Severe Infusion Reactions Research Articles

Severe hypersensitivity reactions to 2 immunotherapy agents in a patient with cutaneous squamous cell carcinoma.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. There is currently limited data on cross-sensitivity between immunotherapy agents. In this case study, we report a case of severe anaphylaxis to both pembrolizumab and cemiplimab. Pembrolizumab (Keytruda) and cemiplimab (Libtayo) are both approved for the treatment of metastatic cutaneous squamous cell carcinoma. Infusion reactions occur rarely with immunotherapy agents. However, if infusion reactions are severe, the treatment should be discontinued, and there is no guidance as to whether another immunotherapy agent may be used. An 87-year-old-male was diagnosed with metastatic cutaneous squamous cell carcinoma expressing a PD-L1 combined positive score of 81%-90%. He was treated with pembrolizumab and, 15 minutes after completion of the first infusion, developed swelling of the eyelids, ears, and tongue in addition to a whole-body rash without pruritus. Due to the severity of the reaction, pembrolizumab was permanently discontinued and the patient was then started on cemiplimab. The patient received a high-dose corticosteroid as premedication before the first infusion of cemiplimab and tolerated the treatment without any adverse effects. However, when the corticosteroid premedication dose was decreased before the second cycle, the patient had a severe infusion reaction to cemiplimab requiring discontinuation. A patient with metastatic cutaneous squamous cell carcinoma developed a severe hypersensitivity reaction to pembrolizumab and subsequently to cemiplimab, despite premedication.

Long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha treatment for patients with Behcet's uveitis: A systematic review and meta-analysis.

This study aims to evaluate the long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha (anti-TNF-α) therapy for patients with Behcet's uveitis (BU) using meta-analysis. We searched the Web of Science and PubMed databases for eligible studies up to December 1, 2022. The quality of each identified study was assessed using the Joanna Briggs Institute's case series literature quality assessment tool. Statistical analysis was conducted using Stata 16.0 software with a random-effects model. Twelve studies comprising 1156 patients with BU were included in our analysis. We found that 85.0% of patients achieved ocular inflammation remission after receiving anti-TNF-α treatment, with a 95% confidence interval (CI) ranging from 78.7% to 90.5%. Additionally, 77.4% (95% CI: 57.5%-92.5%) experienced an improvement in visual acuity (VA). Moreover, the pooled dose reduction of glucocorticoids (GCs) was 11.08 mg (95% CI: -13.34 mg to -8.83 mg). Throughout the follow-up period, the cumulative retention rate of the medication was 67.3% (95% CI: 53.7%-79.6%). Serious adverse events occurred in 5.8% (95% CI: 3.1%-8.9%) of cases, with the three most common types being severe infusion or injection reactions (2.7%; 95% CI: 0.8%-5.4%), tuberculosis (1.3%; 95% CI: 0.0%-3.9%), and bacterial pneumonia (1.3%; 95% CI: 0.1%-3.4%). Subgroup analysis revealed that ocular inflammation remission rates were 89.3% (95% CI: 81.2%-95.5%) for adalimumab treatment and 83.7% (95% CI: 75.3%-90.8%) for infliximab treatment. The drug retention rate after adalimumab therapy was 70.3% (95% CI: 62.0%-78.0%) compared to 66.4% (95% CI: 48.6%-82.2%) for infliximab treatment. Furthermore, the incidence of severe infusion or injection reactions was 2.2% (95% CI: 0.1%-5.8%) following adalimumab treatment and 3.5% (95% CI: 0.7%-7.7%) following infliximab treatment. Anti-TNF-α therapy represents an effective treatment for BU patients with favorable safety profile and high drug retention rate and a potential advantage of adalimumab over infliximab in terms of ocular inflammation remission, drug retention, and the incidence of severe infusion or injection reactions.

Screening practices, efficacy, safety and adherence to biologic therapies in a South African tertiary hospital

IntroductionThe high cost and concern of adverse events, particularly infections, limit the use of biologic therapies. We undertook this retrospective study to document their use for immune-mediated diseases, and explore the screening practices, efficacy, safety, and adherence to bDMARDs in a tertiary hospital.MethodsA folder review of all adult and paediatric patients treated for IMDs with bDMARDs. Changes in disease activity were measured by disease-specific tools at 6, 12, 24-months and at the last available visit, and patient adherence to bDMARDs was explored by folder and pharmacy record review.ResultsWe studied 120 folders; 145 bDMARDs were prescribed (23 patients switched bDMARD). BDMARDs prescribed included tumour necrosis factor inhibitors (TNFi) (76), rituximab (54), tocilizumab (9), anakinra (3), abatacept (1), ustekinumab (1) and tofacitinib (1). The vast majority of patients had an excellent response and achieved low disease activity or remission at their last available visit. Adverse events included severe infection (9) including two cases of tuberculosis (TB), mild skin reaction (6) and severe infusion reactions (4). Therapy was discontinued in 13 patients, most commonly due to infection (5), lack of response (4), or poor adherence (3). Poor adherence was noted in 8/120 (6.7%). Complete latent TB infection screening was performed in only 35 patients (29.2%). Screening for Hepatitis B, C and HIV was performed in 28 (23.3%), 62 (51.7%) and 61 (50.8%) patients, respectively. Only 20.8% and 20.0% received the influenza and pneumococcal vaccination.Discussion and conclusionBiologic therapy was effective, and the most important serious adverse effect was infection, which was significantly associated with TNFi therapy. Vaccination and screening for TB, viral hepatitis and HIV was suboptimal. Of concern, poor adherence to bDMARDs was frequently encountered.

Severe Reaction to Rituximab in Children

Background: Rituximab is a chimeric monoclonal antibody used in various pathologies involving CD20-positive cells. While it is usually well tolerated, infusion-related reactions are frequent but usually mild. Severe reactions such as anaphylaxis and serum sickness nevertheless can occur. Rituximab-induced serum sickness (RISS) is a rare delayed hypersensitivity reaction that may be unrecognized, as it can be confused with severe infection or in some circumstances with primary disease flare-up. We aim to extend our knowledge about severe infusion related reactions to rituximab in children, focusing on RISS and anaphylaxis. Objectives: Our study objective was to study severe reactions to rituximab by evaluating all children and adolescents who received rituximab in our center. Methods: Children and adolescents who received rituximab between 2014 and 2021 at CHU Sainte-Justine, a tertiary and leading pediatric center in Quebec, Canada, were included in the study. Data was collected retrospectively from our electronic medical records in CHU Ste-Justine. The diagnostic criteria proposed by the World Allergy Organization in 2020 were used to classify patients in the anaphylaxis subgroup. Patients with RISS were included if they developed fever and at least rash and/or arthralgia, starting 1 to 30 days following rituximab infusion, and if no other confirmed diagnosis explained symptoms. The study was approved by local Institutional Review Board. Results and discussion: 1534 rituximab infusions in 391 patients were analyzed. A severe infusion reaction to rituximab occurred in 14 patients (3.6%); none resulted in death. Rituximab was prescribed for an auto-immune disease in 61% of cases. Seven patients presented with RISS (1.8%); all were treated for an auto-immune disease including 4 for immune thrombocytopenia (ITP). Mean time from rituximab to RISS was 9 days (ranging from 6 to 12 days). All RISS patients but one presented with the classical triad of fever, rash and arthralgia. Increased C-reactive protein or sedimentation rate was documented in all patients, and decreased complement in 83%. Three patients required admission to intensive care unit due to hemodynamic instability. Patients received corticosteroids and/or intravenous immunoglobulins; mean duration of RISS was 4 days (ranging from 3 to 6 days). Rituximab was reinfused after RISS in one patient; she presented an immediate anaphylactoid reaction after which rituximab was permanently discontinued. Patients who received lower doses of rituximab were less likely to present RISS compared to patients who received higher doses (risk ratio 0.14, CI 0.03-0.74, p=0.016). Although few ITP patients developed RISS, RISS was associated with a greater chance of achieving partial or complete ITP remission (risk ratio 3, CI 1.47-6.14, p=0.033). Such possible association was not observed in other diseases. Seven patients developed severe anaphylaxis (1.8%), 3 of them reacted after the first dose (42.8%). Five of them were able to receive further rituximab infusion, using desensitization protocols. Conclusion: RISS is a rare hypersensitivity reaction in children. To this day, our study is the first to report more than 3 patients in a pediatric setting. RISS in children seems to be more frequent when rituximab is administered for an autoimmune condition, especially ITP. Although the classic triad of fever, rash and arthralgia appears more frequent in children than in adults, RISS should be considered in the differential diagnosis of any suggestive symptom developing within 30 days of infusion. Presence of biological inflammation and/or low serum complement can further support the diagnosis. In all patients, evolution was favorable within a few days with steroids. However, in contrast with anaphylaxis, RISS should be considered as a contraindication for further rituximab therapy.

Long-term outcomes with rituximab as add-on therapy in severe childhood-onset lupus nephritis.

Long-term data pertaining to rituximab as add-on therapy in childhood-onset lupus nephritis (cLN) is scarce. A retrospective cohort study was conducted on all patients with proliferative cLN, diagnosed ≤ 18years and between 2005 and 2021, who received rituximab for LN episodes that were life/organ threatening and/or treatment resistant to standard immunosuppression. Fourteen patients with cLN (female, n = 10) were included, with median follow-up period of 6.9years. LN episodes (class III, n = 1; class IV, n = 11; class IV + V, n = 2) requiring rituximab occurred at 15.6years (IQR 12.8-17.3), urine protein:creatinine ratio was 8.2mg/mg (IQR 3.4-10.1) and eGFR was 28mL/min/1.73 m2 (IQR 24-69) prior to rituximab treatment. Ten and four patients received rituximab at 1500mg/m2 and 750mg/m2, which were given at 46.5days (IQR 19-69) after commencement of standard therapies. Treatment with rituximab resulted in improvements in proteinuria (ps < 0.001), eGFR (ps < 0.01) and serological parameters, including haemoglobin levels, complement 3 levels and anti-dsDNA antibodies, compared with baseline. Rates of complete/partial remission at 6-, 12- and 24-month post-rituximab were 28.6/42.8%, 64.2/21.4% and 69.2/15.3%. All three patients who required acute kidney replacement therapy became dialysis-free after rituximab. Relapse rate following rituximab was 0.11 episodes/patient-year. There was no lethal complication or severe infusion reaction. Hypogammaglobulinaemia was the most frequent complication (45%) but was mostly asymptomatic. Neutropenia and infections were observed in 20% and 25% of treatments. Upon last follow-up, three (21%) and two (14%) patients developed chronic kidney disease (stage 2, n = 2; stage 4; n = 1) and kidney failure, respectively. Add-on rituximab is an effective and safe rescue therapy for cLN patients with life-/organ-threatening manifestations or treatment-resistance. A higher resolution version of the Graphical abstract is available as Supplementary information.

#5348 THE EFFECTS OF RITUXIMAB IN NON-HCV-RELATED MIXED CRYOGLOBULINEMIC VASCULITIS

Abstract Background and Aims Remarkable results in severe HCV-related cryoglobulinemic vasculitis have been obtained with Rituximab. Details of the clinical characteristics and effective treatment of non HCV-related cryogloulinemic syndromes are presently lacking. Method This paper reports on a prospective single-Center open study aimed at evaluating the clinical presentation and effects of Rituximab administered alone in patients with severe non HCV-related cryoglobulinemic syndrome Results The study group included 11 patients followed for at least 6 months. Three patients had type I cryoglobulinemia, 6 had type II and the remaining 2 patients had type III. Mean cryocrit was 2.5%. Four out of 11 patients had symptomatic sicca complex with anti-SSA (Ro)/anti SSB (La) antibodies. All 11 patients presented with biopsy-proven renal involvement, 4 out of 11 with leukocytoclastic vasculitis, and 8 with involvement of the peripheral nervous system. Renal biopsy revealed diffuse membranoproliferative glomerulonephritis (MPGN) in 9 out of 11 patients. Extracapillary proliferation and necrosis of the glomerular tuft was observed in 1 of these 9 cases. Interstitial nephritis together with mesangial expansion and capillary immune deposits were observed in 1 patient. Prevalent interstitial fibrosis and glomerular sclerosis were detected in the remaining case. Patients underwent treatment with rituximab alone. After 6 months we observed a remarkable improvement in the necrotizing skin ulcers and a substantial amelioration of the electrophysiological parameters of motor and sensory peripheral neuropathy. Improvement in both renal function (from 2.8 to 1.4 mg/dl, p &amp;lt; 0.001) and proteinuria (from 4.2 g/24 to 0.4 g/24 h, p &amp;lt; 0.001) was found in 10 out of 11 patients, while 1 could not be fully treated because of a severe infusion reaction and sudden development of anti-Rituximab antibodies. Good renal response was confirmed at the end of follow-up (38.4 months). Three patients had a relapse at 6, 12, and 48 months, respectively. Conclusion In our cohort the administration of 4 once-weekly infusions of Rituximab followed by 2 more infusions after 1 and 2 months proved to be effective in the management of these rare patients.

Serum Albumin fused Flt3L expands a tolDC compartment and amplifies tolerogenic antigen immunotherapy for the prevention of pathogenic anti-drug antibody responses

Abstract From antibodies to enzyme replacement therapies, biologics and protein drugs have become a major part of the medical market and revolutionized medicine. Repeated administration of many of these drugs, however, leads to humoral responses and potentially drug failure via neutralization, clearance, or immune related infusion reactions. Once pathogenic anti-drug antibodies are formed, patients must take broad immunosuppressive drugs, undergo continuous B cell depletion, or discontinue treatment entirely. Currently, no drugs are approved by the FDA to prevent the induction of anti-drug antibodies. Herein, we characterize the effect of our engineered cytokine, Flt3L-SA, in vivoand demonstrate how our molecule expands the dendritic cells while enhancing a tolerogenic, TGFβ expressing subpopulation. We then leverage these dendritic cells to attenuate the antibody response to the highly immunogenic drug Rasburicase and ultimately reduce antibodies by 100-fold when administered as part of a tolerogenic regime with low dose Rasburicase. We also show how this reduction in antibodies results in fewer and less severe infusion reactions upon final challenge, evidencing both a reduction in the antibody response as well as pathology. Future work will aim to determine the exact mechanism by which this tolerance is achieved as well as demonstrate efficacy in the context of a wide range of extremely immunogenic therapies, including enzyme replacement therapeutics for lysosomal storage disorders and AAV therapies. Supported via the Chicago Immunoengineering Innovation Center and the Alper Family Foundation

Safety and Efficacy of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies Amubarvimab Plus Romlusevimab in Nonhospitalized Patients With COVID-19.

Development of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti-SARS-CoV-2 monoclonal antibodies with an extended half-life. To assess the safety and efficacy of amubarvimab plus romlusevimab. Randomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410). Nonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines. Adults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression. Combination of monoclonal antibodies amubarvimab plus romlusevimab or placebo. Nasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death. Eight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events (P<0.001). This reduction was similar between participants with 5 or less and more than 5 days of symptoms at study entry. Grade 3 or higher treatment-emergent adverse events through day 28 were seen less frequently among participants randomly assigned to amubarvimab plus romlusevimab (7.3%) than placebo (16.1%) (P<0.001), with no severe infusion reactions or drug-related serious adverse events. The study population was mostly unvaccinated against COVID-19 and enrolled before the spread of Omicron variants and subvariants. Amubarvimab plus romlusevimab was safe and significantly reduced the risk for hospitalization and/or death among nonhospitalized adults with mild to moderate SARS-CoV-2 infection at high risk for progression to severe disease. National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Analysis of influencing factors and preventive strategies for severe infusion reactions induced by mannatide

Analysis of influencing factors and preventive strategies for severe infusion reactions induced by mannatide

Clinical efficacy and safety of sirolimus in childhood-onset systemic lupus erythematosus in real world.

To investigate the effectiveness and safety of sirolimus in childhood-onset systemic lupus erythematosus in a real world. This is a retrospective real world clinical study. All childhood-onset systemic lupus erythematosus patients treated with sirolimus in Children's Hospital of Hebei Province China were analyzed. They were treated with sirolimus and followed up regularly. The patients had systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, levels of antidouble-stranded DNA antibody, complement components C3 and C4, 24-hour proteinuria and corticosteroid reduction were recorded at baseline and at 6, 12, and 18 months. Adverse events were also collected. Thirty-two patients were enrolled in the study. SLEDAI-2K were improved on all time-points (P < .05). Complement levels increased and the levels of antidouble-stranded DNA antibody decreased during treatment. The mean dose of prednisone tapered and achieved significant reduction after 12 months therapy (15.4 ± 5.8 mg/d to 4.8 ± 2.1 mg/d; P < .05). Sirolimus was well tolerated and only 5 patients (15.6%) experienced adverse events, all of which were classified as infections (2 bacterial infection and 3 viral infections). No deaths, severe infusion reactions, or hypersensitivity reactions were found. Sirolimus use was associated with a decrease in disease activity and ability to tolerate tapering of oral glucocorticoid dose with a favorable risk-benefit profile.

Efficacy of Short-Duration Alemtuzumab in T-Cell Large Granular Lymphocytic Leukemia: Potential for a Response-Adapted Strategy

Introduction T-cell large granular lymphocytic leukemia (T-LGL) is a chronic incurable malignancy where once refractory to immunosuppressive therapy, few treatment options and no optimal treatment consensus exists. Alemtuzumab, 10 milligrams (mg) intravenously (IV) administered daily for a total of 10 doses, has been shown to be effective for relapsed or refractory (R/R) T-LGL (Dumitriu, et al. Lancet Haematol 2016); however, it can be associated with severe infusion reactions and infections. Given the palliative nature of T-LGL-directed treatments and the increasing potential for toxicity with cumulative alemtuzumab exposure, we conducted a retrospective analysis to describe the efficacy and safety of abbreviated alemtuzumab regimens in R/R T-LGL patients. Methods We identified patients ≥18 years with R/R T-LGL who were treated with short-duration (defined as ≤ 5 doses) alemtuzumab between 2012 and 2022 from the University of Washington lymphoma database. Patients who received prior alemtuzumab were excluded. The primary endpoint was overall hematologic response rate (ORR). Secondary efficacy endpoints included hematologic response rate at 3 and 6 months, rate of transfusion independence, progression-free and overall survival. Safety endpoints included rate of infusion reactions and infections, specifically Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation. Results Nine patients meeting criteria were identified (Table 1). Five patients received alemtuzumab 10 mg IV daily for 5 doses and 4 patients received alemtuzumab 10 mg IV weekly for 4 doses. Median age was 65 (range 34-81) years and the median number of prior regimens was 3 (range 1-5). All (100%) patients were refractory to immunosuppressive therapy. Seven (78%), 1 (11%) and 1 (11%) patients had unilineage, bilineage and trilineage cytopenias, respectively. Five patients (56%) had autoimmune comorbidities and five (56%) required periodic transfusions. No patients had myelodysplasia on bone marrow biopsy. Overall, 6 (67%) patients had a hematologic response with 2 patients achieving a partial response (PR) and 4 patients achieving a complete response (CR). ORR at 3 and 6 months was 56% and 44%, respectively. Two (40%) patients achieved transfusion independence. The 3 patients without a hematologic response were retreated with alemtuzumab 10 mg IV daily for 10 doses with 1 subsequently achieving a CR. At a median follow-up time of 7.2 (range 2.3-36.6) months, 3 out of 6 patients who achieved a response had disease relapse; 8 (89%) patients were alive and 1 had died from COVID-19 pneumonia. Among the 5 patients who received alemtuzumab at 10 mg daily for 5 doses, ORR was 40% with 1 patient achieving PR and 1 patient achieving CR. ORR at 3 and 6 months was 40% and 40%, respectively. One (20%) patient had an infusion reaction. Two patients (40%) had subclinical CMV viremia which resolved with valganciclovir. No cases of EBV viremia were noted. Four patients completed alemtuzumab at 10 mg weekly for 4 doses; ORR was 100% with 1 patient achieving PR and 3 achieving CR. Hematologic response rate at 3 and 6 months was 75% and 50%, respectively. Three (75%) patients relapsed at 3, 4 and 14.2 months, respectively; 2 were retreated 4-6 times with alemtuzumab 10 mg IV weekly for 2 to 6 doses each time, with both achieving hematologic responses with each course of treatment. One (25%) patient experienced an infusion reaction. No cases of CMV or EBV viremia were noted. Conclusions Short-duration alemtuzumab is effective and well tolerated in R/R T-LGL with responses observed in 67% overall and no cases of CMV viremia detected in the weekly dosing group. Alemtuzumab given at 10 mg IV weekly for 4 doses or until a response is noted followed by retreatment upon relapse was particularly effective; this abbreviated, response-adapted alemtuzumab strategy should be prospectively explored in this patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rapid infusion of infliximab biosimilars and the incidence and severity of infusion-related reactions in patients with inflammatory bowel disease.

Infliximab is an anti-tumour necrosis factor agent used in the treatment of inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis. While the use of infliximab is well established in the treatment of IBD, there are now four recently FDA-approved infliximab biosimilars that are increasingly used due to their cost-benefit for patients, institutions and payors. In addition, shortening the length of infliximab infusions from 120 min (standard infusion) to 60 min or less (rapid infusion) has been shown to safely provide further cost-benefit while also improving patient convenience. The safety of rapid infusions has been well-established for the infliximab reference product, however, there are limited data available regarding the safety of rapid infusions for infliximab biosimilars. The purpose of this study was to compare the incidence and severity of infusion reactions among patients with IBD receiving rapid infusion of infliximab reference product compared with infliximab biosimilar. This was a retrospective analysis of electronic health record data of patients with a diagnosis of IBD receiving an infliximab reference product or infliximab biosimilar infusion between December 2020 and December 2021. Patient-level variables included demographics, immunomodulator use, IBD-related hospitalization and infliximab trough concentration and antibody levels. Infusion-related variables of interest included total number of infusions, drug, dose, dosing interval, infusion time and use of pre-medications. Infusion-related reactions were defined as safety concerns documented by the administering nurse (anaphylaxis, shortness of breath, hypotension, swelling, rash, pruritus, hives, flushing, chest pain, muscle pain, joint pain, fevers, chills, headache or hypertension) or administration of emergency medications. Fisher's exact test was used to compare reaction rates. A total of 188 patients met inclusion criteria for analysis, and a total of 1124 infusions were administered during the study period. There were no statistically significant differences among any of the pre-specified outcomes. There were no differences in the incidence of infusion reactions among rapid infusion (60 min) infliximab and infliximab biosimilars (p=0.863). Additionally, there were no differences in the incidence of infusion reactions among standard infusion (120 min) infliximab and infliximab biosimilars (p=0.993). Finally, there were no differences among the rate of infusion reactions between rapid infusion of infliximab biosimilars and standard infusion of infliximab biosimilars (p=0.536). Eight patients experienced safety issues, with three patients requiring emergency medications (1.6% of 188 patients). Rapid infusions of infliximab biosimilars were not associated with an increase in the incidence of infusion reactions compared with: rapid infusion of infliximab reference product, standard infusion of infliximab biosimilars, or standard infusion of infliximab reference product. This should reassure clinicians that rapid infusions of infliximab biosimilars are safe in clinical practice.

Non HCV-Related Mixed Cryoglobulinemic Vasculitis With Biopsy-Proven Renal Involvement: The Effects of Rituximab.

In the countries where HCV infection is still endemic, about 90% of subjects with mixed cryoglobulinemia had previously been infected with HCV and about 80% are RNA positive. Remarkable results in severe HCV-related cryoglobulinemic vasculitis have been obtained with Rituximab. Details of the clinical characteristics and effective treatment of non HCV-related cryogloulinemic syndromes are presently lacking. This paper reports on a prospective single-Center open study aimed at evaluating the clinical presentation and effects of Rituximab administered alone in patients with severe non HCV-related cryoglobulinemic syndrome. The study group included 11 patients followed for at least 6 months. Three patients had type I cryoglobulinemia, 6 had type II and the remaining 2 patients had type III. Mean cryocrit was 2.5%. Four out of 11 patients had symptomatic sicca complex with anti-SSA (Ro)/anti SSB (La) antibodies. All 11 patients presented with biopsy-proven renal involvement, 4 out of 11 with leukocytoclastic vasculitis, and 8 with involvement of the peripheral nervous system. Renal biopsy revealed diffuse membranoproliferative glomerulonephritis (MPGN) in 9 out of 11 patients. Extracapillary proliferation and necrosis of the glomerular tuft was observed in 1 of these 9 cases. Interstitial nephritis together with mesangial expansion and capillary immune deposits were observed in 1 patient. Prevalent interstitial fibrosis and glomerular sclerosis were detected in the remaining case. Patients underwent treatment with rituximab alone. After 6 months we observed a remarkable improvement in the necrotizing skin ulcers and a substantial amelioration of the electrophysiological parameters of motor and sensory peripheral neuropathy. Improvement in both renal function (from 2.8 to 1.4 mg/dl, p < 0.001) and proteinuria (from 4.2 g/24 to 0.4 g/24 h, p < 0.001) was found in 10 out of 11 patients, while 1 could not be fully treated because of a severe infusion reaction and sudden development of anti-Rituximab antibodies. Good renal response was confirmed at the end of follow-up (38.4 months). Three patients had a relapse at 6, 12, and 48 months, respectively. In our cohort the administration of 4 once-weekly infusions of Rituximab followed by 2 more infusions after 1 and 2 months proved to be effective in the management of these rare patients.

Immune- and Non-Immune-Mediated Adverse Effects of Monoclonal Antibody Therapy: A Survey of 110 Approved Antibodies.

Identification of new disease-associated biomarkers; specific targeting of such markers by monoclonal antibodies (mAbs); and application of advances in recombinant technology, including the production of humanized and fully human antibodies, has enabled many improved treatment outcomes and successful new biological treatments of some diseases previously neglected or with poor prognoses. Of the 110 mAbs preparations currently approved by the FDA and/or EMA, 46 (including 13 antibody–drug conjugates) recognizing 29 different targets are indicated for the treatment of cancers, and 66, recognizing 48 different targets, are indicated for non-cancer disorders. Despite their specific targeting with the expected accompanying reduced collateral damage for normal healthy non-involved cells, mAbs, may cause types I (anaphylaxis, urticaria), II (e.g., hemolytic anemia, possibly early-onset neutropenia), III (serum sickness, pneumonitis), and IV (Stevens–Johnson syndrome, toxic epidermal necrolysis) hypersensitivities as well as other cutaneous, pulmonary, cardiac, and liver adverse events. MAbs can provoke severe infusion reactions that resemble anaphylaxis and induce a number of systemic, potentially life-threatening syndromes with low frequency. A common feature of most of these syndromes is the release of a cascade of cytokines associated with inflammatory and immunological processes. Epidermal growth factor receptor-targeted antibodies may provoke papulopustular and mucocutaneous eruptions that are not immune-mediated.

Impact of electronic interventions on guideline concordant ordering of rituximab infusion rate.

Rituximab carries a boxed warning for severe or fatal infusion reactions; most occurring with the initial infusion. Prior studies established that if the initial rituximab infusion is tolerated, subsequent infusions can be given safely over 90 min. The University of Chicago Medicine (UCM) did not have a standardized method to document infusion reactions for outpatient chemotherapy patients, making it challenging for providers to know a patients' eligibility for rapid infusion. This quality improvement project focused on a series of interventions to improve documentation and electronic ordering of rituximab. A flowsheet for nurses to record patients' tolerance of chemotherapy infusions was created within the electronic health record (EHR). Following results of flowsheet impact, a second intervention was implemented to modify ordering of rituximab. The primary endpoint was the incidence of guideline concordant rate ordering of rituximab. Secondary endpoints included the incidence of accurate chair time scheduling pre- and post-interventions and nursing compliance with flowsheet documentation. Prior to flowsheet implementation, 85% of patients were infused at the guideline concordant rate, compared to 79% post-implementation. Prior to modification of rituximab ordering in the EHR, 85% of patients were infused at the guideline concordant rate, compared to 87% after implementation. Complete nursing documentation was done 89% of the time when the flowsheet was utilized, compared to 11% pre-interventions. No difference in primary or secondary endpoints was found following our interventions. However, the infusion documentation flowsheet, when used, provided more complete reaction data compared to when it was not used.

LB2. Safety and Efficacy of Combination SARS-CoV-2 Monoclonal Neutralizing Antibodies (mAb) BRII-196 and BRII-198 in Non-Hospitalized COVID-19 Patients

BackgroundSARS-CoV-2 continues to spread and the development of safe and effective therapeutics for the prevention of severe disease remains a priority. BRII-196 and BRII-198 are non-competing anti-SARS-CoV-2 mAbs with YTE triple amino acid substitution in Fc to extend half-life and reduce receptor binding, that are being studied for treatment of COVID-19 in the ACTIV-2 Trial, sponsored by NIAID and led by ACTG.MethodsACTIV-2 evaluates safety/efficacy of investigational agents for treatment of non-hospitalized adults with mild-moderate COVID-19 under a randomized, blinded, controlled adaptive platform. BRII-196/BRII-198 (1000 mg each) as a single dose given as sequential infusions, or placebo to those at high risk of clinical progression (i.e., age ≥ 60 years or presence of other medical conditions) within 10 days of symptom onset and positive test for SARS-CoV-2. The primary endpoint was hospitalization and/or death through day 28. We report Phase 3 BRII-196/BRII-198 trial results per DSMB recommendation following an interim analysis.ResultsBetween January and July 2021, 837 participants (418 active, 419 placebo) from sites in the US (66%), Brazil, South Africa, Mexico, Argentina and the Philippines were randomized and received study product at time of emerging variants. Median age 49 years (Q1, Q3: 39, 58), 51% female, 17% Black/African-American and 49% Hispanic/Latino, with median 6 days from symptom onset. At interim analysis 71% and 97% had a day 28 and 7 visit, respectively. For all available data at interim review, BRII-196/BRII-198 compared to placebo had fewer hospitalizations (12 vs. 45) and deaths (1 vs. 9). At day 28 of follow-up, there was an estimated 78% reduction in hospitalization and/or death (2.4 vs. 11.1%), relative risk 0.22 (95% CI: 0.05, 0.86), P=0.00001 (nominal one-sided). Grade 3 or higher adverse events (AEs) were observed less frequently among BRII-196/BRII-198 participants than placebo (3.8% vs. 13.4%) with no severe infusion reactions or drug related serious AEs.ConclusionBRII-196/BRII-198 was safe, well-tolerated, and demonstrated significant reduction compared to placebo in the risk of hospitalization and/or death among adults with mild-moderate COVID-19 at high risk for progression to severe disease.Disclosures Kara W. Chew, MD, MS, Amgen (Individual(s) Involved: Self): Grant/Research Support; Merck Sharp & Dohme (Individual(s) Involved: Self): Grant/Research Support David Alain Wohl, MD, Gilead Sciences (Individual(s) Involved: Self): Advisor or Review Panel member, Consultant, Research Grant or Support, Scientific Research Study Investigator; Janssen (Individual(s) Involved: Self): Advisor or Review Panel member; Merck (Individual(s) Involved: Self): Advisor or Review Panel member, Research Grant or Support; ViiV (Individual(s) Involved: Self): Advisor or Review Panel member, Research Grant or Support Joseph J. Eron, MD, Gilead Sciences (Consultant, Research Grant or Support)Janssen (Consultant, Research Grant or Support)Merck (Consultant)ViiV (Consultant, Research Grant or Support) David A. Margolis, MD MPH, Brii Biosciences (Employee) Courtney Fletcher, Pharm.D., National Institute of Allergy and Infectious Diseases, NIH (Grant/Research Support) Davey Smith, M.D., Linear Therapies, Matrix Biomed, Bayer (Consultant, Shareholder) Eric Daar, Gilead (Consultant, Grant/Research Support)Merck (Consultant)ViiV (Consultant, Grant/Research Support)

Management of pediatric generalized pustular psoriasis using biologics: An evidence-based review

Management of pediatric generalized pustular psoriasis using biologics: An evidence-based review

Hypersensitivity reactions to monoclonal antibodies: Classification and treatment approach (Review).

The present paper aims to review the topic of adverse reactions to biological agents, in terms of the incriminating mechanisms and therapeutic approach. As a result of immunomodulatory therapy, the last decade has achieved spectacular results in the targeted treatment of inflammatory, autoimmune, and neoplastic diseases, to name a few. The widespread use of biological agents is, however, associated with an increase in the number of observed adverse drug reactions ranging from local erythema to systemic reactions, including life-threatening immunologically mediated events, which justifies the need for a deeper understanding of this subject. Rapid desensitization to biological agents emerges as a treatment strategy for anaphylactic (immediate or delayed) hypersensitivity reactions as well as for severe infusion reactions. Drug desensitization is the administration of progressively increasing doses of the specific preparation until reaching the therapeutic dose in order to induce immunological tolerance and is indicated when the drugs are indispensable to the therapeutic regimen of individuals with hypersensitivity reactions to the preparation, with no reasonable alternatives.

Regaining the Tumor Control in Relapsed/Refractory Hodgkin Lymphoma after Nivolumab Failure with Addition of Another Antineoplastic Agent

Background: Nivolumab induces a high response rate in patients with relapsed and refractory Hodgkin lymphoma (r/r HL). However, a significant proportion of patients eventually becomes refractory to nivolumab monotherapy, representing the group with uncertain prognosis with limited treatment options. The brentuxinab vedotine and bendamustine hydrochloride are two agents with prominent activity in monotherapy for patients with r/r HL.The goal of this preliminary study was to evaluate the safety and the efficacy of two treatment combinations with nivolumab (nivolumab+bendamustine and nivolumab + brentuximab vedotin) in patients with r/r HL after failure of nivolumab therapy.Patients and Methods: 29 (18 m/11 f) patients were included in the study after signing informed consent. The median age was 30 years (range 21-60). There were 2 subgroups of patients: a) the patients received the nivolumab-bendamustine combination (Benda group, n=19) and patients received the nivolumab-brentuximab vedotin combination (BV group, n=10). All patients received previous nivolumab treatment with a median number of infusions 18 (12-24) and had disease progression according to Lugano criteria. 14/19 (74%) of the pts in Benda group had received bendamustine earlier during the course of the disease. In BV group 5/10 (50%) of patients had received brentuximab vedotin therapy at any time during prior treatment. In Benda group, patients received 90 mg/m2 bendamustine on D1 and 2 and 3 mg/kg nivolumab on Day 1 and 14 of the 28-day cycle up to 3 cycles. In BV group patients were treated with 3 mg/kg nivolumab and 1.8 mg/kg brentuximab vedotin on Day 1 of 21-day cycles up to 3 cycles. All patients received at least one cycle of therapy were included in safety analysis. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) (version 4.03). After completion of the Cycle 3 the response evaluation was performed by PET-CT scan and assessed by investigators using Lugano criteria. The duration of median follow-up period was 3 months (range 1-9).Results: In Benda group, 17/19 (89%) of the pts had drug-related adverse events (AEs) of any grade. Grade 3-4 AE's was noted in 6/19 (32%) of treated patients. Fatigue 16/19 (84%), nausea 12/19 (63%) and pyrexia 6/19 (32%) were the most common AEs. Grade 3-4 AE's included 4 cases of pneumonia, 1 uveitis, 1 severe infusion reaction. One patient discontinued treatment prematurely due to adverse events. In BV group, the AEs of any grade have occurred in 5/10 (50%) of the patients. The most common AE was pyrexia, fatigue in 3/10 (33%) and pruritus in 1/10 patient. Grade 3 AEs included 1 case of grade 3 thrombocytopenia, and 1 case of grade 3 skin rash. No Grade 4 AEs were observed during treatment. The response to treatment in Benda group was assessed in 10 patients. The objective response rate (ORR, was defined by achievement of complete or partial response) to the therapy was observed in 9/10 patients with CR rate 40% (4/10). One patient showed disease progression. All patients with CR failed the bendamustine-containing regimen earlier during disease course. In BV group, the response was assessed in 8 patients. The ORR was 75% (6/8), with 3 patients (37,5%) achieving CR and 3 patients (37,5%) obtaining PR. The rest 2 patients (25%) had SD. Among 4 patients who had prior BV treatment and undergo assessment, 1 had CR, 1 had PR and 2 patients had SD after combination treatment. All patients included in safety and response analysis are alive.Conclusion: Early data suggest that although an elevated incidence of AEs in Benda group has been observed,the toxicities with this regimen appear to be manageable and the combination of bendamustine and nivolumab may be an effective salvage therapy in the patients with r/r HL. The combination of nivolumab and brentuximab vedotin represents an effective and tolerable outpatient regimen in the patients with r/r HL after failure of nivolumab therapy. The efficiency of combination in the patients that have failed both of the drugs in monotherapy may suggest the clinical synergy of nivolumab and brentuximab vedotin/bendamustine. DisclosuresNo relevant conflicts of interest to declare.

Successful Management of Treatment-Emergent Chronic Graft-Versus-Host Disease of the Liver Following Nivolumab for Relapsed Hodgkin's Lymphoma after Allogeneic Stem Cell Transplant

PD-1 inhibition has been shown to effectively treat relapsed Hodgkin's lymphoma after allogeneic stem cell transplant (AlloSCT) by augmenting the graft-versus-lymphoma immune response. While PD-1 blockade post-Allo SCT is associated with a high overall response rate, there is also a high rate of severe graft-versus-host disease (GVHD) following treatment (Blood 2017 130:221-228). Many of the reported fatalities in this patient population have been associated with new onset treatment-refractory GVHD. Interestingly, GVHD occurring in this situation commonly manifests in the liver and can have features of both acute and chronic GVHD. This unique complication raises questions about the most effective treatment strategy. We report the successful management of PD-1 inhibitor-associated liver GVHD in a 31-year-old patient with classic Hodgkin's lymphoma, mixed cellularity subtype, who received the PD-1 inhibitor nivolumab for relapsed disease following a matched sibling donor peripheral blood Allo-SCT. The original indication for Allo-SCT was chemosensitive disease relapse following autologous stem cell transplant. The conditioning regimen was reduced-intensity busulfan and fludarabine and GVHD prophylaxis was low dose methotrexate and tacrolimus. Approximately 180 days after Allo-SCT the patient developed extensive chronic GVHD (elevated liver transaminases and decreased FEV1) which was successfully treated with a short course of oral steroids. Positron emission tomography-computed tomography (PET-CT) scan 1 year after Allo-SCT showed recurrent disease above and below the diaphragm. Brentuximab was initiated, resulting in resolution of hypermetabolic lymphadenopathy, but treatment was stopped after the third dose due to a severe infusion reaction. Three months later, PET-CT revealed multiple foci of high metabolic activity suggesting relapse. Vorinostat and sirolimus were initiated, and remission was obtained for the third time after Allo-SCT while on this regimen. After five months of vorinostat and sirolimus, the patient developed a pulmonary infection and subsequent biopsy-proven disease relapse. The patient was started on single agent nivolumab 3 mg/kg. Approximately 30 days after infusion the patient developed painful sclerodermatous lesions on the shins and increasing liver transaminases (Figure 1). Further treatment with nivolumab was held and 1 mg/kg/day of prednisone-equivalent was initiated. After 1 week, no improvement in liver enzymes was observed and prednisone was increased to 2 mg/kg/day. Sirolimus and mycophenolate mofetil were added. Despite initial improvement, transaminases and bilirubin increased again and a liver biopsy on day 48 of therapy showed lymphocytic cholangitis, cholestasis, ductopenia, and portal-to-portal bridging fibrosis consistent with chronic GVHD. AST peaked at 488 U/L, ALT peaked at 1093 U/L, and total bilirubin peaked at 1.7 mg/dL. Prednisone was increased to 3 mg/kg/day and extracorporeal photopheresis and Jakafi were initiated. Liver transaminases steadily declined. Prednisone was slowly tapered and maintenance therapy with Jakafi, sirolimus, and monthly extracorporeal photopheresis has maintained remission without a subsequent GVHD flare. PET/CT six months after nivolumab showed no evidence of disease, and the patient remains in clinical remission more than eight months after treatment. This case study highlights several uncertainties in the management of GVHD following PD-1 blockade. Should patients receive higher doses of steroids upfront (> 1 mg/kg/day)? Should GVHD prophylaxis be used? How should second-line therapies be chosen and how quickly should they be added? The largest case series to date by Haverkos et al. reports a high rate of treatment resistant GVHD suggesting that rapid escalation of immunosuppression is needed. Overall, this case represents a successful management of a newly-recognized and severe form of GVHD that can occur following PD-1 blockade in Allo-SCT recipients. Given that nivolumab is one of the few effective treatment options for relapsed Hodgkin's lymphoma after Allo-SCT, effective strategies for managing GVHD after PD-1 inhibition are needed. [Display omitted] DisclosuresLin:Jazz Pharmaceuticals: Consultancy. Ganguly:Amgen: Other: Advisory Board; Seattle Genetics: Speakers Bureau.