Frequency Of Infusion-related Reactions Research Articles

Infusion-Related Reactions Subsequent to Avelumab, Durvalumab, and Atezolizumab Administration: A Retrospective Observational Study.

Avelumab, 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. This single-center, retrospective observational study collected the medical records of 73 patients who received avelumab, durvalumab, or atezolizumab at Osaka University Hospital. The 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. Our 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.

The frequency and associated factors of infusion-related reactions to rituximab for patients with rheumatoid arthritis

Objectives: Rituximab is an effective biological agent for treating patients with rheumatoid arthritis (RA). Rheumatologists can avoid rituximab therapy because of infusion-related reactions (IRR). There is a lack of data about rituximab-related IRR, especially in rituximab-naïve patients with RA; therefore, we aimed to determine the frequency and associated factors of rituximab-related IRR in these patients. Methods: Baseline demographic, laboratory, and treatment data were noted. One course of rituximab was used in two infusions to 95 rituximab-naïve patients with RA. Standardized premedication was administered before infusions. Rates, severity, and management of IRR were recorded. Efficacy and infections were also noted if there were. Results: Ninety-four of 95 patients completed the rituximab course successfully. We observed a total of 23 IRRs in 20 patients. The frequency of IRR was 12.1%, and serious IRR was 0.52%. Grade 1-2-3 IRRs had a rate of 52.2%, 30.4%, and 17.4%, respectively; grade 4 or 5 IRR wasn’t detected. Age <60 years, anti-CCP <200U/ml and absence of biologic agent use before rituximab was significantly higher in patients with IRR than without IRR (p=0.01, p=0.002, p=0.01 respectively). We found out that if only the disease age is above 60 months, it is protective against IRR as per the results of multivariate model analysis. Conclusion: Results supported that rituximab is a safe biological agent option for patients with RA at secondary central hospitals. Identified risk factors of IRR need to be corroborated in larger studies for safer rituximab therapy.

Intravenous ofatumumab treatment of multiple sclerosis and related disorders: An observational study

BackgroundOfatumumab is an anti-CD20 monoclonal antibody approved for subcutaneous administration for the treatment of relapsing multiple sclerosis (MS), but intravenously administered ofatumumab has been investigated in a phase 2 trial and used off-label. The objective of the present study was to assess disease activity and side effects in relation to longer-term intravenous ofatumumab treatment of MS and related disorders. MethodsWe conducted a retrospective study of patients treated off-label with intravenous ofatumumab for MS, neuromyelitis optica spectrum disease (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) at the Danish Multiple Sclerosis Center. Data was retrieved from the Danish Multiple Sclerosis Registry and through medical chart review. ResultsFifty patients were identified with a median treatment duration of 2.2 years. Annualized relapse rate decreased from 1.03 at baseline to 0.38 during ofatumumab treatment. At 24 months, the probability of having experienced a relapse was 55% and confirmed disability worsening 7%. Frequency of infusion-related reactions was 86% during the first infusion and 42% during the last infusion. Six experienced infections requiring hospitalization. ConclusionOur data indicate a reduction of relapse frequency, stabilization of disability worsening and an acceptable safety profile, although we observed a higher frequency of infusion reactions compared to data from other intravenously administered anti-CD20 monoclonal antibodies. The study supports a class effect of anti-CD20 monoclonal antibodies and the hypothesis that complement activation may be associated to a higher frequency of infusion related reactions.

Efficacy proof-of-concept from a phase 1 study of a novel therapeutic peptide, ST101, targeting the oncogenic transcription factor C/EBPβ in patients with refractory solid tumors.

3014 Background: The oncogenic transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) promotes tumor survival and proliferation and inhibits differentiation. ST101 is a peptide antagonist of C/EBPβ, with anti-tumor activity in prostate cancer (PC), glioblastoma (GBM), breast cancer (BC), melanoma, and other pre-clinical models. Methods: This phase 1 study enrolled patients (pts) with refractory solid tumors with varying histologies. The primary objective was to evaluate safety/tolerability of ST101 and to determine the recommended phase 2 dose (RP2D). Secondary and exploratory objectives included pharmacokinetics (PK), preliminary efficacy (RECIST 1.1), and pharmacodynamic (PD) evaluation. The study used a 3+3 dose-escalation design, with once-weekly IV infusion dosing of ST101 at 0.5, 1, 2, 4, 6, 9 mg/kg or a flat dose of 500 mg. Results: Enrollment in phase 1 was completed in November 2021 with a total of 25 pts with multi-metastatic disease that were refractory to standard therapy. As of February 15, 2022, five pts remain on study with a median treatment duration of 27 weeks’ (16-77). There were no DLTs, dose modifications, or serious adverse events (SAEs) related to ST101. The only AEs of note were G1-2 histaminergic infusion-related reactions (IRRs), largely pruritis and urticaria, managed with antihistamines, montelukast, and interruption/slowing of infusion. IRRs affected 93% of pts on the first dose at ≥4mg/kg and led to prolongation of infusion time. Intensity and frequency of IRRs decrease with repeat dosing. No other AEs were consistently reported. There was no evidence of accumulation upon continued exposure of ST101 and no anti-drug antibodies. Tumor immunohistochemistry showed dose-proportionate staining for ST101 and decreased tumor proliferation in several pts represented by decreased Ki67 expression. Population PK analysis supported flat dosing in phase 2. Five pts continue on treatment with one confirmed partial response in a patient with cutaneous melanoma lasting >42 weeks and four pts with ongoing stable disease. Conclusions: ST101 demonstrated safety at all doses explored and evidence of efficacy across dose levels, particularly higher doses and in pts with melanoma. PK and PD support a dose relationship for efficacy and selection of 500 mg as the RP2D. Pts are now enrolling in phase 2 cohorts to assess response in cutaneous melanoma, GBM, castrate-resistant PC, and HR+ BC. Clinical trial information: NCT04478279. [Table: see text]

A real-world study to evaluate the safety and efficacy of three injectable neurokinin-1 receptor antagonist formulations for the prevention of chemotherapy-induced nausea and vomiting in cancer patients

BackgroundThree different injectable neurokinin-1 (NK-1) receptor antagonist formulations (CINVANTI® [C] vs. intravenous Emend® [E] vs. generic formulations of fosaprepitant [GFF]) were compared with respect to nausea and vomiting control, use of rescue therapy, and the development of infusion reactions over multiple cycles of chemotherapy.MethodsA retrospective analysis from 17 community oncology practices across the USA was conducted on patients who received moderately or highly emetogenic chemotherapy. The co-primary endpoints were the control of chemotherapy-induced nausea and vomiting (CINV) from days 1 to 5 over all cycles and the frequency of infusion-related reactions. Propensity score weighted multivariable logistic regression analysis was used to compare complete CINV control, the use of rescue therapy, and the risk of infusion reactions between groups.ResultsThe study enrolled 294 patients (C = 101, E = 101, GFF = 92) who received 1432 cycles of chemotherapy. Using CINVANTI® as the reference group, comparative effectiveness was suggested in CINV control over all chemotherapy cycles (odds ratio (OR): E vs. C = 1.00 [0.54 to 1.86] and GFF vs. C = 1.12 [0.54 to 2.32]). However, use of rescue therapy was significantly higher in the EMEND® group relative to CINVANTI® (OR = 2.69; 95%CI: 1.06 to 6.84). Infusion reactions were also numerically higher in the EMEND® group, but the difference did not reach statistical significance (OR = 4.35; 95%CI: 0.83 to 22.8).ConclusionsIn this real-world analysis, patients receiving CINVANTI® had a reduced need for CINV rescue therapy and a numerically lower incidence of infusion reactions.

Abstract P06-03: ST101, a peptide targeting oncogenic transcription factor C/EBPβ: initial safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) data from an ongoing phase 1 dose escalation study in patients with advanced, metastatic solid tumors

Abstract Introduction: The oncogenic transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) is normally active in embryofetal development, but inactive and suppressed in mature cells. Upregulation or activation of C/EBPβ in cancer promotes tumor survival and proliferation while inhibiting its differentiation. ST101 is a peptide antagonist of C/EBPβ, with anti-tumor activity in glioblastoma (GBM), breast cancer (BC), prostate cancer (PC), melanoma, and other models. ST101 penetrates the blood-brain barrier, as demonstrated in a mouse model and biodistribution studies. We have also demonstrated the tumor-specificity of ST101 in numerous in vitro cell lines. Methods: We conducted the phase 1 portion of a phase 1-2 study in patients with refractory solid tumors. The primary objective was to evaluate safety and tolerability of ST101. Secondary and exploratory objectives included PK, preliminary efficacy, and PD from serial biopsies. The study used a 3+3 design, dosing ST101 IV at 0.5, 1, 2, 4, 6, and 8 (now modified to 9) mg/kg weekly (QW). Phase 2 will include four cohorts of patients with specific cancers: HR+ breast cancer, cutaneous melanoma, GBM, and castrate-resistant PC at the recommended phase 2 dose (RP2D). Results: As of July 2021, 18 pts were enrolled, and the last cohort (9 mg/kg) is underway. Patients received a median of 6 weeks’ treatment (range 2 – 45). There were no dose-limiting toxicities, dose modifications, or SAEs related to ST101. The only adverse events (AEs) of note were G1-2 histaminergic infusion-related reactions (IRRs), largely pruritis and urticaria, managed with antihistamines, montelukast, and interruption/slowing of infusion. IRRs affected 100% pts on the 1st dose of ST101 at 4mg/kg. Montelukast was added to the antihistamine premedication regimen in the 6 mg/kg cohort, which attenuated IRRs. 66% of patients in the 6 mg/kg experienced an IRR on the first dose. The intensity and frequency of IRRs decreased with repeat dosing across all cohorts. No other AEs were consistently reported. PK was dose-proportionate, with continued exposure. There was no evidence of accumulation, and no anti-drug antibodies were detected. Tumor immunohistochemistry showed dose-proportionate staining for ST101 and a trend of decreased Ki67 staining (proliferation marker) after ST101 exposure. One confirmed partial response in a patient with metastatic cutaneous melanoma refractory to standard therapy is still on study, and 3 pts with varied histologies have had stable disease lasting 18-45 weeks (1 ongoing). Conclusions: ST101 demonstrated safety at all doses explored and evidence of efficacy across dose levels, particularly higher doses. PK and PD support a dose relationship for efficacy, and we will select a QW RP2D for the phase 2 expansion cohorts by September 2021. Citation Format: Nehal J. Lakhani, Hendrik-Tobias Arkenau, Stefan N. Symeonides, Jeffry Evans, Meredith A. McKean, Elisa Fontana, Manojkumar Bupath, Alistair McLaren, Sreenivasa Chandana, Tze-en Ding, Emerson A. Lim, Jim Rotolo, Gina Capiaux, Rob Michel, Stephen Kaesshaefer, Alice S. Bexon, Gerald S. Falchook. ST101, a peptide targeting oncogenic transcription factor C/EBPβ: initial safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) data from an ongoing phase 1 dose escalation study in patients with advanced, metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P06-03.

Post-Marketing Observational Study to Assess the Incidence of Infusion-Related Reactions in Adult Patients with Therapy-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes Who Were Treated with CPX-351

Post-Marketing Observational Study to Assess the Incidence of Infusion-Related Reactions in Adult Patients with Therapy-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes Who Were Treated with CPX-351

Incidence and Management of Olaratumab Infusion-Related Reactions.

PURPOSE:Olaratumab is a human monoclonal immunoglobulin G1 antibody against platelet-derived growth factor receptor-α. We report the nature and frequency of infusion-related reactions (IRRs) with olaratumab in clinical trials and postmarketing reports.METHODS:Data from patients exposed to olaratumab across nine clinical trials were reviewed for IRRs. Blood samples were also analyzed for pre-existing immunoglobulin E anti–galactose-α-1,3-galactose (anti–α-Gal) antibodies.RESULTS:In the clinical trials, IRRs were identified in 70 of 485 patients (14.4%). The most frequent symptoms included flushing, fever or chills, and dyspnea. For 68 of 70 patients (97.1%), the first IRR occurred during the first two cycles of treatment. Grade 3 or worse IRRs were reported in 11 patients (2.3%), all during the first infusion and usually within 15 minutes of the start of the infusion. One IRR-related fatality (0.2%) occurred in a nonpremedicated patient with grade 3 or worse cardiac comorbidities. There was an association between grade 3 or worse IRRs and pre-existing anti–α-Gal antibodies, with a trend toward higher IRR rates in US geographies known to have a higher prevalence of anti–α-Gal antibodies. IRRs in postmarketing reports were consistent in nature and severity with those in the clinical trials.CONCLUSION:Premedication with corticosteroids and antihistamines should occur in all patients before olaratumab infusion, as indicated in labels in the United States and the European Union. Patients receiving olaratumab should be monitored for IRRs in a setting where resuscitation equipment is available for the treatment of IRRs.

Efficacy and safety of alemtuzumab in a real-life cohort of patients with multiple sclerosis.

No postmarketing randomised clinical trials are available about alemtuzumab, and real-world data are limited. We aimed to analyse the efficacy and safety of alemtuzumab in a single-centre cohort of patients with relapsing-remitting MS. Patients who took alemtuzumab were enrolled. We collected the following data: age, sex, MS history, expanded disability status scale (EDSS), relapses, magnetic resonance imaging (MRI) parameters after alemtuzumab, and adverse events. EDSS scores before alemtuzumab and at the last follow-up were compared by Wilcoxon test. Time to first relapse was analysed after dividing the cohort on the basis of previous treatment. Ninety patients were enrolled [women 74.4%; naïve 7; mean follow-up 27months (SD 23)]. The EDSS was reduced from a median of 2.5 (IQR 1.5-4) before alemtuzumab to 2.0 (IQR 1.5-3.5) after (p = 0.025). The time to first relapse was shorter in patients shifting from a second-line therapy (p = 0.011). Over 2 years, 43.7% had no evidence of disease activity. We observed infusion-related reactions in 95.5% patients, including 11.1% with pneumonitis, thyroiditis in 11%, and thrombocytopenia in 3.3%. We confirmed the clinical and MRI efficacy of alemtuzumab in the clinical setting and the frequency of infusion-related reactions. Compared with that in clinical trials, higher number of patients developed pneumonitis during infusion.

3025 POSTER Impact of pre-medication on the frequency of infusion-related reactions (IRRs) and efficacy in patients (pts) treated with cetuximab plus irinotecan for metastatic colorectal cancer (mCRC): the MABEL study

3025 POSTER Impact of pre-medication on the frequency of infusion-related reactions (IRRs) and efficacy in patients (pts) treated with cetuximab plus irinotecan for metastatic colorectal cancer (mCRC): the MABEL study

Infusion-related reactions (IRR) associated with cetuximab plus irinotecan treatment in patients with irinotecan-resistant metastatic colorectal cancer (mCRC): Findings from the MABEL study

4137 Background: Cetuximab is an IgG1 anti-EGFR monoclonal antibody, active alone and in combination with irinotecan in mCRC patients (pts) who have failed prior irinotecan therapy. In previous studies with cetuximab, IRRs were observed in a small proportion of pts especially at the first infusion. Methods: MABEL investigated cetuximab plus irinotecan in pts with EGFR-detectable mCRC whose last treatment regimen contained irinotecan. A secondary objective of MABEL was to further study cetuximab-related adverse events. Study treatment was cetuximab, initial dose 400 mg/m2, weekly 250 mg/m2, plus irinotecan with dose and schedule as pre-study. Data analyzed included prophylactic pre-medication, IRRs and medication for IRRs. Prophylactic medication given before the first cetuximab infusion was categorized as chlorphenamine antihistamines, antihistamines other than chlorphenamine, and any antihistamines plus corticosteroids. Results: Overall, 1147 pts were treated in this study: median age was 62 years [25–84], Karnofsky performance status was =70% and 64% pts were male. 1,122 patients were pre-treated with antihistamines. The frequency of IRRs was lower in pts who received antihistamines plus corticosteroids than in pts who received antihistamines alone (9.6% vs 25.6% any grade, 1% vs 4.7% grade 3/4 IRRs). The primary efficacy variable of MABEL was the 12-weeks progression-free survival (PFS) status. Efficacy results by pre-medication groups for PFS (see table ) and overall survival do not suggest differences related to prophylactic pre-medication. Conclusions: The data suggest that the type of pre-medication impacts on the occurrence of IRRs, and that the addition of corticosteroids to antihistamines reduces IRRs without altering antitumor efficacy in the analyzed pre-medication groups. [Table: see text] No significant financial relationships to disclose.

High-dose weekly liposomal amphotericin B antifungal prophylaxis following reduced-intensity conditioning allogeneic stem cell transplantation

The use of high-dose corticosteroids for graft-versus-host disease (GVHD) treatment represents a major risk factor for long-term invasive fungal infections. The aim of this study was to investigate the safety and tolerance of weekly prophylactic administration of once-weekly high-dose (7.5 mg/kg) of liposomal amphotericin B (L-AmB) therapy in 21 adult patients receiving high-dose prednisone (2 mg/kg/day) for acute GVHD therapy after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT). Patients received a median of 4 (range, 1-8) infusions of L-AmB. Seven patients (33%; 95% confidence intervals (CI), 13-53%) discontinued taking the study drug owing to study drug-related adverse events, including elevated serum creatinine (>1.5 times from baseline values; n=5), hypotension and pain (n=1), and violent chest pain and arrhythmia (n=1). The overall frequency of infusion-related reactions was 29% (n=6; 95% CI, 10-48%), but these reactions were always transient and relieved by stopping the infusion. This safety data provide support for an efficacy study of this prophylaxis strategy, because this may help further improving the outcome of RIC or nonmyeloablative allo-SCT.