Previous Regimens Research Articles

Patient-Reported Outcomes Through 1 Year of an HIV-1 Clinical Trial Evaluating Long-Acting Cabotegravir and Rilpivirine Administered Every 4 or 8Weeks (ATLAS-2M).

BackgroundAdvances in HIV-1 therapeutics have led to the development of a range of daily oral treatment regimens, which share similar high efficacy rates. Consequently, more emphasis is being placed upon the individual’s experience of treatment and impact on quality of life. The first long-acting injectable antiretroviral therapy for HIV-1 (long-acting cabotegravir + rilpivirine [CAB + RPV LA]) may address challenges associated with oral treatment for HIV-1, such as stigma, pill burden/fatigue, drug–food interactions, and adherence. Patient-reported outcomes (PROs) collected in an HIV-1 clinical trial (ATLAS-2M; NCT03299049) comparing participants’ experience with two dosing regimens (every 4 weeks [Q4W] vs. every 8 weeks [Q8W]) of CAB + RPV LA are presented herein.MethodsPRO endpoints evaluated through 48 weeks of therapy included treatment satisfaction (HIV Treatment Satisfaction Questionnaire [HIVTSQ]), treatment acceptance (“General Acceptance” domain of the Chronic Treatment Acceptance [ACCEPT®] questionnaire), acceptability of injections (Perception of Injection [PIN] questionnaire), treatment preference (questionnaire), and reasons for switching to/continuing long-acting therapy (exploratory endpoint; questionnaire). Participants were randomized 1:1 to receive CAB + RPV LA Q8W or Q4W. Results were stratified by prior CAB + RPV exposure in either preplanned or post hoc analyses.ResultsOverall, 1045 participants were randomized to the Q8W (n = 522) and Q4W (n = 523) regimens; 37% (n = 391/1045) had previously received CAB + RPV in ATLAS. For participants without prior CAB + RPV exposure, large increases from baseline were reported in treatment satisfaction in both long-acting arms (HIVTSQ status version), with Q8W dosing statistically significantly favored at Weeks 24 (p = 0.036) and 48 (p = 0.004). Additionally, improvements from baseline were also observed in the “General Acceptance” domain of the ACCEPT questionnaire in both long-acting arms for participants without prior CAB + RPV exposure; however, no statistically significant difference was observed between arms at either timepoint (Week 24, p = 0.379; Week 48, p = 0.525). Significant improvements (p < 0.001) in the “Acceptance of Injection Site Reactions” domain of the PIN questionnaire were observed from Week 8 to Weeks 24 and 48 in both arms for participants without prior CAB + RPV exposure. Participants with prior CAB + RPV exposure reported high treatment satisfaction (mean [HIVTSQ status version]: Q8W 62.2/66.0; Q4W 62.0/66.0), treatment acceptance (mean: Q8W 89.3/100; Q4W 91.2/100), and acceptance of injection site reactions (mean [5 = not at all acceptable; 1 = totally acceptable]: Q8W 1.72; Q4W 1.59) at baseline/Week 8 that were maintained over time. Participants without prior CAB + RPV exposure who received Q8W dosing preferred this regimen over oral CAB + RPV (98%, n = 300/306). Among those with prior Q4W exposure, 94% (n = 179/191) preferred Q8W dosing versus Q4W dosing (3%, n = 6/191) or oral CAB + RPV (2%, n = 4/191).ConclusionsBoth long-acting regimens provided high treatment satisfaction and acceptance, irrespective of prior CAB + RPV exposure, with most participants preferring Q8W dosing over both the Q4W regimen and their previous daily oral regimen. The PRO data collected at Week 48 support the therapeutic potential of CAB + RPV LA.FundingViiV Healthcare and Janssen.Trial RegistrationATLAS-2M: ClinicalTrials.gov NCT03299049, registered October 2, 2017.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40271-021-00524-0.

Cefiderocol-Based Combination Therapy for "Difficult-to-Treat" Gram-Negative Severe Infections: Real-Life Case Series and Future Perspectives.

Cefiderocol is a new cephalosporin displaying against extensively resistant (XDR) Gram-negative bacteria. We report our experience with cefiderocol-based combination therapies as “rescue” treatments in immunocompromised or critically ill patients or in patients with post-surgical infections who had failed previous regimens. A total of 13 patients were treated from 1 September 2020 to 31 March 2021. In total, 5/13 (38%) patients were classified as critically ill, due to severe COVID-19 lung failure; 4/13 (31%) patients had post-surgical infections and 4/13 (31%) had severe infections in immunocompromised subjects due to solid organ transplantation (2/4) or hematological malignancy (2/4). Overall, 10/13 infections were caused by carbapenem-resistant Acinetobacter baumannii, one by KPC-positive ceftazidime/avibactam-resistant Klebsiella pneumonia and two by Pseudomonas aeruginosa XDR. Based on clinical, microbiological and hematobiochemical evaluation, cefiderocol was associated with different companion drugs, particularly with fosfomycin, high-dose tigecycline and/or colistin. Microbiological eradication was achieved in all cases and the 30-day survival rate was 10/13; two patients died due to SARS-CoV-2 lung failure, whereas one death was attributed to subsequent infections. No recurrent infections within 30 days were reported. Finally, we hereby discuss the therapeutic potential of cefiderocol and the possible place in the therapy of this novel drug.

Physiologically Relevant Concentrations of Dolutegravir, Emtricitabine, and Efavirenz Induce Distinct Metabolic Alterations in HeLa Epithelial and BV2 Microglial Cells.

Microglia, the resident brain phagocytes, likely play a key role in human immunodeficiency virus (HIV) infection of the central nervous system (CNS) and subsequent neuropathogenesis; however, the nature of the infection-induced changes that yield damaging CNS effects and the stimuli that provoke microglial activation remains elusive, especially in the current era of using antiretroviral (ARV) drugs for ARV therapy (ART). Altered microglial metabolism can modulate cellular functionality and pathogenicity in neurological disease. While HIV infection itself alters brain energy metabolism, the effect of ARV drugs, particularly those currently used in treatment, on metabolism is understudied. Dolutegravir (DTG) and emtricitabine (FTC) combination, together with tenofovir (TAF or TDF), is one of the recommended first line treatments for HIV. Despite the relatively good tolerability and safety profile of FTC, a nucleoside reverse transcriptase inhibitor, and DTG, an integrase inhibitor, adverse side effects have been reported and highlight a need to understand off-target effects of these medications. We hypothesized that similar to previous ART regimen drugs, DTG and FTC side effects involve mitochondrial dysfunction. To increase detection of ARV-induced mitochondrial effects, highly glycolytic HeLa epithelial cells were forced to rely on oxidative phosphorylation by substituting galactose for glucose in the growth media. We assessed ATP levels, resazurin oxidation-reduction (REDOX), and mitochondrial membrane potential following 24-hour exposure (to approximate effects of one dose equivalent) to DTG, FTC, and efavirenz (EFV, a known mitotoxic ARV drug). Further, since microglia support productive HIV infection, act as latent HIV cellular reservoirs, and when dysfunctional likely contribute to HIV-associated neurocognitive disorders, the experiments were repeated using BV2 microglial cells. In HeLa cells, FTC decreased mitochondrial REDOX activity, while DTG, similar to EFV, impaired both mitochondrial ATP generation and REDOX activity. In contrast to HeLa cells, DTG increased cellular ATP generation and mitochondrial REDOX activity in BV2 cells. Bioenergetic analysis revealed that DTG, FTC, and EFV elevated BV2 cell mitochondrial respiration. DTG and FTC exposure induced distinct mitochondrial functional changes in HeLa and BV2 cells. These findings suggest cell type-specific metabolic changes may contribute to the toxic side effects of these ARV drugs.

A retrospective study on the efficacy and safety of sorafenib or lenvatinib combined with sintilimab in patients with advanced hepatocellular carcinoma.

e16127 Background: To evaluate the efficacy and safety of sorafenib or lenvatinib combined with sintilimab in patients with advanced hepatocellular carcinoma. Methods: This retrospective study included patients with advanced/metastatic hepatocellular carcinoma who received sintilimab (iv. 200 mg, Q3W) combined with sorafenib (oral, 400 mg twice-daily) (cohort A) or lenvatinib (oral, 12 mg/day for bodyweight≥60 kg or 8 mg/day for bodyweight &lt; 60 kg) (cohort B) as first line therapy between March 2019 to December 2020 in the 5th medical center of the PLA general hospital of China. The primary endpoint was Progression-Free Survival (PFS), and the secondary endpoints included the Objective Response Rate (ORR), Disease Control Rate (DCR), Overall Survival (OS), Time to Progression (TTP) and safety. Results: 45 patients were enrolled, of which 29 were in the cohort A and 16 were in the cohort B. Except for the extrahepatic metastasis (62.1% vs 25.0%, P= 0.029), there were no significant differences in age, gender, weight, ECOG performance status, Child-Pugh, BCLC staging, and the proportion of previous treatment regimens between the two cohorts. The mean (±SD) exposure cycles in the two cohorts were 7.2±6.7 vs 7.1±4.7 ( P= 0.584). The median PFS of cohort A (8.2 months, 95%CI 3.1-19.5) was longer than that of cohort B (5.2 months, 95%CI 2.0-10.8), but there was no significant difference (HR 0.55, 95%CI 0.24-1.29, P = 0.161). However, there was no significant difference between the two cohorts in ORR (24.1% vs 6.3%, P= 0.226), DCR (82.8% vs 75.0%, P= 0.700) and median TTF (8.2 vs 4.6months, HR 0.49, 95%CI 0.21- 1.10, P= 0.074). OS data were not yet mature. There was no significant difference in the incidence of all grades and grade 3-4 adverse events between the two cohorts. The most common grade 3-4 adverse events in the two cohorts were hand-foot syndrome (17.2%, 5/29) and lung infection (12.5%, 2/16). There was 1 patient (immune hepatitis) in cohort A and 2 patients (pulmonary infection) in cohort B leading to treatment interruption due to adverse events, and no deaths due to treatment. Conclusions: Sorafenib or lenvatinib combined with sintilimab showed a good efficacy and safety in patients with advanced hepatocellular carcinoma, the safety and tolerability profiles were consistent with those previously observed. Sorafenib plus sintilimab provided an improved PFS versus lenvatinib, which requires a large sample of randomized controlled trial to confirm.[Table: see text]

Inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection: a prospective cohort study and immunological network analysis

SummaryBackgroundHIV-1 mediated dysregulation of the immune response to tuberculosis and its effect on the response to antitubercular therapy (ATT) is incompletely understood. We aimed to analyse the inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection undergoing ATT, with specific focus on the effect of ART and HIV-1 viraemia in those co-infected with HIV-1.MethodsIn this prospective cohort study and immunological network analysis, a panel of 38 inflammatory markers were measured in the plasma of a prospective patient cohort undergoing ATT at Khayelitsha Site B clinic, Cape Town, South Africa. We recruited patients with sputum Xpert MTB/RIF-positive rifampicin-susceptible pulmonary tuberculosis. Patients were excluded from the primary discovery cohort if they were younger than 18 years, unable to commence ATT for any reason, pregnant, had unknown HIV-1 status, were unable to consent to study participation, were unable to provide baseline sputum samples, had more than three doses of ATT, or were being re-treated for tuberculosis within 6 months of their previous ATT regimen. Plasma samples were collected at baseline (1–5 days after commencing ATT), week 8, and week 20 of ATT. We applied network and multivariate analysis to investigate the dynamic inflammatory profile of these patients in relation to ATT and by HIV status. In addition to the discovery cohort, a validation cohort of patients with HIV-1 admitted to hospital with CD4 counts less than 350 cells per μL and a high clinical suspicion of new tuberculosis were recruited.FindingsBetween March 1, 2013, and July 31, 2014, we assessed a cohort of 129 participants (55 [43%] female and 74 [57%] male, median age 35·1 years [IQR 30·1–43·7]) and 76 were co-infected with HIV-1. HIV-1 status markedly influenced the inflammatory profile regardless of ATT duration. HIV-1 viral load emerged as a major factor driving differential inflammatory marker expression and having a strong effect on correlation profiles observed in the HIV-1 co-infected group. Interleukin (IL)-17A emerged as a key correlate of HIV-1-induced inflammation during HIV–tuberculosis co-infection.InterpretationOur findings show the effect of HIV-1 co-infection on the complexity of plasma inflammatory profiles in patients with tuberculosis. Through network analysis we identified IL-17A as an important node in HIV–tuberculosis co-infection, thus implicating this cytokine’s capacity to correlate with, and regulate, other inflammatory markers. Further mechanistic studies are required to identify specific IL-17A-related inflammatory pathways mediating immunopathology in HIV–tuberculosis co-infection, which could illuminate targets for future host-directed therapies.FundingNational Institutes of Health, The Wellcome Trust, UK Research and Innovation, Cancer Research UK, European and Developing Countries Clinical Trials Partnership, and South African Medical Research Council.

Durability of non-nucleotide reverse transcriptase inhibitor-based first-line ART regimens after 7 years of treatment in rural Uganda: A prospective cohort study.

Most antiretroviral therapy (ART) programs in resource-limited settings have historically used non-nucleotide reverse transcriptase inhibitor (NNRTI)-based regimens with limited access to routine viral load (VL) testing. We examined the long-term success of these regimens in rural Uganda among participants with 1 measured suppressed VL.We conducted a prospective cohort study of participants who had been on NNRTI-based first-line regimens for ≥4 years and had a VL <1000 copies/mL at enrollment in Jinja, Uganda. We collected clinical and behavioral data every 6 months and measured VL again after 3 years. We quantified factors associated with virologic failure (VF) (VL ≥ 1000 copies/mL) using Wilcoxon Rank Sum, chi-square, and Fisher's Exact Tests.We enrolled 503 participants; 75.9% were female, the median age was 45 years, and the median duration of time on ART was 6.8 years (IQR = 6.0–7.6 years). Sixty-nine percent of participants were receiving nevirapine, lamivudine, and zidovudine regimens; 22.5% were receiving efavirenz, lamivudine, and zidovudine; and 8.6% were receiving other regimens. Of the 479 with complete follow-up data, 12 (2.5%) had VL ≥ 1000 copies/mL. VF was inversely associated with reporting never missing pills (41.7% of VFs vs 72.8% non-VFs, P = .034). There were differences in distribution of the previous ART regimens (P = .005), but no clear associations with specific regimens. There was no association between having a VL of 50 to 999 copies/mL at enrollment and later VF (P = .160).Incidence of VF among individuals receiving ART for nearly 7 years was very low in the subsequent 3 years. NNRTI-based regimens appear to be very durable among those with good initial adherence.

Encorafenib: A Review in Metastatic Colorectal Cancer with a BRAF V600E Mutation.

Encorafenib (Braftovi®) is an oral small molecule BRAF inhibitor used in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, who have received prior systemic therapy. In a clinical trial in adults with BRAF V600E-mutated mCRC who had disease progression after one or two previous regimens (BEACON CRC), encorafenib plus cetuximab was associated with a significantly longer median overall survival (OS), a higher objective response rate (ORR) and longer median progression-free survival (PFS), compared with standard therapy. Encorafenib plus cetuximab had a manageable tolerability profile in BEACON CRC. Current evidence suggests that encorafenib plus cetuximab combination therapy is an important targeted regimen for patients with mCRC and a BRAF V600E mutation who have received prior therapy.

Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study

Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody-drug conjugate, in this patient population. This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396. 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1-13·0). The confirmed objective response rate was 24% (95% CI 16-33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes. Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer. Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.

Clinical characteristics and factors associated with triple therapy use in newly diagnosed patients with COPD

There is limited information about the initiation of triple therapy (TT) in patients with chronic obstructive pulmonary disease (COPD) in primary care. This was an observational, population-based study in patients identified from a primary care electronic medical records database in Catalonia from 2011 to 2015 aimed to identify the use of TT in patients with newly diagnosed COPD. A total of 69,668 newly diagnosed patients were identified of whom 11,524 (16.5%) initiated TT, of whom 8626 initiated TT at or immediately after COPD diagnosis. Among them, 72.3% were GOLD A/B, 14.6% were frequent exacerbators, and 7.1% had asthma–COPD overlap (ACO). Variables associated with TT initiation were: male sex, older age, previous exacerbations, ACO, a previous treatment regimen containing an inhaled corticosteroid, previous pneumonia, and history of lung cancer. A significant number of COPD patients in Primary Care initiated TT shortly after or even before an established COPD diagnosis.

Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. AstraZeneca and Merck.

A standardized glucose–insulin–potassium infusion protocol in surgical patients: Use of real clinical data from a clinical data warehouse

AimsWe evaluated the clinical usefulness of a new unified glucose–insulin–potassium (GIK) regimen in a general surgical department. MethodsSurgical patients treated under the previous diverse GIK regimens (September 2016 to August 2017) and the new unified GIK regimen (September 2017 to August 2018) were identified in records of the Clinical Data Warehouse of Seoul National University Bundang Hospital. Serial and area under the curve (AUC) glucose levels, and percentages of time within the target glucose levels were compared in propensity score matched patients in the diverse GIK regimen and in the unified GIK regimen (n = 227 in each group). ResultsThe AUC of glucose at 6 h and 12 h was lower under the unified GIK regimen than the diverse GIK regimen. The percentage of target glucose levels was higher in the unified GIK regimen compared to the diverse GIK regimen (81.5% vs. 75.0%, P = 0.026), but the occurrence of hypoglycaemia did not differ significantly between groups. ConclusionsThe unified GIK regimen was more effective than the diverse GIK regimen for glycaemic control and did not increase the number of patients developing hypoglycaemia. This validated written GIK regimen can be safely used in a general surgical department.

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma

BackgroundIdecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma.MethodsIn this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150×106 to 450×106 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses).ResultsOf 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)–negative status (<10−5 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of 49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion.ConclusionsIde-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome. (Funded by bluebird bio and Celgene, a Bristol-Myers Squibb company; KarMMa ClinicalTrials.gov number, NCT03361748.)

Real-World Effectiveness and Safety of Insulin Glargine 300 U/mL in Patients with T2D Uncontrolled on NPH or Premixed Insulins as Part of Routine Clinical Practice in Bulgaria: ToUPGRADE Study

IntroductionThe aim of this study is to demonstrate the real-life effectiveness and safety of insulin glargine 300 U/mL (Gla-300) in patients with type 2 diabetes (T2D) previously uncontrolled on NPH ± prandial insulin or premixed insulins in routine clinical practice in Bulgaria.MethodsThis was a 24-week prospective, observational study performed in 40 inpatient and outpatient sites across the country.ResultsA total of 286 patients were included in the study. The mean age (± SD) was 61.2 ± 10.0 years with duration of diabetes of 11.64 ± 7.5 years and body mass index (BMI) of 32.1 ± 5.7 kg/m2. HbA1c before Gla-300 initiation was 9.8 ± 1.0%, and fasting plasma glucose (FPG) was 13.1 ± 3.4 mmol/L. HbA1c and FPG change from baseline to week 24 was − 1.86% (p < 0.001) and − 4.8 mmol/L (p < 0.001), respectively. The proportion of patients reaching their individualized HbA1c at week 24 was 39.1% (95% CI 33.3–45.1%), while the proportion of patients reaching their individualized HbA1c target without confirmed and/or severe hypoglycaemia was 34.8% (95% CI 29.2–40.7%). At study end, 19.0% (95% CI 14.6–24.1%) achieved HbA1c < 7%. Body weight decreased from 88.3 to 87.0 kg from baseline to week 24 with mean change of − 1.3 kg (p < 0.001). The incidence and event rates of anytime confirmed (≤ 3.9 mmol/L) and/or severe hypoglycaemia were low: 7.7% and 0.42 events per patient-year, respectively. The overall Insulin Treatment Satisfaction Questionnaire (ITSQ) score increased from 53.2 to 78.2 from baseline to week 24 and the difference of 25.1 ± 21.5 points was significant (p < 0.001).ConclusionsIn real-life settings, Gla-300 significantly improved glycaemic control and insulin treatment satisfaction in people with T2D who were inadequately controlled with NPH ± prandial insulin or premixed insulin analogues. Improvement of glycaemic control was associated with a very low risk of hypoglycaemia and with significant weight loss irrespective of the previous insulin regimen. Video Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01022-0.

Abstract PD3-11: A randomized, open-label, phase III trial of pertuzumab re-treatment in HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab, trastuzumab, and chemotherapy: The Japan Breast Cancer Research Group-M05 (PRECIOUS) study

Abstract Background: Patients (pts) with HER2-positive locallyadvanced/metastatic breast cancer (LA/MBC) previously treated with pertuzumab(P)-containing regimens have few therapeutic options. The efficacy of Pre-treatment combined with trastuzumab (T)+chemotherapy as 3 or 4 -line chemotherapy was examined in such pts. Methods: Pts previously treated with P-containing regimens as1st/2nd-line treatment for LA/MBC were randomly assigned 1:1 to two groups(P+T+chemotherapy based on physicians’ choice (C) (PTC), and T+C (TC)),stratified by estrogen receptor status, previous P treatment duration, numberof previous chemotherapy regimens, and presence or absence of visceralmetastasis. The primary endpoint was investigator-assessed progression-freesurvival (PFS). Superiority of PTC to TC will be tested using a stratifiedlog-rank test that accounts for all stratification factors, and a one-sidedP-value of less than 0.05 will be considered an indicator of superiority. Thedistribution of PFS will be estimated using the Kaplan-Meier method. In addition,the hazard ratio and one-sided 95% CI of the therapeutic effect between thegroups will be calculated using the Cox proportional hazard model. Secondaryendpoints included independent reviewer assessed PFS, PFS in pts treated withT-DM1 as the latest regimen (PFS after T-DM1), objective response rate (ORR),overall survival (OS), safety, and health-related quality of life (HR-QoL). Results: Of the 219 pts enrolled, 217 (108 PTC, 109 TC) wereincluded in the intent-to-treat analysis. At the data cutoff (July 31, 2019),PFS and OS events were 184 (84.8%) and 84 (38.7%), respectively. Medianfollow-up time was 14.2 months (mo). Investigator-assessed PFS wassignificantly better in the PTC group (median PFS 5.3 vs. 4.2 mo; HR = 0.755[One-sided 95%CI upper limit, 0.967]; One-sided stratified log-rank test p =0.0217). Median PFS after T-DM1 (5.3 vs. 4.2 mo; HR = 0.801 [One-sided 95%CIupper limit, 1.061]; One-sided log-rank test p = 0.0952) and OS (28.8 vs. 23.4mo; HR = 0.713, [One-sided 95%CI upper limit, 1.026], One-sided log-rank test p= 0.062) tended to be longer in the PTC group, though further follow-up isneeded. The ORR with measurable disease (PTC (n = 90) 18.9% vs. TC (n = 92)19.6%) did not differ between the groups. The serious adverse event rate didnot differ between the groups (17.9% vs. 21.3%). There were no new safetysignals included cardiac events in the groups. In the comparison of HR-QoL bytime to deterioration analysis, there was no significant difference between thegroups in FACT-B trial outcome index (PTC 2.8 mo vs. TC 4.3 mo; HR = 1.274,log-rank test p = 0.2289).Conclusions: P re-treatment as 3 or 4 -line chemotherapy wasactive and feasible. P re-treatment can be a standard treatment option forpatients with HER2-positive LA/MBC previously treated with P.(ClinicalTrials.gov number: NCT02514681) Citation Format: Yutaka Yamamoto, Hiroji Iwata, Taira Naruto, Norikazu Masuda, Masato Takahashi, Tetsuhiro Yoshinami, Takayuki Ueno, Tatsuya Toyama, Takashi Yamanaka, Toshimi Takano, Masahiro Kashiwaba, Koichiro Tsugawa, Yoshie Hasegawa, Kenji Tamura, Hiroshi Tada, Fumikata Hara, Shigehira Saji, Satoshi Morita, Masakazu Toi, Shinji Ohno, Japan Breast Cancer Research Group. A randomized, open-label, phase III trial of pertuzumab re-treatment in HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab, trastuzumab, and chemotherapy: The Japan Breast Cancer Research Group-M05 (PRECIOUS) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-11.

Role of Consolidation Durvalumab in Patients With EGFR- and HER2-Mutant Unresectable Stage III NSCLC

IntroductionDespite the recent advance of consolidation durvalumab in the treatment of unresectable stage III NSCLC, not every patient benefits from durvalumab and the predictive markers of response have been difficult to identify. MethodsWe performed a retrospective analysis of patients with unresectable stage III NSCLC treated with consolidation durvalumab after definitive chemoradiation from January 2018 to March 2020. ResultsA total of 36 patients with unresectable stage III NSCLC were treated with consolidation durvalumab. Of these patients, 14 had tumor mutations in the ERBB family including 11 EGFR and 3 ERBB2. The ERBB2/EGFR tumor mutation cohort was more likely to be nonsmokers; otherwise, the two groups were similar in age, sex, programmed death-ligand 1 expression, and type of previous chemotherapy regimen. Patients in the ERBB2/EGFR cohort had a significantly shorter disease-free survival compared with the EGFR or ERBB2 wild-type cohort (7.5 mo versus not reached, p = 0.04). ConclusionsConsolidation durvalumab seems to be less efficacious in patients with ERBB2/EGFR-mutant tumors. Future work should seek to evaluate this in the prospective setting and provide insight into the optimal treatment of ERBB2/EGFR-mutant stage III NSCLC.

Long-term follow-up after acute achilles tendon rupture — Does treatment strategy influence functional outcomes?

BackgroundPatients struggle to fully recover after an Achilles tendon rupture. Although several studies has investigated surgical and non-surgical treatment, the best treatment is still uncertain. The aim of this study was to investigate long-term patient-reported outcomes and objective measures 4 years after acute Achilles tendon rupture and compare whether outcomes differed between patients treated on basis of the previous regimen preferring surgical treatment and the new regimen preferring functional rehabilitation. MethodsAchilles tendon Total Rupture Score (ATRS), number of re-ruptures and the objective measures; Achilles tendon resting angle, calf circumference, heel-rise height, and muscle endurance were measured at a 4-year follow-up. Patients were recruited from Aalborg University Hospital. ResultsSeventy-six patients were included (29% female). The mean ATRS was 71.4 (95% CI: 65.8 to 77.1) at 4 years follow-up. No difference in ATRS was observed between Previous regimen and New regimen at any timepoint (time x group interaction, (p=0.851). The injured side was still significantly impaired compared with the non-injured side in terms of all objective measures. Impairments in objective measures were not dependent on the preferred treatment strategy. ConclusionsPatient reported impairments and objective functional deficits persist 4 years after an acute Achilles tendon rupture. No differences in patient reported outcome or objective measures at the 4 years follow-up was observed between the old treatment regimen preferring surgery compared with the new treatment regimen preferring functional rehabilitation.

Effectiveness and Safety of Clofarabine Monotherapy or Combination Treatment in Relapsed/Refractory Childhood Acute Lymphoblastic Leukemia: A Pragmatic, Non-interventional Study in Korea.

PurposeEffectiveness and safety of clofarabine (one of the treatment mainstays in pediatric patients with relapsed/refractory acute lymphoblastic leukemia [ALL]) was assessed in Korean pediatric patients with ALL to facilitate conditional coverage with evidence development.Materials and MethodsIn this multicenter, prospective, observational study, patients receiving clofarabine as mono/combination therapy were followed up every 4–6 weeks for 6 months or until hematopoietic stem cell transplantation (HSCT). Response rates, survival outcomes, and adverse events were assessed.ResultsSixty patients (2–26 years old; 65% B-cell ALL, received prior ≥ 2 regimen, 68.3% refractory to previous regimen) were enrolled and treated with at least one dose of clofarabine; of whom 26 (43.3%) completed 6 months of follow-up after the last dose of clofarabine. Fifty-eight patients (96.7%) received clofarabine combination therapy. Overall remission rate (complete remission [CR] or CR without platelet recovery [CRp]) was 45.0% (27/60; 95% confidence interval [CI], 32.4 to 57.6) and the overall response rate (CR, CRp, or partial remission [PR]) was 46.7% (28/60; 95% CI, 34.0 to 59.3), with 11 (18.3%), 16 (26.7%), and one (1.7%) patients achieving CR, CRp, and PR, respectively. The median time to remission was 5.1 weeks (95% CI, 4.7 to 6.1). Median duration of remission was 16.6 weeks (range, 2.0 to 167.6 weeks). Sixteen patients (26.7%) proceeded to HSCT. There were 24 deaths; 14 due to treatment-emergent adverse events.ConclusionRemission with clofarabine was observed in approximately half of the study patients who had overall expected safety profile; however, there was no favorable long-term survival outcome in this study.

A retrospective evaluation of the efficacy of midazolam and ketamine as premedication for paediatric patients undergoing elective surgery

Background: Preoperative anxiety is common in paediatric patients and is associated with negative postoperative outcomes. Sedative premedication may alleviate some of this anxiety. A new sedation protocol using midazolam and ketamine in combination was instituted at our tertiary hospital. We aimed to evaluate the efficacy and the side effect profile of this regimen. Methods: We conducted a retrospective review of paediatric surgical patients who received oral midazolam (0.25 mg/kg) together with ketamine (3 mg/kg) as premedication, prior to induction of anaesthesia for elective surgery. The Watcha scale was used to assess preoperative and postoperative behaviour. Premedication efficacy was assessed using the Wilson sedation scale together with the 4-point anxiety scale. We further compared the incidence of significant preoperative anxiety with the incidence from a previous study. Results: We included 146 patients in our study. There was optimal sedation (Wilson sedation score = 1/2) in 47.9% of the patients (CI 39.9–56.1) with failed sedation (Wilson sedation score = 0) in 34.9% (CI 27.6–43.1) and over-sedation (Wilson sedation score = 3/4) in 17.1% (CI 11.8–24.2) of the patients. Optimal anxiolysis (4-point anxiety scale = 1) was achieved in 76.0% of the patients (CI 68.4–82.3). Failed anxiolysis (4-point anxiety scale = 2/3/4) occurred in 23.3% of the patients (CI 17.7–31.6). The majority of patients had no side effects (79.5%; CI 72.1–85.3). For those who experienced side effects, the most common was hypersalivation (12.3%; CI 7.9–18.8). The incidence of postoperative delirium was 3.4% (CI 1.4–8.0) and there was significantly less anxiety compared to our previous regimen (5.5%; CI 2.7–10.6 versus 13.5%; p = 0.007). Conclusion: The combination of midazolam and ketamine appears effective in providing safe sedation and reducing preoperative anxiety. Side effects occurred in up to a fifth of patients; predominantly hypersalivation. The combination of midazolam and ketamine for premedication should be considered for ASA I–II patients without contraindications undergoing elective surgery.

Cluster Analysis of Clozapine Consumer Perspectives and Comparison to Consumers on Other Antipsychotics.

Despite its unique efficacy, clozapine remains underutilized in the United States. Perceptions about clozapine and barriers to its use have been examined among prescribers, but insufficiently studied among consumers. We surveyed 211 antipsychotic consumers (86 on clozapine and 125 on other antipsychotics) on their medication-related perspectives in a public hospital system in Atlanta, Georgia, USA. In contrast to their previous regimen, 72% of clozapine consumers reported they were more satisfied with clozapine. When compared with consumers taking other antipsychotics, clozapine consumers reported more side effects but did not differ on other measures of satisfaction or efficacy. We found Caucasians to be overrepresented among clozapine, as compared to other antipsychotic consumers. Side effects most strongly associated with poor safety ratings were sedation, limb jerking, and dizziness when standing. However, clozapine was only rated less safe by consumers who experienced more than one of these side effects. We used an unsupervised clustering approach to identify three major groups of clozapine consumers. Cluster A (19%) had the lowest safety ratings, aversion to blood work, and a high rate of side effects that associate with lower safety ratings. Cluster B (25%) experienced more hospitalizations and reported satisfaction with clozapine that correlated with efficacy ratings, irrespective of safety ratings. Cluster C (56%) experienced fewer hospitalizations, fewer previous drug trials, greater educational attainment, lower rates of smoking, and rated clozapine more highly. This work identifies common side effects that influence the subjective safety of clozapine and suggests that attitudes toward clozapine depend on context-specific factors.

Rabies post-exposure prophylaxis in Germany − What are the challenges?

Rabies post-exposure prophylaxis (R-PEP) including wound treatment, vaccination and application of rabies immunoglobulin (RIG) is essential in preventing rabies mortality. Today, Germany is officially declared free from terrestrial rabies and rabies is only found in bats. However, physicians in A&E Departments are frequently consulted on the need for R-PEP. We retrospectively analysed patients who received R-PEP at the A&E Department of the University Hospital Bonn between 01.01.2013 and 30.06.2019. Demographic data, travel history, clinical and laboratory findings, previous rabies vaccinations and R-PEP vaccination regimen were recorded. During the study period, 90 patients received R-PEP at the University Hospital Bonn, in 10 cases without indication for R-PEP. Altogether, we found deviations from R-PEP guidelines in 51% (n = 41/80). Infiltration of RIG was missed in 12 patients and incorrectly administrated in 24 patients. Furthermore, vaccination scheme was incorrect in 11 patients. Correct wound washing and documentation of tetanus status was missing in 14% and 63% of patients, respectively. Despite rabies elimination in Germany patients frequently seek advice for R-PEP, the majority returning from foreign travel. Our data show that there is a high need for education on indication for R-PEP before and after travel and for implementation of precise R-PEP guidelines in daily clinical practice.