistant disease. Thus, these unmet challenges in the treatment of resistant forms of MN require newer approaches. Several emerging new agents-developed primarily for the treatment of hematological malignancies or rheumatoid diseases-are currently being evaluated in MN. Herein we conducted a narrative review on future therapeutic strategies in the disease. Among the different novel therapies, newer anti-CD20 agents (e.g. obinutuzumab), anti-CD38 (e.g. daratumumab, felzartamab), immunoadsorption or anti-complement therapies (e.g. iptacopan) have gained special attention. In addition, several technologies and innovations developed primarily for cancer (e.g. chimeric antigen receptor T-cell therapy, sweeping antibodies) seem particularly promising. In summary, the future therapeutic landscape in MN seems encouraging and will definitely move the management of this disease towards a more precision-based approach.

Follicular lymphoma (FL) is the most common low-grade lymphoma, and although nodal FL is highly responsive to treatment, the majority of patients relapse repeatedly, and the disease has been incurable with a poor prognosis. However, primary FL of the gastrointestinal tract has been increasingly detected in Japan, especially due to recent advances in small bowel endoscopy and increased opportunities for endoscopic examinations and endoscopic diagnosis. However, many cases are detected at an early stage, and the prognosis is good in many cases. In contrast, in Europe and the United States, gastrointestinal FL has long been considered to be present in 12%-24% of Stage-IV patients, and the number of advanced gastrointestinal cases is expected to increase. This editorial provides an overview of the recent therapeutic advances in nodal FL, including antibody-targeted therapy, bispecific antibody therapy, epigenetic modulation, and chimeric antigen receptor T-cell therapy, and reviews the latest therapeutic manuscripts published in the past year. Based on an understanding of the therapeutic advances in nodal FL, we also discuss future possibilities for gastroenterologists to treat gastrointestinal FL, especially in advanced cases.