Low Rate Of Serious Adverse Events Research Articles

P1126: MOSUNETUZUMAB IS EFFICACIOUS AND WELL TOLERATED IN PATIENTS AGED <65 AND ≥65 YEARS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA AND ≥2 PRIOR THERAPIES: SUBGROUP ANALYSIS OF A PIVOTAL PHASE II STUDY

Background: Advancing age is associated with a decline in immune function and an increase in the incidence of comorbidity (Castellino et al. 2017). Vulnerability to treatment-related toxicities may also increase with age. Mosunetuzumab is a T-cell engaging CD20xCD3 bispecific monoclonal antibody (Ab) that redirects T cells to eliminate malignant B cells. In a pivotal Phase II study (NCT02500407), mosunetuzumab induced deep and durable remissions and had a favorable safety profile in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior therapies (Budde et al. ASH 2021). Aims: In the current study, we evaluated the efficacy and safety of mosunetuzumab in pts aged <65 and ≥65 years (age stratification per ESMO Clinical Practice Guidelines for management of newly diagnosed and R/R FL; Dreyling et al. 2021) in the pivotal Phase II study. Methods: All pts had Grade (Gr) 1–3a FL and ECOG performance status (PS) 0–1, and were R/R to ≥2 prior therapies, including an anti-CD20 Ab and an alkylating agent. Intravenous mosunetuzumab was given in 21-day cycles with Cycle (C) 1 step-up dosing: C1 Day (D) 1: 1mg; C1D8 2mg; C1D15 and C2D1: 60mg; D1 of C3+: 30mg. Pts with a complete response (CR) by C8 completed therapy; pts with a partial response or stable disease continued treatment for up to 17 cycles, unless disease progression or unacceptable toxicity occurred. The primary endpoint was CR (as best response) rate by PET/CT assessed by Independent Review Committee using standard response criteria (Cheson et al. 2007). Cytokine release syndrome (CRS) was graded using ASTCT criteria (Lee et al. 2019). All pts provided informed consent. Results: As of August 27, 2021, 90 pts had received mosunetuzumab; 67% were aged <65 years and 33% were aged ≥65 years. Of 30 pts aged ≥65 years, median age was 71 years (range: 65–90) and 43% had ECOG PS 1 at entry, 53% had FLIPI 3–5, and 70% had Ann Arbor stage III/IV disease. Median number of prior therapies in the older age group was 3 (range: 2–8); 77% were refractory to a prior anti-CD20 Ab and 43% were double-refractory to a prior anti-CD20 Ab and an alkylating agent. Compared with younger pts, those aged ≥65 years had a numerically higher objective response rate (87% [95% CI: 69–96] vs 77% [95% CI: 64–87]) and CR rate (70% [95% CI: 51–85] vs 55% [95% CI: 42–68]). The 18-month event-free rate for duration of response was 54% (95% CI: 31–76) in pts aged ≥65 years and 59% (95% CI: 43–74) in those aged <65 years. The rate of Gr 3–4 adverse events (AEs) was comparable in the older and younger age groups (73% vs 68%, respectively). A lower rate of serious AEs of any Gr was observed in pts aged ≥65 years (37% vs 52%). One patient in each age group discontinued treatment due to mosunetuzumab-related AEs. CRS occurred less frequently in pts aged ≥65 years than in those aged <65 years (30% vs 52%), while CRS events were predominantly low-Gr in both groups (age ≥65 vs <65 years: Gr 1, 20% vs 28%; Gr 2, 7% vs 22%); high-Gr CRS was uncommon (one patient in each group). All CRS events resolved. No cases of aphasia, seizures, encephalopathy or cerebral edema occurred. Rates of serious AEs of infection (any Gr) were comparable in pts aged ≥65 and <65 years (17% vs 22%, respectively). The PK disposition of mosunetuzumab was also comparable in pts aged ≥65 and <65 years. Summary/Conclusion: Mosunetuzumab is efficacious and well tolerated in older and younger pts with R/R FL and ≥2 prior therapies. In older pts (aged ≥65 years), numerically lower rates of CRS and serious AEs were observed.

Sustained physical activity in peripheral artery disease: Associations with disease severity, functional performance, health-related quality of life, and subsequent serious adverse events in the LITE randomized clinical trial.

This study investigated cross-sectional associations of peripheral artery disease (PAD) severity (defined by the ankle-brachial index (ABI)) and amounts of daily sustained physical activity (PA) (defined as > 100 activity counts per minute lasting 5 consecutive minutes or more). This study also investigated associations of amounts of daily sustained PA with 6-minute walk (6MW) distance and the Short Form-36 physical functioning domain (SF-36 PF) score in cross-sectional analyses and with serious adverse events (SAEs) in longitudinal analyses of people with PAD. PA was measured continuously for 10 days using a tri-axial accelerometer at baseline in 277 participants with PAD randomized to the LITE clinical trial. In regression analyses, each 0.15 lower ABI value was associated with a 5.67% decrease in the number of daily bouts of sustained PA (95% CI: 3.85-6.54; p < 0.001). Every additional bout of sustained PA per day was associated with a 4.56-meter greater 6MW distance (95% CI: 2.67-6.46; p < 0.0001), and a 0.81-point improvement in SF-36 PF score (95% CI: 0.34-1.28; p < 0.001). Participants with values of daily bouts of sustained PA below the median had higher rates of SAEs during follow-up, compared to participants above the median (41% vs 24%; p = 0.002). In conclusion, among participants with PAD, lower ABI values were associated with fewer bouts of daily sustained PA. A greater number of bouts of daily sustained PA were associated with better 6MW performance and SF-36 PF score, and, in longitudinal analyses, lower rates of SAEs. Clinicaltrials.gov ID: NCT02538900.

Compassionate Use of Remdesivir in Pregnant Women With Severe Coronavirus Disease 2019.

BackgroundRemdesivir is efficacious for severe coronavirus disease 2019 (COVID-19) in adults, but data in pregnant women are limited. We describe outcomes in the first 86 pregnant women with severe COVID-19 who were treated with remdesivir. MethodsThe reported data span 21 March to 16 June 2020 for hospitalized pregnant women with polymerase chain reaction–confirmed severe acute respiratory syndrome coronavirus 2 infection and room air oxygen saturation ≤94% whose clinicians requested remdesivir through the compassionate use program. The intended remdesivir treatment course was 10 days (200 mg on day 1, followed by 100 mg for days 2–10, given intravenously). ResultsNineteen of 86 women delivered before their first dose and were reclassified as immediate “postpartum” (median postpartum day 1 [range, 0–3]). At baseline, 40% of pregnant women (median gestational age, 28 weeks) required invasive ventilation, in contrast to 95% of postpartum women (median gestational age at delivery 30 weeks). By day 28 of follow-up, the level of oxygen requirement decreased in 96% and 89% of pregnant and postpartum women, respectively. Among pregnant women, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum women, 89% were extubated, 89% recovered, and 84% were discharged. Remdesivir was well tolerated, with a low incidence of serious adverse events (AEs) (16%). Most AEs were related to pregnancy and underlying disease; most laboratory abnormalities were grade 1 or 2. There was 1 maternal death attributed to underlying disease and no neonatal deaths. ConclusionsAmong 86 pregnant and postpartum women with severe COVID-19 who received compassionate-use remdesivir, recovery rates were high, with a low rate of serious AEs.

Tu1091 POST-COLONOSCOPY COMPLICATIONS WITHIN ONE MONTH; PATIENT SATISFACTION, AND PATIENT EXPERIENCE

The ASGE recently summarized complications of colonoscopy. How we present these risks when describing these, and when obtaining informed consent, should depend on having a true risk assessment. Patients may choose where and from whom they may receive treatment for adverse events (AEs) from colonoscopies. Thus, unless specific AEs and outcomes are proactively searched for, they might never be discovered. Establish accurate rates of colonoscopy-related AEs and identify modifiable factors to improve patient satisfaction, patient experience, and possibly other medical outcomes. Patients who underwent outpatient colonoscopies at one large academic hospital were contacted one month later by a medical secretary who used a standard questionnaire. Over a 34-month period, 2483 randomized patients were contacted. 149 refused to participate. 178 patients reported having suffering from abdominal pain, bleeding, or fever. 28/178 sought medical care. Among them, 21/178 (11.8%) contacted their primary care physician and 19/21 were referred to emergency departments, where 12/19 were admitted. Two additional patients were directly hospitalized without the emergency department. 11/14 were hospitalized at our hospital and three were admitted to other hospitals. 11/14 hospitalized patients had had procedures during their colonoscopies (n=5 polypectomies, n=4 biopsies, n=2 polypectomies + biopsies). 6/2334 patients were hospitalized for reasons unrelated to the colonoscopy and 2 patients were hospitalized for elective surgeries. 6/2134 patients were hospitalized for colonoscopy-related complications. The reasons for colonoscopy-related hospitalizations included intestinal perforation, post-polypectomy bleeding and abdominal pain due to the procedure. On a scale from one to five, the average overall patient satisfaction was 4.89 (n=2334). 2118 (98.6%) of patients would recommend to friends to undergo a colonoscopy at our center. 14/2334 patients suffered from serious AEs that were determined to be related to the colonoscopy. 3/14 serious AEs would have gone unnoticed even if every patient with an SAE treated at this hospital had been reported to the GI institute due to hospitalization at other hospitals. There were no mortalities. In this study, we found high levels of patient satisfaction. This may increase adherence to screening guidelines, increasing prevention and early treatments thus reducing morbidity and mortality. This study demonstrated low rates of serious AEs. Individual endoscopists found to have less desirable outcomes should be directed towards improving care. Knowing our AE rates helps us to properly prepare patients. Focus should be given to ensuring a high level of patient satisfaction and experience as well as minimizing true complication rates on a local level, not only based on literature statistics.

180 Long-Term Outcomes of Arthroplasty for Cervical Myelopathy Versus Radiculopathy, and Arthroplasty Versus Arthrodesis for Cervical Myelopathy

Abstract INTRODUCTION Cervical disc arthroplasty (CDA) is an effective treatment for symptomatic cervical disc disease (SCDD). Concerns remain about the appropriateness of CDA to treat patients with myelopathy. This study compares long-term safety and effectiveness of CDA in patients with myelopathy versus radiculopathy. METHODS Retrospective analysis of prospective 84-month data from IDE clinical trial of CDA vs ACDF for SCDD at 2 adjacent levels: NDI, neck/arm pain, SF-36 PCS, neurological status, adverse events (AEs), secondary surgeries at index and adjacent levels. A total of 397 patients were enrolled: 287 radiculopathy alone and 110 myelopathy +/− radiculopathy. Two comparisons were performed: 1)CDA for myelopathy vs radiculopathy. 2)CDA vs ACDF for myelopathy. RESULTS &gt;All groups significantly improved for NDI, neck/arm pain, and PCS at 84 months. Comparison#1: Myelopathy and radiculopathy groups showed similar improvement for NDI (37.8 vs 35.8, P = 0.352), neck pain (12.0 vs 12.1, P = 0.477), arm pain (11.6 vs 9.6, P = 0.480), and PCS (14.1 vs 13.7, P = 0.863). Both groups had similar maintenance or improvement in neurological status (87.2% vs 93.5%, P = 0.218), serious AEs (54.5% vs 57.5%, P = 0.291) secondary surgeries at index (3.7% vs 4.4%, P = 0.839) and adjacent levels (3.7% vs 7.6%, P = 0.367). Comparison#2: The CDA and ACDF groups showed similar improvement for NDI (37.8 vs 31.1, P = 0.147), neck pain (12.0 vs 10.4, P = 0.337), arm pain (11.6 vs 11.4, P = 0.791) and PCS (14.1 vs 11.2, P = 0.363). Both groups had similar maintenance or improvement in neurological status (87.2% vs 96.2%, P = 0.409) and similar rates of secondary surgeries at the index (3.7% vs 9.4%, P = 0.374) and lower rates of surgeries at adjacent levels (3.7% vs 15.4%, P = 0.088). Compared to ACDF, CDA group demonstrated lower rates of serious AEs (54.5% vs 65.9%, P = 0.019). CONCLUSION Long-term, CDA is safe and effective for the treatment of myelopathy. Myelopathy patients gain similar improvement from CDA to patients with radiculopathy only. Furthermore, myelopathy patients report similar levels of improvement from CDA compared with ACDF, but suffer fewer serious AEs

High efficacy of Sofosbuvir plus Simeprevir in a large cohort of Spanish cirrhotic patients infected with genotypes 1 and 4.

Hepatitis C (HCV) therapy with Sofosbuvir (SOF)/Simeprevir (SMV) in clinical trials and real-world clinical practice, showed high rates of sustained virological response (SVR) in non-cirrhotic genotype (GT)-1 and GT-4 patients. These results were slightly lower in cirrhotic patients. We investigated real-life effectiveness and safety of SOF/SMV with or without ribavirin (RBV) in a large cohort of cirrhotic patients. This collaborative multicentre study included data from 968 patients with cirrhosis infected with HCV-GT1 or 4, treated with SOF/SMV±RBV in 30 centres across Spain between January-2014 and December-2015. Demographic, clinical, virological and safety data were analysed. Overall SVR was 92.3%; the majority of patients were treated with RBV (62%) for 12weeks (92.4%). No significant differences in SVR were observed between genotypes (GT1a:94.3%; GT1b:91.7%; GT4:91.1%). Those patients with more advanced liver disease (Child B/C, MELD≥10) or portal hypertension (platelet count≤100×109 /L, transient elastography≥21Kpa) showed significantly lower SVR rates (84.4%-91.9%) than patients with less advanced liver disease (93.8%-95.9%, P<.01 in all cases). In the multivariate analysis, the use of RBV, female gender, baseline albumin≥35g/L, MELD<10 and lack of exposure to a triple therapy regimen were independent predictors of SVR (P<.05). Serious adverse events (SAEs) and SAE-associated discontinuation events occurred in 5.9% and 2.6%. In this large cohort of cirrhotic patients managed in the real-world setting in Spain, SOF/SMV±RBV yielded to excellent SVR rates, especially in patients with compensated liver cirrhosis. In addition, this combination showed to be safe, with low rates of SAEs and early discontinuations.

Necuparanib combined with nab-paclitaxel + gemcitabine in patients with metastatic pancreatic cancer: Phase 2 results.

370 Background: The Phase 1 portion of a Phase 1/2 trial of Necuparanib (“Necu”) combined with nab-paclitaxel (nabP) + gemcitabine (gem) in patients with metastatic pancreatic cancer (ClinicalTrials.gov Identifier NCT01621243) showed acceptable safety and tolerability and encouraging signals of activity and established a dose for the randomized, placebo (PBO)-controlled Phase 2 portion. Methods: In Phase 2, patients received daily s.c. injections of either 5 mg/kg Necu daily or PBO, combined with i.v. 125 mg/m2 nabP and 1000 mg/m2 gem (Days 1, 8, 15 of each 28-day cycle). The primary endpoint was overall survival (OS); other endpoints included progression-free survival (PFS), response rates, safety, and CA19.9 levels. An interim futility analysis was conducted in July 2016 once 57 deaths (50% of the target number of 114 events required for trial completion) had occurred. Results: The analysis was conducted on data from 120 randomized patients (62 Necu, 58 PBO). The Z-score for futility was -0.42 (prespecified boundary of -0.148 was crossed as actual score was lower). Median OS was Necu = 10.71 and PBO = 9.99 months; hazard ratio (HR) = 1.12 (favoring PBO); OS curves were intertwined. PFS was Necu = 5.52 and PBO = 6.93 months; HR = 0.97. RECIST response rates were comparable between arms: complete response, Necu = 0%, PBO = 3%; partial response, Necu = 26%, PBO = 26%; stable disease, Necu = 31%, PBO = 34%; disease control rate, Necu = 56%, PBO = 64%. The most common Grade 3+ adverse events (AEs) were neutropenia (Necu = 33%, PBO = 33%), thrombocytopenia (Necu = 27%, PBO = 5%), and anemia (Necu = 22%, PBO = 11%). There were lower rate of serious AEs with Necu (48%) vs. PBO (60%). Modest increases in APTT, AST, and ALT were noted following Necu relative to PBO. 23% of Necu and 5% of PBO patients were IgG positive with an anti-heparin/PF4 antibody titer of ≥ 0.4 at any time. There were no treatment differences for decreases in CA19.9. Conclusions: No new safety signals were observed and the toxicity profile was considered manageable; however, Necu in combination with nabP and gem did not show a sufficient level of efficacy in metastatic pancreatic cancer to warrant continued enrollment. Clinical trial information: NCT01621243.

Long-term safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901

Objective: To review long-term safety data from the rollover study ETV-901, focusing on adverse events (AEs) with a potential nucleos(t)ide association.Methods: The open-label study ETV-901 (AI463901) assessed the safety of entecavir in chronic hepatitis B patients who received entecavir, lamivudine or adefovir monotherapy in previous entecavir Phase II/III studies. Long-term cumulative safety results are based on reported AEs, regardless of causal relationship.Results: Median exposure to entecavir in study ETV-901 was 184 weeks. Commonly reported AEs (≥ 10%) were upper respiratory tract infection, headache and nasopharyngitis. Most AEs were mild to moderate; 203 (19%) patients reported grade 3 – 4 AEs, with 45 (4%) considered related to entecavir. There were 14 (1%) discontinuations due to AEs. On-treatment alanine aminotransferase (ALT) flares were reported in 32 (3%) patients and were associated with a reduction in hepatitis B virus DNA of more than 2 log10 copies/ml in 25/32 patients. AEs potentially associated with nucleos(t)ide analogs were infrequent, the most common being myalgia (n = 54; 5%) and neuropathy-related AEs (hypoparesthesia and hyperparesthesia, polyneuropathy; n = 42; 4%).Conclusions: Long-term administration of entecavir was associated with low rates of serious AEs, discontinuations due to AEs and ALT flares. AEs potentially associated with nucleos(t)ide use occurred at low rates.

P84 Low rates of nucleos(t)ide-associated adverse events in the long-term experience with entecavir

IntroductionIn Phase III studies evaluating treatment of chronic hepatitis B (CHB), entecavir demonstrated superior efficacy compared to lamivudine and a comparable safety and tolerability profile. Long-term safety data from the...

M1901 Low Rates of Nucleos(T)Ide-Associated Adverse Events in the Long-Term Experience With Entecavir

Introduction In Phase III studies evaluating treatment of chronic hepatitis B (CHB), entecavir demonstrated superior efficacy compared to lamivudine and a comparable safety and tolerability profile. Long-term safety data from the rollover study ETV-901 are reviewed, focussing on adverse events (AEs) with a potential nucleos(t)ide association. Method Long-term cumulative safety and tolerability results are based on investigator-reported AEs, regardless of causal relationship. Results Median exposure to entecavir in ETV-901 was 168 weeks. Of the 1045 treated patients, 402 (38%) had received entecavir for =5 years at the time of analysis. Also, 488 (47%) patients had additional prior entecavir exposure from Phase II or III participation. Baseline characteristics were: mean age 41 years; 804 (77%) male, 539 (52%) Asian, and 480 (46%) Caucasian. The most common AEs (=10%) were upper respiratory tract infection, headache and nasopharyngitis. On-treatment alanine aminotransferase (ALT) flares were reported in 3% of patients. The cumulative rate of serious AEs was 15%. Discontinuations due to AEs were 1% (n=13), and generally (n=11) occurred during the first 2 years of ETV-901. Selected AEs with a potential nucleos(t)ide association are described below. Conclusion Entecavir is a safe and well-tolerated treatment for patients with CHB and compensated liver disease. Long-term administration of entecavir was associated with low rates of serious AEs, discontinuations due to AEs and ALT flares. Spontaneous reports of AEs potentially associated with nucleos(t)ide use occurred at low rates.