Tolerability and Safety of Switching from Rituximab to Ocrelizumab: Evaluating Factors Associated with Infusion Related Reactions.
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ABSTRACT: Background
Ocrelizumab and rituximab are frequently used treatments for multiple sclerosis (MS). Data on switching from rituximab to ocrelizumab is limited.Objectives
To assess the frequency, severity, and factors of infusion related reactions (IRRs) in patients with MS who switch from rituximab to ocrelizumab, compared to those who stay on rituximab.Methods
Prospective study on MS patients aged 18-65, on rituximab for at least 2 cycles, who either switched to ocrelizumab (switch group) or stayed on rituximab (comparator group) (n = 100 each). Participants were followed for IRRs, safety, and tolerability over 12 months.Results
The proportion of IRRs in patients who continue on rituximab (14%) were similar to those who switched to ocrelizumab on Day 1 (14%; p = 1.000) and Week 24 (12%; p = 0.647) but higher than at Day 15 (4%; 0.005). The risk of IRRs for the switch group was associated with the presence of B cells (CD19 and/or CD20 counts ≥1%) increasing by 5.01 (1.49, 16.82) times on Day 1 (p = 0.007). Antidrug antibodies to ocrelizumab were not associated with IRRs. No other safety concerns were identified in switching to ocrelizumab.Conclusion
IRRs are similar between both groups, which suggests that it is safe to switch from rituximab to ocrelizumab.
SUBMITTER: Alvarez E
PROVIDER: S-EPMC8743958 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundInfusion-related reactions (IRRs) are the most common adverse event (AE) associated with infusion of rituximab, an anti-CD20 monoclonal antibody.ObjectiveOur objective was to evaluate the impact of dosing/infusion patterns and certain baseline characteristics on IRR occurrence during the first rituximab infusion administered as the biosimilar PF-05280586 (RTX-PF) or reference rituximab sourced from the EU (RTX-EU, MabThera®) in patients with CD20+ low-tumor-burden follicular lymphoma.Patients and methodsRituximab (RTX-PF, n=196; RTX-EU, n=198) was administered (375 mg/m2) on days 1, 8, 15, and 22 (one cycle), with a follow-up period through 52 weeks. The relationships between infusion rate, drug exposure, and IRR incidence were assessed by logistic regression analysis and pharmacokinetic modeling and simulation. Baseline CD20 level, antidrug antibody (ADA) status, and tumor burden according to IRR occurrence (yes/no) were compared descriptively.ResultsMedian rituximab infusion duration on day 1 was 3.50 h for each of the two groups. There was a positive correlation between infusion rate and all-grade IRRs occurring within 24 h after infusion (p < 0.0001). Patients who developed IRRs had a higher median baseline CD20+ level. IRR incidence was unaffected by baseline ADA status. Drug exposure did not predict IRR incidence. Baseline tumor burden was similar between patients with and without IRRs.ConclusionsResults of this analysis provide a better understanding of IRRs after the first rituximab (RTX-PF or RTX-EU) infusion and demonstrate a potential correlation of infusion rate and other factors with IRR at the individual and population levels. Infusion-rate escalation steps continue to be needed to manage IRRs.Trial registration (date of registration)ClinicalTrials.gov Identifier: NCT02213263 (11 August 2014); and EudraCT: 2014-000132-41 (10 October 2014).
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Project description:Added to standard chemotherapy, rituximab improved survival in patients with non-Hodgkin's lymphoma; added to fludarabine-based regimens, it improved response and survival in patients with chronic B-cell lymphocytic leukemia.
| S-EPMC2835489 | biostudies-other
Project description:OBJECTIVE:The objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA). METHODS:This was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented. RESULTS:Overall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups. Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions. Serious infusion-related reactions were rare (0.1%). Serious infections occurred more frequently with OCR500+MTX. In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3-4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, -1.3 to 2.4). Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03-3.06). The incidence of human anti-human antibodies was <5%. Long-term follow-up indicated no differences in malignancy rates between the treatment groups. There was no apparent difference in time to B-cell repletion between the OCR dose groups. CONCLUSIONS:In placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX. TRIAL REGISTRATION:STAGE ClinicalTrials.gov NCT00406419 SCRIPT ClinicalTrials.gov NCT00476996 FILM ClinicalTrials.gov NCT00485589 FEATURE ClinicalTrials.gov NCT00673920.
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Project description:The standard dose of ceftaroline fosamil for patients with normal renal function is 600?mg diluted in 250?ml by 60?min intravenous infusion every 12?h. This two part phase I trial (NCT01577589) assessed safety and local tolerability of multiple ceftaroline fosamil 50?ml and 250?ml infusions, and pharmacokinetics following single administrations of each infusion volume.Part A was a placebo-controlled, double-blind, multiple dose crossover study. Twenty-four healthy subjects were randomized to simultaneous, bilateral ceftaroline fosamil 600?mg and placebo infusions in each arm (50?ml then 250?ml or vice versa) every 12?h for 72?h, with a ? 4.5 day washout. Local tolerability was evaluated by the Visual Infusion Phlebitis scale, with scores ?2 considered infusion site reactions (ISRs). Part B was an open label crossover study. Ten subjects were randomized to single 50?ml and 250?ml ceftaroline fosamil 600?mg infusions on days 1 and 3 (washout on day 2). Blood samples for pharmacokinetic analysis were taken over 24?h.In part A, four subjects (16.7%) experienced ISRs, all of which were associated with placebo infusions. No ISRs were reported for either ceftaroline fosamil 50?ml or 250?ml. Plasma pharmacokinetics (ceftaroline fosamil, active ceftaroline and an inactive metabolite) were similar following single 50?ml and 250?ml infusions in part B.No new safety concerns were identified for ceftaroline fosamil 600?mg 50?ml compared with 250?ml. These findings suggest infusion volumes down to 50?ml may be used in patients with fluid intake restrictions.
| S-EPMC4256619 | biostudies-literature
Project description:Infusion-related reactions (IRRs) are common with monoclonal antibodies (mAbs) and timely related to drug administration and have been reported as anaphylaxis, anaphylactoid reactions and cytokine release syndrome, among other terms used. We address risk management measures for individual patients and for the study and propose a consistent reporting approach in an attempt to allow cross-molecule comparisons. Once the symptoms of IRR have resolved, the mAb may be restarted. Rechallenge should not be done for suspected IgE-mediated anaphylaxis and Grade 4 IRRs. Management of IRRs for subsequent patients includes administration of premedication, which, however, does not prevent IgE-mediated anaphylaxis. Reporting approach: (1) Report as IRRs, reactions occurring during or within 24 h after an infusion. Negative skin Prick test and absent or undetectable allergen-specific IgE levels have high negative predictive value for an IgE-mediated allergic reaction. If IgE-mediated anaphylaxis is suspected based on medical history and/or laboratory test results, the reaction should be reported as suspected (IgE mediated) anaphylaxis. (2) Collect signs and symptoms with grades to allow characterization of IRRs. IRRs pathogenesis is of scientific interest and has impact on drug development. Animal toxicology studies are neither predictive of severe IRRs nor of anaphylaxis in human. Preclinical tests should be further developed to identify patients at risk for severe IRRs, for complement activation-related pseudoallergy and for IgE-mediated anaphylaxis. The proposed approach should help standardizing data collection and analysis of IRRs in an attempt to enable comparisons across molecules.
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Project description:IntroductionOcrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study.MethodsENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing-remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs.ResultsAt first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [- 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion.ConclusionENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions.Clinical trials registrationSubstudy of ENSEMBLE (NCT03085810).RegistrationMarch 21, 2017.
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Project description:IntroductionStudies investigating rates and risk factors for serious safety events (SSEs) during rituximab treatment of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and related disorders are limited.MethodsRituximab-treated patients with MS, NMOSD, or related disorders at the Rocky Mountain and New York University MS Care Centers were included. The follow-up period was defined as the time from the initial dose of rituximab up to 12 months of last dose of rituximab or ocrelizumab (in patients who switched). Clinician-reported and laboratory data were retrospectively collected from electronic medical records.ResultsOne-thousand patients were included comprising 907 MS, 77 NMOSD, and 16 related disorders. Patients had a mean follow-up of 31.1 months and a mean cumulative rituximab dose of 4012 mg. Of the 169 patients who switched to ocrelizumab, the mean ocrelizumab dose was 1141 mg. Crude incidence rate per 1000 person-years (PY) for lymphopenia was 19.2, neutropenia 5.6, and hypogammaglobulinemia 17.8. Infections resulting in either hospitalization, IV antibiotics, or using antibiotics ≥14 days occurred at a rate of 38.6/1000 PY. Risk factors for infection were duration of therapy, male gender, increased disability, prior exposure to immunosuppression/chemotherapy, lymphopenia, and hypogammaglobulinemia. Particularly, wheelchair-bound patients had 8.56-fold increased odds of infections. Crude incidence rates of malignant cancer were 3.5, new autoimmune disease 2.3, thromboembolic event 3.1, and mortality of 5.4 per 1000 PY.InterpretationRates of SSEs in patients with MS, NMOSD, and related disorders were low. Through properly assessing risk:benefit of B-cell depleting therapy in neuroinflammatory disorders and continual monitoring, clinicians may decrease the risk of serious infections.
| S-EPMC7480911 | biostudies-literature
Project description:To assess the safety of ocrelizumab (OCR) shorter duration infusion in patients with MS. ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early stage relapsing-remitting MS received OCR 600 mg initially as two 300 mg IV infusions 2 weeks apart and subsequently as a single 3.5-hour 600 mg infusion every 24 weeks for 192 weeks. In ENSEMBLE PLUS, OCR 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration). The primary end point was the proportion of patients with infusion-related reactions (IRRs) after the first randomized dose (assessed during and up to 24 hours postinfusion). From November 1, 2018, to September 27, 2019, 580 patients were randomized 1:1 to the conventional or shorter infusion group. After the first randomized dose, 67 of 291 patients (23.1%) in the conventional and 71 of 289 patients (24.6%) in the shorter infusion group experienced IRRs. Most IRRs were mild or moderate in both groups; one patient in each group experienced a severe IRR, and in both groups, 98.6% (136 of 138) of all IRRs resolved without sequelae. No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuation occurred. During the first randomized dose, 14 of 291 (4.8%) and 25 of 289 (8.7%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. The frequency and severity of IRRs were similar between conventional and shorter OCR infusions. Shortening the infusion time to 2 hours reduces the total infusion site stay time and lessens the overall patient and site staff burden. This interventional study provides Class I evidence that the frequency and severity of IRRs were similar at the first randomized dose using OCR (600 mg) infusions of conventional and shorter duration in patients with relapsing-remitting MS. NCT03085810.
| S-EPMC7286651 | biostudies-literature
Project description:Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in the DDC gene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno-associated virus serotype 2 vector encoding human AADC (AAV2-hAADC) in AADC-deficient children. Unfortunately, patients presented only modest amelioration of motor symptoms, which authors acknowledged could be due to insufficient transduction of putamen. We hypothesize that, with the development of a highly accurate MRI-guided cannula placement technology, a more effective approach might be to target the affected mid-brain neurons directly. Transduction of AADC-deficient dopaminergic neurons in the substantia nigra and ventral tegmental area with locally infused AAV2-hAADC would be expected to lead to restoration of normal dopamine levels in affected children. The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of non-human primates. Animals received either vehicle, low or high AAV2-hAADC vector dose and were euthanized 1, 3 or 9 months after surgery. Our data indicate that effective mid-brain transduction was achieved without untoward effects.
| S-EPMC4274790 | biostudies-literature
Project description:BackgroundAvelumab, durvalumab, and atezolizumab are anti-programmed death-ligand 1 (PD-L1) antibodies approved for clinical application in Japan. Despite targeting the same molecule, avelumab elicits a different frequency of infusion-related reactions (IRRs) compared with durvalumab and atezolizumab, leading to differences in premedication recommendations. This study aimed to collect information to verify the relationship during IRRs and the characteristics of antibody molecules, by investigating the frequency of IRRs caused by three types of antibodies and the actual status of prophylactic measures.MethodsThis single-center, retrospective observational study collected the medical records of 73 patients who received avelumab, durvalumab, or atezolizumab at Osaka University Hospital.ResultsThe frequency of IRRs was 50.0% (12/24) for avelumab, 31.0% (8/27) for durvalumab, and 18.2% (4/22) for atezolizumab. The IRRs were grade 2 in seven patients and grade 1 in five patients treated with avelumab, grade 2 in six patients and grade 1 in two patients treated with durvalumab, and grade 1 in all patients treated with atezolizumab. Among patients in whom symptoms were observed during the first administration, measures were taken to prevent IRRs for the second administration, but cases were confirmed in which symptoms reappeared, especially in patients who received durvalumab.ConclusionOur findings indicate that the frequency of IRRs due to anti-PD-L1 antibodies is higher than that previously reported in clinical trials and different modifications in antibody molecules may affect the difference in IRR frequency.
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