Evaluation of cut-off values in acute paracetamol overdose following the United Kingdom guidelines

Background The United Kingdom guideline for acute paracetamol overdose has recommended the use of ‘100-treatment line’. Emergency medical centers in some developing countries lack the resources for timely reporting of paracetamol concentrations, hence treatment depends on reported dose. This study aimed to examine whether using an reported dose is safe to predict concentration above the 100-line. Methods Data were retrieved from two emergency medical centers retrospectively, between 2010 and 2017. The inclusion criteria were single acute paracetamol overdose, presentation within 15 h, and age ≥ 14 years. Multiple linear regression was performed to determine the effect of ingested dose on paracetamol concentration. Subgroups were created based on ingested dose, rate of concentration above 100-line were investigated. Results One hundred and seventy-two patients were enrolled in the primary analysis; median dose was 133.3 mg/kg and 46 (37.8%) had concentration above 100-line in the first test. Only dose per weight was moderately correlated with the first concentration (R2 = 0.410, p < 0.001). In the ≤200 mg/kg ingestion group, 18 patients showed concentration above 100-line and 8 showed acute liver injury. The cut-off value of 150 mg/kg showed 82.6% sensitivity and 73.8% specificity to predict concentration above 100-line. Conclusion Where paracetamol concentration is not available and activated charcoal is readily used, following United Kingdom guideline, it is safe to use an ingested dose of > 150 mg/kg as the cut-off value for N-acetylcysteine treatment with risk stratification for hepatotoxicity if the patient is ≥14 years and visit the ED within 15 h after an acute paracetamol overdose.

Efficacy of MAVIG X-Ray Protective Drapes in Reducing CTO Operator Radiation

Background. The MAVIG X-ray protective drape (MXPD) has been shown to reduce operator radiation dose during percutaneous coronary interventions (PCI). Whether MXPDs are also effective in reducing operator radiation during chronic total occlusion (CTO) PCI, often with dual access, is unknown. Methods. We performed a prospective, randomized-controlled study comparing operator radiation dose during CTO PCI (n = 60) with or without pelvic MXPDs. The primary outcomes were the difference in first operator radiation dose (μSv) and relative dose of the first operator (radiation dose normalized for dose area product) at the level of the chest in the two groups. The effectiveness of MXPD in CTO PCI was compared with non-CTO PCI using a patient-level pooled analysis with a previously published non-CTO PCI randomized study. Results. The use of the MXPD was associated with a 37% reduction in operator dose (weighted median dose 26.0 (IQR 10.00–29.47) μSv in the drape group versus 41.8 (IQR 30.82–60.59) μSv in the no drape group; P < 0.001 ) and a 60% reduction in relative operator dose (median dose 3.5 (IQR 2.5–5.4) E/DAPx10−3 in the drape group versus 8.6 (IQR 4.2–12.5) E/DAPx10−3 in the no drape group; P = 0.001 ). MXPD was equally effective in reducing operator dose in CTO PCI compared with non-CTO PCI ( P value for interaction 0.963). Conclusions. The pelvic MAVIG X-ray protective drape significantly reduced CTO operator radiation dose. This trial is clinically registered with https://www.clinicaltrials.gov (unique identifier: NCT04285944).

Radiation Proctitis: The Potential Role of Hyaluronic Acid in the Prevention and Restoration of Any Damage to the Rectal Mucosa among Prostate Cancer Patients Submitted to Curative External Beam Radiotherapy

Aim: To evaluate if hyaluronic acid reduces proctitis episodes with respect to corticosteroids in prostate cancer patients submitted to radical or adjuvant radiotherapy. Methods: A consecutive series of eligible patients received hyaluronic acid enemas as supportive care (experimental group, from January 2013 to June 2015). A historical group (control group), treated from October 2011 to December 2012, received beclomethasone dipropionate suppositories. We registered each patient’s data regarding acute and chronic proctitis. All patients were treated with static-intensity-modulated radiotherapy coupled to a daily set-up verification with orthogonal anterior–posterior/lateral X-ray pairs. Results: A total of 269 patients, 175 in the experimental group and 94 in the control group, was evaluated; 2 Gy/day (up to a total median dose of 80 Gy) and 2.7 Gy/day (up to a total median dose of 67.5 Gy) fractionation schemes were used for 216 and 53 patients, respectively. All patients had a good tolerance to radiotherapy, reporting no G3 or greater proctitis. No significant difference was reported concerning the total rate of proctitis between the two groups but only with respect to its grade: a higher G2 rate within the control group. There was no correlation between daily dose fractionation and toxicity grade. Conclusions: Hyaluronic acid enemas might be effective in reducing the severity of radiation proctitis.

The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

Aims: The absolute number of chronic phase CML patients (pts) reaching the treatment-free remission (TFR) criteria has been substantially increased by the use of second-generation TKI (TKI2), initiated since diagnosis, comparing to Imatinib first-line. However, the relative rate of unsuccessful TFR (i. e. pts loosing their MMR after TKI2 cessation) still remains around 50% at 2 years and beyond, whatever the TKI2 was. The aim of this study is to analyse the rate of successful TFR in pts receiving Nilotinib (Nilo) or Dasatinib (Dasa) first-line obtaining the appropriate criteria. Methods: Observational retrospective study in 3 reference centers of the French group of CML lead between 2010 and 2021. Eligible pts were CP CML pts initiating either Nilo 300 mg BID or Dasa 100 mg daily since diagnosis, until cessation for sustained MR4.5 (i.e. ≥2 years on ≥4 datapoints). Data were retrospectively collected according to the national regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2009, 2013 and 2020 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) for TFR. In this regard, the TKI2 was resumed in case of loss of MMR. All BCR-ABL1 assessments were performed in the 3 reference laboratories, standardised and expressed in % (IS) with ≥32,000 copies of ABL1 as control. All patients were harbouring major BCR-ABL1 transcripts. The primary endpoint was the survival without loss of MMR after TKI2 cessation. The secondary endpoints were the kinetics of MMR loss, and the identification of factors influencing MMR loss. Results: Seventy-two pts were reported (47 Nilo, 25 Dasa) with 57% females with a median age at diagnosis of 48 (36.75-61.25) years. The median follow-up since diagnosis was 9.26 (3.75-13.75) years (8.8 for Nilo and 9.47 for Dasa p=ns) and after TKI2 cessation 3.94 (0.7-8.8) years (3.92 for Nilo and 3.90 for Dasa p=ns). Sokal scores were 42% Low, 41% Intermediate, 17% High in Nilo and 39% L, 25% I and 35% H in Dasa pts (p=ns). ELTS scores were 50% L, 22% I, 9.5% H (18.5% Uk) in Nilo and 46.5% L, 28.5% I and 3.5% H (21.5% Uk) in Dasa pts (p=0.95). Five (9%) pts harboured ACA at diagnosis in the Nilo group and 2 (7%) in the Dasa group (p=1.00). The median time from TKI2 initiation to sustained MR4.5 was 19 (3.12-36) months in the Nilo group and 16 (6.3-39) months in the Dasa group (p=0.644). The duration of sustained MR4.5 until cessation was 3.04 (1.5-9.3) years for Nilo and 2.65 (1.11-7.95) for Dasa (p=0.96). The median dosing of Nilo was 600 (300-800) mg daily and 80 (20-100) mg at TKI2 cessation. None of these patients switched to another TKI during the follow-up. TKI2 cessation occurred after 60.5 (43-74.5) months in the Nilo group and 68 (39-90) months in the Dasa group (p=0.581). Thirty-seven pts out of 47 (79%) were BCR-ABL1 undetectable at Nilo cessation 18/25 (72%) at Dasa cessation (p=0.60). At M3 after discontinuation, 58% of pts remained undetectable after Nilo cessation and 30.4% after Dasa cessation (p=0.05).The median survival of pts without loss of MMR was not reached in the Nilo group, and was 14 (4.73-NR) months in the Dasa group, (p=0.042) as analysed by the KM method (Figure 1.). Two patients died (1 Nilo, 1 Dasa) from competing events (solid tumours) after unsuccessful TFR. Twenty-eight pts (14 Dasa, 14 Nilo) restarted their TKI2 after MMR loss and all regained ≥ MMR after 3 months of Dasa at a median dose of 75 (40-100) mg daily and all except one (who regained MMR at M12) after resumption of Nilo at a median dose of 350 (300-600) mg daily. Univariate analysis identified pts with H+I Sokal (as compared to low) as an unfavourable factor for successful TKI2 cessation [HR=0.35 (0.15-0.83), p=0.017] and type of TKI2 (Nilo as reference vs Dasa) was discriminant [HR=2.1 (1.01-4.35), p=0.047]. Multivariate analysis identified the type of TKI2 as a significant factor impacting on TFR outcome [HR 2.11 (0.97-4.55], p=0.05]. Conclusions: As it is likely that no prospective head-to-head comparison will be performed in this setting, on this limited series of pts, we conclude that the outcome of TFR seems to be different according to the TKI2 used since diagnosis, suggesting the impact of distinct biological variables modified by the type of TKI2 on the long run (such as immunological system, BM micro-environment, others) on TFR outcome. Figure 1 Figure 1. Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Low-Dose Nivolumab Plus Brentuximab Vedotin As a Bridge to Stem Cell Transplantation in Relapsed/Refractory Classical Hodgkin Lymphoma

Background: Up to one-third of patients with Hodgkin lymphoma (HL) are not responsive to first-line therapy or eventually relapse. New drugs, including anti-PDL1 (i.e., nivolumab) and monoclonal antibodies (i.e., brentuximab vedotin (BV)), have changed the landscape in the treatment of HL. However, the financial toxicity associated with these new drugs is worrisome and are practically inaccessible to most patients living in low-middle income countries. The approved dose of nivolumab in refractory classical Hodgkin Lymphoma (HL) is 3 mg/kg, but lower doses have demonstrated efficacy. Objective: To assess the efficacy of low-dose nivolumab at a fixed dose of 40 mg, 100 mg, or 140 mg in combination with BV 1.8 mg/kg every three weeks in patients with relapsed or refractory (R/R) HL. Methods: We conducted a retrospective analysis of adults with R/R HL who received BV at 1.8 mg/kg and low-dose nivolumab at a fixed dose of 40 mg, 100 mg, or 140 mg IV every three weeks. Patients were routinely offered the highest dose possible that could be afforded for at least 4 cycles, as treatment costs were covered out of pocket. We calculated treatment responses, and overall survival (OS), and progression-free survival (PFS) with the Kaplan-Meier method. Results: A total of 10 patients (50% male, median of age 26.5 years (15-50)) with R/R HL were included; n=7 relapsed and n=3 refractory patients. Median follow-up was 11.5 months (range, 5-18) (antes o después del BV/nivo?). The median previous lines of treatment were three (range, 1-4) and regimens were ESHAP (2, 20%), IGEV (3, 30%)), CGEV (1, 10%), ICE (3, 30%), and allogenic transplantation (1, 10%). Six patients (60%) had received radiotherapy (median dose: 21.5 Gy, range: 20-25). Five patients (50%) received 40 mg of nivolumab, n=3 100 mg (30%) and n=2 140mg (20%). The median dose per cycle was 0.93 mg/kg (range, 0.48-1.9 mg/kg). After a median of 4 (range, 4-8) cycles of low-dose nivolumab + BV the overall response rate was 80% (n=8); five obtained a complete response (CR) (50%) and n=3 a partial response (30%) . One patient (10%) had stable disease, and the other progressed (10%). Grade 1 or 2 adverse events occurred in n=6 patients (60%), including neuropathy (n=2), grade 1 leucopenia (n=3), fever (n=1), and myalgia (n=1). No grade III or IV adverse events were reported. One-year OS and PFS was 83.3%. Transplant consolidation was conducted in six cases (60%) (three autologous and three haploidentical), three are awaiting transplantation and one relapsed after achieving CR before transplant conditioning. One patient died on day +21 after haploidentical transplantation in the context of progressive disease. Conclusion: A short course of low-dose nivolumab and BV showed remarkable efficacy, achieving response in most patients with minimal toxicity and allowed patients with R/R HL who could not afford standard doses to undergo transplantation. The real-world safety and efficacy of low-dose nivolumab and BV should be further addressed in more extensive prospective studies. Figure 1 Figure 1. Disclosures Gomez-De Leon: ASH: Research Funding; Sanofi: Honoraria; Novartis: Honoraria; Abbvie: Honoraria. Gomez-Almaguer: Janssen: Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau.

1282. Ceftolozane/Tazobactam Use in Critically Ill Patients Receiving Intermittent or Continuous Renal Replacement Therapy

Background Our hospital recommends ceftolozane/tazobactam (CT) as a broad-spectrum agent for treatment of Gram-negative bacilli in patients with a recent or current multidrug resistant (MDR) Pseudomonas infection. CT is utilized in patients who are on renal replacement therapy (RRT) yet little data exist on the efficacy in this population. Currently there are no FDA-approved dosing recommendations for patients on continuous veno-venous hemodialysis (CVVHD). The purpose of this study was to describe the indications, dosing and outcomes of patients on CT while receiving RRT. Methods All patients receiving CT from 2015-20 were included if on RRT, either CVVHD or intermittent hemodialysis (iHD). Clinical success was defined as the absence of pre-treatment signs/symptoms and/or no escalated antibiotic treatment within 48 hours of completing therapy. 30-day mortality was defined as death from any cause within 30 days of CT completion. Patients treated after 2019 approval of higher dosing for hospital-associated/ventilator-acquired pneumonia (HAP/VAP) were noted. Results 17 patients received 24 courses of CT while on RRT, 9 (53%) were immunocompromised. All patients were treated in the ICU for an MDR Pseudomonas infection. As shown in table 1, the most common indications were 49% HAP/VAP, 17% complicated intra-abdominal (cIAI), or 17% urinary tract infections (cUTI). 4 (24%) patients had additional treatment courses of CT started empirically when infection was suspected. Median time to initiation for all courses was 2 days after obtaining cultures and median duration was 7 days. 12 patients were on CVVHD (median flow rate 2.5L/hr) and 7 were on iHD. 2 patients received iHD after CVVHD. Median dose while on CVVHD was 1500mg every 8 hours. The median dose on iHD was that approved by FDA for cIAI and cUTI: 750mg x1 followed by 150mg every 8 hours. Clinical success was achieved in 12 (71%) patients and 30-day mortality was 8 (47%). Table 1: Details on first courses of CT for patients on RRT *Denotes treatment after 2019 FDA approval of 3g q8h for treatment of HAP/VAP in patients with normal renal function **Flow rate: Medium 1.5-2L/hr; High: &gt;2.5L/hr +NA denotes patient that had passed away and therefore additional C/T courses were not applicable Conclusion This case series provides real-world results of outcomes for critically ill patients on RRT treated with CT. Clinical success rates were similar to other published literature despite the severity of illness of this cohort, which is corroborated by the high 30 day, all-cause mortality. Ultimately, further evaluation of CT dosing in patients on RRT is warranted. Disclosures Laura A. Puzniak, PhD, Merck & Co., Inc. (Employee) Kelly Harris, PharmD, BCPS, Merck & Co. Inc (Employee) Trevor C. Van Schooneveld, MD, FACP, BioFire (Individual(s) Involved: Self): Consultant, Scientific Research Study Investigator; Insmed (Individual(s) Involved: Self): Scientific Research Study Investigator; Merck (Individual(s) Involved: Self): Scientific Research Study Investigator; Rebiotix (Individual(s) Involved: Self): Scientific Research Study Investigator Scott J. Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP, Merck & Co., Inc (Grant/Research Support) Scott J. Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP, Merck & Co., Inc (Individual(s) Involved: Self): Research Grant or Support

959 Safety and anti-tumor activity of TCR-engineered autologous, PRAME-directed T cells across multiple advanced solid cancers at low doses – clinical update on the ACTengine® IMA203 trial

BackgroundAdoptive cell therapy demonstrated significant clinical benefit in patients with hematological malignancies but results in most solid tumors have been less encouraging so far.In the IMA203 trial we are treating advanced solid cancer patients utilizing TCR-engineered T cells (TCR-T) directed against an HLA-A*02-restricted peptide derived from the highly prevalent cancer testis antigen PRAME. This target was selected due to homogenous expression and exceptionally high target peptide density per tumor cell (assessed by quantitative mass spectrometry), two features we hypothesize to be critical determinants of anti-tumor activity in TCR-T trials.MethodsThis ongoing first-in-human, dose escalation, multi-indication trial enrolls HLA-A*02:01- and PRAME-positive recurrent and/or refractory solid cancer patients, who failed all available standard treatments. Eligible patients undergo leukapheresis and an autologous TCR-T product is manufactured. After lymphodepletion with fludarabine and cyclophosphamide, T cells are infused, followed by low-dose IL-2. The primary objective of the trial is to assess the safety and tolerability of IMA203. Secondary objectives are to evaluate the anti-tumor activity and pharmacodynamics using molecular and immunological methods.ResultsAs of August 15, 2021, 16 heavily pre-treated patients received IMA203 T cells across multiple escalating dose levels (DL). Absolute IMA203 doses infused ranged from 0.08 to 0.81x109 transduced CD8 T cells per patient, which to our knowledge did not lead to anti-tumor responses in other TCR-T trials. Treatment-emergent adverse events after IMA203 infusion were transient and manageable. Most common events were expected cytopenias (G1-4), CRS and ICANS (both G1-2) and 1 DLT in DL2 (reported earlier). All evaluable patients (N=12) achieved disease control (i.e. best overall response: stable disease [SD] or partial response [PR]) and 6 patients demonstrated PRs according to RECIST1.1 with 2 of these PRs being confirmed. While all 3 patients treated at DL1 (median dose: 0.11x109) experienced SD, a PR was observed in 6/9 patients treated beyond DL1 (median dose: 0.30x109). Responses were seen in patients with synovial sarcoma (N=3), malignant melanoma (N=2) and head and neck cancer (N=1). Robust engraftment of T cells was observed in all patients and tumor infiltration by TCR-modified T cells was demonstrated in patients with evaluable on-treatment biopsies.ConclusionsTo our knowledge IMA203 is the first TCR-T product candidate that induced frequent tumor responses across multiple solid cancers using transduced T cells at doses below 1 billion and has a manageable safety profile. The next step is to assess response rates at higher dose levels and durability of responses.Trial RegistrationNCT03686124Ethics ApprovalThe study was approved by the institutional review board/ethics committee as required for each participating site.

Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial

Purpose In neurogenic orthostatic hypotension, blood pressure falls when upright owing to impaired release of norepinephrine, leading to dizziness. Ampreloxetine, a selective norepinephrine reuptake inhibitor, increases circulating norepinephrine levels. This study explored the safety of ampreloxetine and its effect on blood pressure and symptoms in patients with neurogenic orthostatic hypotension. Methods A multicenter ascending-dose trial (range 1–20 mg, Part A) was followed by a 1 day, double-blind, randomized, placebo-controlled study (median dose 15 mg, Part B). Eligible patients then enrolled in a 20-week, open-label, steady-state extension phase (median dose 10 mg, Part C) followed by a 4-week withdrawal. Assessments included the Orthostatic Hypotension Symptom Assessment Scale (item 1), supine/seated/standing blood pressure, and safety. Results Thirty-four patients (age 66 ± 8 years, 22 men) were enrolled. Part A: The proportion of participants with a positive response (i.e., increase from baseline in seated systolic blood pressure of ≥ 10 mmHg) was greater with the 5 and 10 mg ampreloxetine doses than with placebo or other active ampreloxetine doses. Part B: Seated blood pressure increased 15.7 mmHg 4 h after ampreloxetine and decreased 14.2 mmHg after placebo [least squares mean difference (95% CI) 29.9 mmHg (7.6–52.3); P = 0.0112]. Part C: Symptoms of dizziness/lightheadedness improved 3.1 ± 3.0 points from baseline and standing systolic blood pressure increased 11 ± 12 mmHg. After 4 weeks of withdrawal, symptoms returned to pretreatment levels. The effect of ampreloxetine on supine blood pressure was minimal throughout treatment duration. Conclusion Ampreloxetine was well tolerated and improved orthostatic symptoms and seated/standing blood pressure with little change in supine blood pressure. Trial registration NCT02705755 (first posted March 10, 2016).

Efficacy and Safety of Subcutaneous Infusion of Non-formulated Furosemide in Patients with Worsening Heart Failure: a Real-World Study

We aimed to evaluate the efficacy (short-term changes in surrogates of decongestion) and safety following the ambulatory administration of subcutaneous furosemide (SCF) in patients with WHF. Fifty-five ambulatory patients were treated with SCF administered by an elastomeric pump for at least 72 h. Surrogates of congestion were assessed at baseline, 72 h, and 30 days. Spot urinary sodium (uNa+) was assessed at baseline, 24-48-72 h, and 30 days. The median (IQI) of NT-proBNP and uNa+ at baseline was 5218 pg/mL (2856-10878) and 68±3 mmol/L, respectively. Following administration of SCF (median dose of 100 mg/daily), we found a sustained increase in uNa+ during the first 72 h of treatment compared to baseline, paralleled with evidence of decongestion at 72 h, and 30 days. No significant safety concerns were observed. SCF was an effective and safe diuretic strategy for outpatient congestion management. Graphical abstract

Clinical Outcomes of Intra-arterial Chemoradiotherapy and Neoadjuvant Chemoradiotherapy Followed by Surgery for Maxillary Sinus Squamous Cell Carcinoma

Background: Although intra-arterial chemoradiotherapy (CRT) followed by surgery has been the standard of care for patients with advanced maxillary sinus squamous cell carcinoma (MSSCC), concurrent intra-arterial chemotherapy and high-dose radiotherapy without surgery has emerged as a promising alternative. Objectives: This study aimed to evaluate the ability of intra-arterial CRT alone to increase the overall survival (OS) of patients with MSSCC. Patients and Methods: Forty patients with histologically confirmed MSSCC, who were treated at Tokyo Medical University Hospital (Tokyo, Japan) between February 1999 and June 2015, were enrolled in this study. Twenty-seven patients were treated with intra-arterial CRT (median dose of 60 Gy) without surgery (CRT group), whereas 13 patients were treated with neoadjuvant intra-arterial CRT (median dose of 40 Gy), followed by surgery (S group). The association of OS with age, performance status, T factor (mean tumor size according to the tumor-node-metastasis [TNM] grading system), N factor (mean lymph node involvement according to the TNM grading system), and treatment method was assessed. Results: The median follow-up duration was 36.0 months. There were no significant differences regarding the patients’ characteristics between the two groups. The treatment method was the only significant prognostic factor for OS. The five-year OS rates were 92% and 55% in the CRT and S groups, respectively (P = 0.01). Conclusion: The intra-arterial CRT (60 Gy) without surgery yielded improved survival outcomes in patients with advanced MSSCC as compared to the neoadjuvant intra-arterial CRT (40 Gy) followed by surgery.