Browsing by Subject "Rituximab"
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Item Depletion of the Chimeric Drug Rituximab from Biological Samples(Elsevier, 2017) Book, Benita K.; Pescovitz, Mark D.; Guo, Lili; Wiebke, Eric A.; Department of Surgery, IU School of MedicineItem Diffuse Alveolar Hemorrhage(Springer Nature, 2019-07-24) Desai, Hem; Smith, Joshua; Williams, Mark Daren; Medicine, School of MedicineDiffuse alveolar hemorrhage[DAH] is a serious condition that can be life threatening. It can be caused by a constellation of disorders which presents with hemoptysis, anemia, and diffuse alveolar infiltrates. Respiratory failure from DAH can be so severe that it has been called an ARDS mimic/imitator. Early recognition is crucial because prompt diagnosis and treatment are required for survival. DAH should be distinguished from other causes of pulmonary hemorrhage caused by localized pulmonary abnormalities and the bronchial circulation. Early bronchoscopy with bronchoalveolar lavage (BAL) is generally required to confirm the diagnosis of DAH and rule out infection. Progressively bloody bronchoalveolar lavage samples can distinguish DAH. Systemic vasculitis is one of the most common causes of DAH and can be pathologically defined by the presence of cellular inflammation, vessel destruction, tissue necrosis, and eventually, organ dysfunction. Corticosteroids and immunosuppressive agents remain the gold standard for the treatment. The following case illustrates a patient who was dependent on dialysis, then presented with hemoptysis. Bronchoscopy demonstrated progressively bloody bronchoalveolar lavage samples consistent with diffuse alveolar hemorrhage. Serologic testing was consistent with microscopic polyangiitis. The patient experienced a clinical remission with cyclophosphamide and corticosteroids.Item Dysthyroid optic neuropathy: update on pathogenesis, diagnosis, and management(Taylor & Francis, 2017) Blandford, Alexander D.; Zhang, Dalia; Chundury, Rao V.; Perry, Julian D.; Ophthalmology, School of MedicineINTRODUCTION: Dysthyroid optic neuropathy (DON) is a severe manifestation of thyroid eye disease (TED) that can result in permanent vision loss. Management is complex, multidisciplinary, and involves medical and/or surgical therapies. This review describes current concepts in the epidemiology, pathophysiology, diagnosis, and treatment of DON. AREAS COVERED: An extensive review of the literature was performed to detail current concepts on the diagnosis and management of DON. This includes utilization of various medical and surgical modalities for disease management. EXPERT COMMENTARY: DON can result in permanent blindness and often requires the use of corticosteroids and surgical decompression. We favor the use of intravenous corticosteroids and a transcaruncular approach when surgical decompression is indicated. The use of orbital radiation for DON is often reserved for patients that are poor surgical candidates and/or patients with refractory disease.Item Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study(Wolters Kluwer, 2022-01-25) Nowak, Richard J.; Coffey, Christopher S.; Goldstein, Jonathan M.; Dimachkie, Mazen M.; Benatar, Michael; Kissel, John T.; Wolfe, Gil I.; Burns, Ted M.; Freimer, Miriam L.; Nations, Sharon; Granit, Volkan; Smith, A. Gordon; Richman, David P.; Ciafaloni, Emma; Al-Lozi, Muhammad T.; Sams, Laura Ann; Quan, Dianna; Ubogu, Eroboghene; Pearson, Brenda; Sharma, Aditi; Yankey, Jon W.; Uribe, Liz; Shy, Michael; Amato, Anthony A.; Conwit, Robin; O'Connor, Kevin C.; Hafler, David A.; Cudkowicz, Merit E.; Barohn, Richard J.; NeuroNEXT NN103 BeatMG Study Team; Neurology, School of MedicineObjective: To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG). Methods: The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks. Results: Of the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified. Conclusions: While rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG. Classification of evidence: This study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year.Item Physician decision making in selection of second-line treatments in immune thrombocytopenia in children.(Wiley, 2018-07) Grace, Rachael F.; Despotovic, Jenny M.; Bennett, Carolyn M.; Bussel, James B.; Neier, Michelle; Neunert, Cindy; Crary, Shelley E.; Pastore, Yves D.; Klaassen, Robert J.; Rothman, Jennifer A.; Hege, Kerry; Breakey, Vicky R.; Rose, Melissa J.; Shimano, Kristin A.; Buchanan, George R.; Geddis, Amy; Haley, Kristina M.; Lorenzana, Adonis; Thompson, Alexis; Jeng, Michael; Neufeld, Ellis J.; Brown, Travis; Forbes, Peter W.; Lambert, Michele P.; Pediatrics, School of MedicineImmune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second-line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second-line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment-related factors: side effect profile (58%), long-term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision-making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P = .003). Splenectomy and rituximab were chosen for the possibility of inducing long-term remission (P < .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P < .001). Physicians chose rituximab in patients with lower expected adherence (P = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision-making in selecting second-line ITP treatments, given the absence of comparative trials. It highlights shared decision-making and the need for well-conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians.Item Review of the Role of Rituximab in the Management of Adult Minimal Change Disease and Immune-Mediated Focal and Segmental Glomerulosclerosis(Karger, 2023-08-18) Aslam, Ahsan; Koirala, Abbal; Medicine, School of MedicineBackground: Minimal change disease and primary FSGS are podocytopathies but are also immune-mediated diseases. Rituximab acts via multiple mechanisms by tilting the balance between autoreactive B and T cells in favor of regulatory B and T cells. The consequences are decreased production of cytokines, chemokines, and permeability factors by these cells. In the past decade, we have seen the discovery of autoantibodies mediating nephrotic syndrome (anti-annexin A2 antibody, anti-UCHL1 antibody, and anti-nephrin antibody), and rituximab decreases their production. Rituximab also binds to podocyte SMPDL3b and has direct podocyte actions. Summary: Rituximab's role in managing these primary podocytopathies has been discussed in this brief review. Rituximab has been used extensively in children and adults with frequently relapsing and steroid-dependent nephrotic syndrome. However, rituximab is not very promising in adult steroid-resistant nephrotic syndrome. Although ofatumumab would cause prolonged B-cell depletion and is fully humanized, it is unclear if it is superior to rituximab in preventing relapse of nephrotic syndrome. Key messages: Rituximab therapy can induce prolonged remission in adults with frequently relapsing and steroid-dependent nephrotic syndrome. However, no good data exist on using rituximab in steroid-resistant nephrotic syndrome.Item Rituximab, B-lymphocyte depletion, and preservation of beta-cell function(Massachusetts Medical Society, 2009-11-26) Pescovitz, Mark D.; Greenbaum, Carla J.; Krause-Steinrauf, Heidi; Becker, Dorothy J.; Gitelman, Stephen E.; Goland, Robin; Gottlieb, Peter A.; Marks, Jennifer B.; McGee, Paula F.; Moran, Antoinette M.; Raskin, Philip; Rodriguez, Henry; Schatz, Desmond A.; Wherrett, Diane; Wilson, Darrell M.; Lachin, John M.; Skyler, Jay S.; Type 1 Diabetes TrialNet Anti-CD20 Study Group; Medicine, School of MedicineBACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. METHODS: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. RESULTS: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. CONCLUSIONS: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition.Item Second-line treatments in children with immune thrombocytopenia: Effect on platelet count and patient-centered outcomes(Wiley, 2019-04-03) Grace, Rachael F.; Shimano, Kristin A.; Bhat, Rukhmi; Neunert, Cindy; Bussel, James B.; Klaassen, Robert J.; Lambert, Michele P.; Rothman, Jennifer A.; Breakey, Vicky R.; Hege, Kerry; Bennett, Carolyn M.; Rose, Melissa J.; Haley, Kristina M.; Buchanan, George R.; Geddis, Amy; Lorenzana, Adonis; Jeng, Michael; Pastore, Yves D.; Crary, Shelley E.; Neier, Michelle; Neufeld, Ellis J.; Neu, Nolan; Forbes, Peter W.; Despotovic, Jenny M.; Pediatrics, School of MedicineImmune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and hemorrhagic risk. While many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding or improve health related quality of life (HRQoL). There are a number of available second-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. ICON1 is a prospective, multi-center, observational study of 120 children starting second-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (p=0.04). Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84% to 48%, p=0.01 and 81% to 43%, p=0.004) and non-skin-related bleeding symptoms (58% to 14%, p=0.0001 and 54% to 17%, p=0.0006) after 1 month of treatment. HRQoL significantly improved on all treatments. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments. These results are hypothesis generating and help to improve our understanding of the effect of each treatment on specific patient outcomes. Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP.Item Zandelisib with continuous or intermittent dosing as monotherapy or in combination with rituximab in patients with relapsed or refractory B-cell malignancy: a multicentre, first-in-patient, dose-escalation and dose-expansion, phase 1b trial(Elsevier, 2022) Pagel, John M.; Soumerai, Jacob D.; Reddy, Nishitha; Jagadeesh, Deepa; Stathis, Anastasios; Asch, Adam; Salman, Huda; Kenkre, Vaishalee P.; Iasonos, Alexia; Llorin-Sangalang, Judith; Li, Joanne; Zelenetz, Andrew D.; Medicine, School of MedicineBackground: Phosphatidylinositol 3-kinase p110δ (PI3Kδ) inhibitors are efficacious in B-cell malignancies. Immune-related adverse events might be mitigated with intermittent dosing. We aimed to evaluate the safety and antitumour activity of zandelisib, a potent novel PI3Kδ inhibitor, with continuous or intermittent dosing as monotherapy or in combination with rituximab, in patients with relapsed or refractory B-cell malignancy. Methods: We conducted a first-in-patient, dose-escalation and dose-expansion, phase 1b trial at ten treatment centres across Switzerland and the USA. Eligible patients were aged 18 years or older with relapsed or refractory B-cell malignancy (limited to follicular lymphoma or chronic lymphocytic leukaemia during dose escalation) and an Eastern Cooperative Oncology Group performance status of 0-2, and had received at least one previous line of therapy and no previous PI3Kδ inhibitor treatment. In the dose-escalation study, participants received oral zandelisib once daily (60 mg, 120 mg, or 180 mg; we did not evaluate four additional planned dose levels). The 60 mg dose was further evaluated as monotherapy or with intravenous rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3-6, using a continuous daily schedule or intermittent dosing therapy (days 1-28 of cycles 1-2 and days 1-7 of subsequent cycles) in 28-day cycles. Treatment was continued until evidence of disease progression, intolerance, or withdrawal of consent by the patient. Primary endpoints were safety (dose-limiting toxicities and maximum tolerated dose), minimum biologically effective dose, and a composite endpoint to assess the activity of each dose level, and were analysed by intention to treat. The zandelisib monotherapy and zandelisib-rituximab combination cohorts have completed accrual, but accrual to a cohort evaluating zandelisib with zanubrutinib is ongoing. This study is registered with ClinicalTrials.gov, NCT02914938. Findings: Between Nov 17, 2016, and June 2, 2020, 100 patients were assessed for eligibility and 97 were enrolled and received zandelisib monotherapy (n=56) or zandelisib plus rituximab (n=41), with zandelisib administered on either a continuous schedule (n=38) or with intermittent dosing (n=59). No dose-limiting toxicities were observed, the objective of determining the maximum tolerated dose was abandoned, and antitumour activity was similar across the evaluated doses activity (objective responses in 11 [92%; 95% CI 61·5-99·8] of 12 patients at both 60 mg and 120 mg doses, and in five [83%; 95% CI 35·9-99·6] of six patients at 180 mg). With a median duration of exposure of 15·2 months (IQR 3·7-21·7), the most common grade 3-4 adverse events were neutrophil count decrease (ten [17%] of 59 patients in the intermittent dosing group and four [11%] of 38 in the continuous dosing group), diarrhoea (three [5%] and eight [21%]), pneumonia (one [2%] and six [16%]), alanine aminotransferase increase (three [5%] and two [5%]), and colitis (two [3%] and one [3%]). 26 (44%) of 59 patients in the intermittent dosing group and 29 (76%) of 38 patients in the continuous dosing group had grade 3-4 adverse events. Treatment-related serious adverse events occurred in eight (21%) patients in the continuous dosing group and five (8%) patients in the intermittent dosing group. There were no treatment-related deaths. Interpretation: Zandelisib 60 mg once daily on an intermittent dosing schedule was safe, with low frequency of grade 3 or worse adverse events, warranting the ongoing global phase 2 and phase 3 trials.