Major Clinical Response Research Articles

Rituximab Therapy for Adult Refractory Systemic Lupus Erythematosus with Neurological and/or Psychiatric Presentations: A PRISMACompliant Meta-Analysis

Rituximab (RTX) is used off-label for refractory cases of systemic lupus erythematosus (SLE) with extrarenal activity, including neurological and/or psychiatric (N/P) presentations. However, evidence from randomized controlled trials is limited. This study aimed to conduct a pooled analysis of the effectiveness and safety of RTX therapy for adult refractory SLE with N/P manifestations. Electronic searches in PubMed, Epistemonikos, and ICTRP databases and statistical analysis were conducted in May 2023. Electronic searches identified 20 studies (25 reports). A total of 59 patients (53 females; 90%) were included, with a mean age of 33.5±10.6 years and a median disease duration of 3.5 years (range, 0.08 to 25.0) who were followed up post-RTX therapy for a median time of 12 months (range, 3.0 to 46.2). The rate of clinical response (partial or major) was 90% (95% CI, 83 to 96) (n = 57 patients). A third of responders relapsed after a median time of 9.5 months (range, 3.0 to 33.0). Pooled pre-RTX/post-RTX scores for Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (n = 13) were 19±15/7±5 and for neurological British Isles Lupus Assessment Group (BILAG) (n = 29) were A/D (13), A/C (5), B/D (7), B/C (2), and A/A (2). Patients without mood disorder had a higher chance of clinical response {relative risk (RR) 1.4 (1.03 to 1.48)}. Patients who benefited the most from RTX therapy were those with psychosis (a higher chance of major clinical response; RR 1.9 (1.02 to 2.34)), without acute confusional state (a lower chance of relapse; RR 0.08 (0.006 to 0.791)), and with disease duration <3 years (a lower chance of relapse; RR 0.18 (0.014 to 0.992)). Infection rate during treatment was 33% (7/21). RTX therapy had good effectiveness. The pooled evidence for safety outcomes was limited and of low certainty.

Evaluation of the Efficacy and Safety of Anifrolumab in Moderate-to-Severe Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease, which poses significant challenges due to its chronic nature and complex clinical manifestations.For patients with moderate-to-severe SLE, anifrolumab, a monoclonal antibody that targets the type 1 interferon receptor (IFNAR), has emerged as a cutting-edge treatment option that can reduce disease activity, prevent organ damage from the illness or side effects resulting from medications, and enhance the quality of life for those living with SLE. Consequently, this drug has received approval from major regulatory agencies. Anifrolumab's safety, effectiveness, and long-term results are assessed in this systematic review using information from clinical trials, real-world research, and retrospective analysis. In particular, clinical investigations, such as the MUSE Phase II and TULIP Phase III trials, showed that anifrolumab significantly improved important outcomescompared to placebo, including the SLE Responder Index, major clinical response, and disease activity ratings. During extended use, anifrolumab demonstrated significant sustained efficacy and a tolerable safety profile, with controllable side events mostly associated with viral infections. Moreover, subgroup analyses, demonstrating that Asian patients and individuals with a strong interferon gene profile are particularly responsive to anifrolumab, underscore the importance of customized treatment methods. Anifrolumab's safety and effectiveness were further validated by real-world data, particularly in patients who reached the Lupus Low Disease Activity State (LLDAS), where the drug decreased glucocorticoid consumption and disease activity. Overall, anifrolumab shows great promise as a treatment for moderate-to-severe SLE, providing significant efficacy together with a manageable safety profile. To fully explore its therapeutic potential and optimize therapy approaches for the management of SLE, further research is necessary, especially in lupus nephritis and other disease subsets.

Rectal Sparing Approach after preoperative Radio- and/or Chemo-therapy (ReSARCh): a prospective, multicenter, observational study.

Rectal-sparing approaches for patients with rectal cancer who achieved a complete or major response following neoadjuvant therapy constitute a paradigm of a potential shift in the management of patients with rectal cancer; however, their role remains controversial. The aim of this study was to investigate the feasibility of rectal-sparing approaches to preserve the rectum without impairing the outcomes. This prospective, multicenter, observational study investigated the outcomes of patients with clinical stage II-III mid-low rectal adenocarcinoma treated with any neoadjuvant therapy, and either transanal local excision or watch-and-wait approach, based on tumor response (major or complete) and patient/surgeon choice. The primary endpoint of the study was rectum preservation at a minimum follow-up of 2 years. Secondary endpoints were overall, disease-free, local and distant recurrence-free, and stoma-free survival at 3 years. Of the 178 patients enrolled in 16 centers, 112 (62.9%) were managed with local excision and 66 (37.1%) with watch-and-wait. At a median (interquartile range) follow-up of 36.1 (30.6-45.6) months, the rectum was preserved in 144 (80.9%) patients. The 3-year rectum-sparing, overall survival, disease-free survival, local recurrence-free survival, and distant recurrence-free survival was 80.6% (95% CI 73.9-85.8), 97.6% (95% CI 93.6-99.1), 90.0% (95% CI 84.3-93.7), 94.7% (95% CI 90.1-97.2), and 94.6% (95% CI 89.9-97.2), respectively. The 3-year stoma-free survival was 95.0% (95% CI 89.5-97.6). The 3-year regrowth-free survival in the watch-and-wait group was 71.8% (95% CI 59.9-81.2). In rectal cancer patients with major or complete clinical response after neoadjuvant therapy, the rectum can be preserved in about 80% of cases, without compromising the outcomes.

CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-up

BackgroundTreatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission.MethodsWe evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology–European League against Rheumatism (ACR–EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded.ResultsThe median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR–EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell–associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization.ConclusionsIn this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.)

Predictors of British Isles Lupus Assessment Group-based outcomes in patients with systemic lupus erythematosus: Analysis from the Systemic Lupus International Collaborating Clinics Inception Cohort.

We aimed to identify factors associated with a significant reduction in SLE disease activity over 12months assessed by the BILAG Index. In an international SLE cohort, we studied patients from their 'inception enrolment' visit. We also defined an 'active disease' cohort of patients who had active disease similar to that needed for enrolment into clinical trials. Outcomes at 12months were; Major Clinical Response (MCR: reduction to classic BILAG C in all domains, steroid dose of ≤7.5mg and SLEDAI ≤ 4) and 'Improvement' (reduction to ≤1B score in previously active organs; no new BILAG A/B; stable or reduced steroid dose; no increase in SLEDAI). Univariate and multivariate logistic regression with Least Absolute Shrinkage and Selection Operator (LASSO) and cross-validation in randomly split samples were used to build prediction models. 'Inception enrolment' (n = 1492) and 'active disease' (n = 924) patients were studied. Models for MCR performed well (ROC AUC = .777 and .732 in the inception enrolment and active disease cohorts, respectively). Models for Improvement performed poorly (ROC AUC = .574 in the active disease cohort). MCR in both cohorts was associated with anti-malarial use and inversely associated with active disease at baseline (BILAG or SLEDAI) scores, BILAG haematological A/B scores, higher steroid dose and immunosuppressive use. Baseline predictors of response in SLE can help identify patients in clinic who are less likely to respond to standard therapy. They are also important as stratification factors when designing clinical trials in order to better standardize overall usual care response rates.

Nasal airway microRNA profiling of infants with severe bronchiolitis and risk of childhood asthma: A multicenter prospective study.

Severe bronchiolitis (i.e., bronchiolitis requiring hospitalization) during infancy is a major risk factor for childhood asthma. However, the exact mechanism linking these common conditions remains unclear. We examined the longitudinal relationship between nasal airway miRNAs during severe bronchiolitis and the risk of developing asthma. In a 17-center prospective cohort study of infants with severe bronchiolitis, we sequenced their nasal miRNA at hospitalization. First, we identified differentially expressed miRNAs (DEmiRNAs) associated with the risk of developing asthma by age 6 years. Second, we characterized the DEmiRNAs based on their association with asthma-related clinical features, and expression level by tissue and cell types. Third, we conducted pathway and network analyses by integrating DEmiRNAs and their mRNA targets. Finally, we investigated the association of DEmiRNAs and nasal cytokines. In 575 infants (median age=3 months), we identified 23 DEmiRNAs associated with asthma development (e.g., hsa-miR-29a-3p, FDR<0.10), particularly in infants with respiratory syncytial virus infection (FDRinteraction<0.05). These DEmiRNAs were associated with 16 asthma-related clinical features (FDR<0.05)-e.g., infant eczema and corticosteroid use during hospitalization. These DEmiRNAs were also highly expressed in lung tissue and immune cells (e.g., TH cells, neutrophils). Third, DEmiRNAs were negatively correlated with their mRNA targets (e.g., hsa-miR-324-3p/IL13), which were enriched in asthma-related pathways (FDR<0.05)-e.g., toll-like receptor, PI3K-Akt, and FcɛR signaling pathways, and validated by cytokine data. In a multicenter cohort of infants with severe bronchiolitis, we identified nasal miRNAs during illness that were associated with major asthma-related clinical features, immune response, and risk of asthma development.

Immunotherapy for localized dMMR/MSI tumors: First interim analysis of the IMHOTEP trial.

2591 Background: Immune checkpoint inhibitors (ICI) have demonstrated their efficacy in advanced dMMR/MSI (deficient mismatch repair/microsatellite instability) tumors and increasing data are also accumulating in localized resectable stages with about 60% of pathological complete response rate. The goal of the IMHOTEP trial is to assess the safety and efficacy of peri-operative pembrolizumab in localized dMMR/MSI tumors independently of their anatomical origin. Methods: IMHOTEP is a prospective, multicenter, phase II study aimed to include 120 patients (pts) with localized resectable dMMR/MSI tumors, eligible for curative surgery. Pembrolizumab 400 mg flat dose is administered as a perioperative treatment with 1 or 2 doses every 6 weeks before surgery and thereafter every 6 weeks for one year. Primary objective is to evaluate the pathological complete response (pCR) rate defined as ypT0N0 stage. Secondary objectives are to assess major pathological response, centralized pathological review, safety, clinical response rate, recurrence-free survival and overall survival. Here, we present the interim analysis of safety and pathologic response data for the first 70 treated pts. Results: Median age was 67.5 years (26-89), 54.3% were males, and 42.0% were ECOG-PS 0. Surgery was performed in 54/70 pts including 27/35 colorectal (CRC), 16/21 oesogastric (OGC), 4/5 endometrial (EC) and 7/9 other (6 small intestine, 1 bile duct) (OC) cancers. 16 pts (22.9%) were not operated, mainly due to patient’s decision following complete clinical response (n=7). Only one patient was not submitted to surgery because of disease progression. Focusing on the 54 operated pts, 31 and 23 pts received 1 and 2 neoadjuvant pembrolizumab doses respectively. The pCR rate was 38.9% (40.7%, 25.0%, 0.0% and 85.7% in CRC, OGC, EC and OC respectively). Grade 3-4 immune-related adverse events were observed in 4 (5.7%) patients including transaminases increase (n=1), arthritis (n=1), acute kidney injury (n=1) and pneumonitis (n=1). Conclusions: In this IMHOTEP interim analysis, we observed a limited complete pathologic response rate to short-course neoadjuvant pembrolizumab. If we add patients in clinical complete response who chose not to be operated to those with pCR, our results compare with those previously reported. But we can also hypothesize that preoperative treatment duration should be prolonged to obtain more pCR. Overall, tolerance of pembrolizumab was acceptable without new safety signal. Centralized pathological review, major pathological response evaluation and clinical response rate analysis are ongoing. IMHOTEP trial has been registered (first post: March 12th, 2021). Clinical trial information: NCT04795661 .

OA25 Identification of biomarkers to stratify response to combination therapy with belimumab and rituximab in a randomized trial, BEAT-LUPUS for systemic lupus erythematosus

Abstract Background/Aims The BEAT-lupus double-blind randomised trial demonstrated that belimumab (anti-BAFF antibody) reduced the number of severe-flares (compared to placebo) after B-cell depletion (rituximab) in patients with systemic lupus erythematosus (SLE)(1). We longitudinally immune profiled patients recruited to the trial to identify which patients would benefit most from belimumab after rituximab combination therapy. Methods We constructed two models (because the number of patients who provided serum/blood RNA samples and peripheral blood mononuclear cells differed) using baseline data to predict a major clinical response (MCR)(2) to belimumab after rituximab at 52-weeks utilising conventional and machine learning approaches: A) Model 1: serum autoantibodies and cytokines, peripheral blood RNA expression, clinical data, and routinely collected laboratory-markers (10 responders, 11 non-responders). B) Model 2: B-cell flow-cytometry (8 responders, 8 non-responders). The emerging key variables were then used as effect modifiers comparing response to belimumab and placebo after rituximab. Results Baseline serum IgA2 anti-dsDNA antibody levels emerged from model 1 as the key predictor of MCR with an AUROC (area under the curve of the receiver operator characteristic) of 0.81 (95% CI: 0.70-0.96) in predicting an MCR by 52-weeks in the belimumab arm. An optimal cut point of serum IgA2 anti-dsDNA antibody (10.7 AU/arbitrary unit), derived from AUROC, was applied as an effect modifier which improved the delta between response to belimumab vs placebo from 13% (without the effect modifier) to 48% (95% CI: 10-70; p = 0.021) (Belimumab - 64% [9 responders, 5 non-responders], placebo - 16% [2 responders, 10 non-responders]). Belimumab significantly reduced serum IgA2 anti-dsDNA antibody levels compared to placebo at 52-weeks (difference: 20 AU; 95% CI: 13-27; p &amp;lt; 0.001) only in those patients who achieved an MCR, falling by 60% from baseline (difference: 23 AU; 95% CI: 11-35; p &amp;lt; 0.001, compared to non-response). Prediction model 2 identified the frequency of T-bet+CD11c+DNM-2 (double negative memory B-cell, type-2: CD11c+T-bet+CD38-CD27-IgD-CD21-CD24-) as the strongest predictor of MCR by 52-weeks in the belimumab arm with an AUROC of 1.00 (95% CI: 1.00-1.00). Using T-bet+CD11c+DNM-2 as an effect modifier (optimal cut point: 14.2% of total B-cells) the delta improved from 13% to 71% (95% CI: 23-92; p = 0.007) (Belimumab - 100% [8 responders, 0 non-responders], placebo - 29% [2 responders, 5 non-responders]). The frequency of T-bet+CD11c+DNM-2 was significantly lower in the belimumab arm at 52-weeks compared to placebo (difference: 6%; 95% CI: 3-11; p = 0.001), and dropped by 48% from baseline in belimumab responders (difference with non-responders: 11%; 95% CI: 6-15; p &amp;lt; 0.001). Conclusion High baseline serum IgA2 anti-dsDNA antibody and peripheral blood T-bet+CD11c+DNM-2 B-cell frequency could guide patient selection for belimumab after rituximab combination therapy thereby improving outcomes and access to targeted therapies for patients with SLE. Exploration of the underlying mechanisms and confirmation of these results including combining the two prediction models in a larger clinical trial are required. Reference 1. Shipa M, et al. Annals of Internal Medicine. 2021;174:1647-57. 2. McDonald S, et al. Lupus Sci Med. 2022;9:e000584. Disclosure M. Shipa: Grants/research support; Versus arthritis, LUPUS-UK. M. Parvaz: None. D. Nguyen: None. L. Santos: None. D.A. Isenberg: Consultancies; Astra Zeneca, Eli Lilly, Merck Serono, Servier and UCB. C. Gordon: Consultancies; Center for Disease Control and Prevention, AbbVie, Amgen, Astra-Zeneca, EMD Serono, MGP, Sanofi and UCB. M.R. Ehrenstein: Consultancies; GSK. Grants/research support; Versus arthritis.

Identification of biomarkers to stratify response to B-cell-targeted therapies in systemic lupus erythematosus: an exploratory analysis of a randomised controlled trial.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with widespread immune dysregulation and diverse clinical features. Immune abnormalities might be differentially associated with specific organ involvement or response to targeted therapies. We aimed to identify biomarkers of response to belimumab after rituximab to facilitate a personalised approach to therapy. In this exploratory analysis of a randomised controlled trial (BEAT-LUPUS), we investigated immune profiles of patients with SLE recruited to the 52-week clinical trial, which tested the combination of rituximab plus belimumab versus rituximab plus placebo. We used machine learning and conventional statistics to investigate relevant laboratory and clinical biomarkers associated with major clinical response. BEAT LUPUS is registered at ISRCTN, 47873003, and is now complete. Between Feb 2, 2017, and March 28, 2019, 52 patients were recruited to BEAT-LUPUS, of whom 44 provided clinical data at week 52 and were included in this analysis. 21 (48%) of 44 participants were in the belimumab group (mean age 39·5 years [SD 12·1]; 17 [81%] were female, four [19%] were male, 13 [62%] were White) and 23 (52%) were in the placebo group (mean age 42·1 years [SD 10·5]; 21 [91%] were female, two [9%] were male, 16 [70%] were White). Ten (48%) of 21 participants who received belimumab after rituximab and eight (35%) of 23 who received placebo after rituximab had a major clinical response at 52 weeks (between-group difference of 13% [95% CI -15 to 38]). We found a predictive association between baseline serum IgA2 anti-double stranded DNA (dsDNA) antibody concentrations and clinical response to belimumab after rituximab, with a between-group difference in major clinical response of 48% (95% CI 10 to 70) in patients with elevated baseline serum IgA2 anti-dsDNA antibody concentrations. Moreover, among those who had a major clinical response, serum IgA2 anti-dsDNA antibody concentrations significantly decreased from baseline only in the belimumab group. Increased circulating IgA2 (but not total) plasmablast numbers, and T follicular helper cell numbers predicted clinical response and were both reduced only in patients who responded to belimumab after rituximab. Serum IgA2 anti-dsDNA antibody concentrations were also associated with active renal disease, whereas serum IgA1 anti-dsDNA antibody and IFN-α concentrations were associated with mucocutaneous disease activity but did not predict response to B-cell targeted therapy. Patients with a high baseline serum interleukin-6 concentration were less likely to have a major clinical response, irrespective of therapy. This exploratory study revealed the presence of distinct molecular networks associated with renal and mucocutaneous involvement, and response to B-cell-targeted therapies, which, if confirmed, could guide precision targeting of advanced therapies for this heterogenous disease. Versus Arthritis, UCLH Biomedical Research Centre, LUPUS UK, and GSK.

Successful Treatment with &amp;lt;sup&amp;gt;177&amp;lt;/sup&amp;gt;Lutetium-Dotatate and Maintenance Octreotide in a Patient with Esthesioneuroblastoma with Central Nervous System Invasion: Case Report and Review of the Literature

This article presents a case of a patient with relapsed esthesioneuroblastoma (ENB), an aggressive rare tumor that arises from the specialized sensory epithelial olfactory cells in the skull base area, which was initially treated with endoscopic surgery, followed by adjuvant radiotherapy. After local relapse, new surgical approaches and subsequent lines of platin-based chemotherapy were performed. A PET-CT with 68GALIUM DOTATATOC (PET-DOTATOC) showed intense uptake of disease, compatible with the presence of somatostatin receptors, in the face, nodes, liver, bones, and meningeal area. Treatment with 4 cycles of 177Lutetium-Dotatate was performed, followed by maintenance octreotide, with a major radiological and clinical response that is lasting more than 1 year after treatment. This article describes a rare case of a skull-base tumor, with multiple recurrences, in which disease control was achieved with a targeted Peptide Receptor Radionuclide Therapy (PRRT) with 177Lutetium-Dotatate, and discusses factors that could influence the incorporation of this form of therapy. Previous case reports proved the potential efficacy of this therapy usually given for low-grade neuroendocrine tumors and will be carefully reviewed.

Comprehensive genetic and functional analyses of Fc gamma receptors influence on response to rituximab therapy for autoimmunity.

Rituximab is widely used to treat autoimmunity but clinical response varies. Efficacy is determined by the efficiency of B-cell depletion, which may depend on various Fc gamma receptor (FcγR)-dependent mechanisms. Study of FcγR is challenging due to the complexity of the FCGR genetic locus. We sought to assess the effect of FCGR variants on clinical response, B-cell depletion and NK-cell-mediated killing in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). A longitudinal cohort study was conducted in 835 patients [RA=573; SLE=262]. Clinical outcome measures were two-component disease activity score in 28-joints (2C-DAS28CRP) for RA and British Isles Lupus Assessment Group (BILAG)-2004 major clinical response (MCR) for SLE at 6 months. B-cells were evaluated by highly-sensitive flow cytometry. Single nucleotide polymorphism and copy number variation for genes encoding five FcγRs were measured using multiplex ligation-dependent probe amplification. Exvivo studies assessed NK-cell antibody-dependent cellular cytotoxicity (ADCC) and FcγR expression. In RA, carriage of FCGR3A-158V and increased FCGR3A-158V copies were associated with greater 2C-DAS28CRP response (adjusted for baseline 2C-DAS28CRP). In SLE, MCR was associated with increased FCGR3A-158V, OR 1.64 (95% CI 1.12-2.41) and FCGR2C-ORF OR 1.93 (95% CI 1.09-3.40) copies. 236/413 (57%) patients with B-cell data achieved complete depletion. Homozygosity for FCGR3A-158V and increased FCGR3A-158V copies were associated with complete depletion in combined analyses. FCGR3A genotype was associated with rituximab-induced ADCC, and increased NK-cell FcγRIIIa expression was associated with improved clinical response and depletion invivo. Furthermore, disease status and concomitant therapies impacted both NK-cell FcγRIIIa expression and ADCC. FcγRIIIa is the major low affinity FcγR associated with rituximab response. Increased copies of the FCGR3A-158V allele (higher affinity for IgG1), influences clinical and biological responses to rituximab in autoimmunity. Enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping may stratify patients for optimal treatment protocols. Medical Research Council, National Institute for Health and Care Research, Versus Arthritis.

Valuing Health Gain from Composite Response Endpoints for Multisystem Diseases

ObjectivesThis study aimed to demonstrate how to estimate the value of health gain after patients with a multisystem disease achieve a condition-specific composite response endpoint. MethodsData from patients treated in routine practice with an exemplar multisystem disease (systemic lupus erythematosus) were extracted from a national register (British Isles Lupus Assessment Group Biologics Register). Two bespoke composite response endpoints (Major Clinical Response and Improvement) were developed in advance of this study. Difference-in-differences regression compared health utility values (3-level version of EQ-5D; UK tariff) over 6 months for responders and nonresponders. Bootstrapped regression estimated the incremental quality-adjusted life-years (QALYs), probability of QALY gain after achieving the response criteria, and population monetary benefit of response. ResultsWithin the sample (n = 171), 18.2% achieved Major Clinical Response and 49.1% achieved Improvement at 6 months. Incremental health utility values were 0.0923 for Major Clinical Response and 0.0454 for Improvement. Expected incremental QALY gain at 6 months was 0.020 for Major Clinical Response and 0.012 for Improvement. Probability of QALY gain after achieving the response criteria was 77.6% for Major Clinical Response and 72.7% for Improvement. Population monetary benefit of response was £1 106 458 for Major Clinical Response and £649 134 for Improvement. ConclusionsBespoke composite response endpoints are becoming more common to measure treatment response for multisystem diseases in trials and observational studies. Health technology assessment agencies face a growing challenge to establish whether these endpoints correspond with improved health gain. Health utility values can generate this evidence to enhance the usefulness of composite response endpoints for health technology assessment, decision making, and economic evaluation.

Electrochemotherapy of Primary Colon Rectum Cancer and Local Recurrence: Case Report and Prospective Analysis

Purpose: Surgery, radiotherapy, and oncological treatment (chemotherapy and antineoplastic antibodies) are standard treatments of rectal cancer. ECT has shown its effectiveness and suitability in deep solid tumors conducted in both preclinical and clinical studies. We show here an update and preliminary results with locally advanced rectum cancer (LARC) treated with ECT. Methods: Two patients with major clinical response to restaging after neoadjuvant treatment for LARC were subjected to ECT 12 weeks after completing chemo-radiation therapy. One patient was subjected to ECT on a colorectal local recurrence formed after neoadjuvant treatment for LARC and surgery. Computed Tomography and Magnetic Resonance Imaging were used to assess ECT response. Results: The results showed stable disease in two of the three patients treated, while one patient achieved a complete response. The local control of disease is maintained in the patient follow-up. For each patient, a reduction in pain was observed and for the patient with local recurrence, a reduction in bleeding present before ECT was also achieved. Conclusion: Preliminary results showed that ECT is a safe and effective treatment in patients with a major clinical response or local recurrence after neoadjuvant therapy for LARC and allows a reduction in pain and bleeding with a consequent improvement to quality of life.

Predictors of treatment response in a lupus nephritis population: lessons from the Aspreva Lupus Management Study (ALMS) trial

ObjectivesTo identify predictors of overall lupus and lupus nephritis (LN) responses in patients with LN.MethodsData from the Aspreva Lupus Management Study (ALMS) trial cohort was used to identify baseline predictors...

OA13 Comprehensive genetic and functional analyses of Fc gamma receptors explain response to rituximab therapy for autoimmune rheumatic diseases

Abstract Background/Aims Rituximab is widely used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) but clinical response varies. Efficacy is determined by the efficiency of depletion, which may depend on a variety of Fc gamma receptor (FcγR)-dependent mechanisms. Previous research was limited by complexity of the FCGR locus, not integrating copy number variation with functional SNP, and small sample size. Here, we aimed to assess the effect of the full range of FcγRs variants on depletion, clinical response and functional effect on NK-cell-mediated killing in two rheumatic diseases with a view to personalised B-cell depleting therapies. Methods A prospective longitudinal study was conducted in 873 patients (RA = 611; SLE=262) from four cohorts (BSRBR-RA, BILAG-BR, Leeds RA and Leeds SLE Biologics). For RA, the outcome measures were 3C-DAS28CRP and 2C-DAS28CRP at 6 (+/-3) months post-rituximab (adjusted for baseline DAS28). For SLE, major clinical response (MCR) was defined as improvement of active BILAG-2004 domains to grade C/better at 6 months. B-cell depletion was evaluated by highly-sensitive flow cytometry. Qualitative and quantitative polymorphisms for five major FcγRs were measured using a commercial multiplex ligation-dependent probe amplification. Median NK cell FcγRIIIa expression (CD3-CD56+CD16+) and NK-cell degranulation (CD107a) in the presence of rituximab-coated Daudi/Raji B-cell lines were assessed using flow cytometry. Results In RA, for FCGR3A, carriage of V allele (coefficient -0.25 [SE 0.11]; p = 0.02) and increased copies of V allele (-0.20 [0.09]; p = 0.02) were associated with better 2C-DAS28 response. Irrespective of FCGR3A genotype, increased gene copies were associated with a better response. In SLE, 177/262 (67.6%) achieved BILAG response (MCR=34.4%; Partial=33.2%). MCR was associated with increased copies of FCGR3A-158V allele, OR 1.64 (95% CI 1.12-2.41) and FCGR2C-ORF allele 1.93 (1.09-3.40). Of patients with B-cells data in the combined cohort, 236/413 (57%) achieved complete depletion post-rituximab. Only homozygosity for V allele and higher copies of FCGR3A V allele were associated with increased odds of depletion. Patients with complete depletion had higher NK cell FcγRIIIa expression at rituximab initiation than those with incomplete depletion (p = 0.04) and this higher expression was associated with improved EULAR response in RA. Moreover, for FCGR3A, degranulation activity was increased in V allele carriers vs FF genotype in the combined cohort; p = 0.02. Conclusion FcγRIIIa is the major low affinity FcγR and increased copies of the FCGR3A-158V allele, encoding the allotype with a higher affinity for IgG1, was associated with clinical and biological responses to rituximab in two autoimmune diseases. This was supported by functional data on NK cell-mediated cytotoxicity. In SLE, increased copies of the FCGR2C-ORF allele was also associated with improved response. Our findings indicate that enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping could stratify patients for optimal treatment protocols. Disclosure M. Md Yusof: None. J. Robinson: None. V. Davies: None. D. Wild: None. M. Morgan: None. J. Taylor: None. Y. El-Sherbiny: None. D. Morris: None. L. Liu: None. A. Rawstron: None. M. Buch: None. D. Plant: None. H. Cordell: None. J. Isaacs: None. I. Bruce: None. P. Emery: Grants/research support; PE has received consultancy fees and funding for research from Roche within the last 3 years. A. Barton: None. T. Vyse: None. J. Barrett: None. E. Vital: Grants/research support; EMV has received consultancy fees and funding for research from Roche within the last 3 years. A. Morgan: None.

THUNDER 2: THeragnostic Utilities for Neoplastic DisEases of the Rectum by MRI guided radiotherapy

BackgroundNeoadjuvant chemoradiation therapy (nCRT) is the standard treatment modality in locally advanced rectal cancer (LARC). Since response to radiotherapy (RT) is dose dependent in rectal cancer, dose escalation may lead to higher complete response rates. The possibility to predict patients who will achieve complete response (CR) is fundamental. Recently, an early tumour regression index (ERI) was introduced to predict pathological CR (pCR) after nCRT in LARC patients.The primary endpoints will be the increase of CR rate and the evaluation of feasibility of delta radiomics-based predictive MRI guided Radiotherapy (MRgRT) model.MethodsPatients affected by LARC cT2-3, N0-2 or cT4 for anal sphincter involvement N0-2a, M0 without high risk features will be enrolled in the trial. Neoadjuvant CRT will be administered using MRgRT. The initial RT treatment will consist in delivering 55 Gy in 25 fractions on Gross Tumor Volume (GTV) plus the corresponding mesorectum and 45 Gy in 25 fractions on the drainage nodes. Chemotherapy with 5-fluoracil (5-FU) or oral capecitabine will be administered continuously.A 0.35 Tesla MRI will be acquired at simulation and every day during MRgRT. At fraction 10, ERI will be calculated: if ERI will be inferior than 13.1, the patient will continue the original treatment; if ERI will be higher than 13.1 the treatment plan will be reoptimized, intensifying the dose to the residual tumor at the 11th fraction to reach 60.1 Gy.At the end of nCRT instrumental examinations are to be performed in order to restage patients. In case of stable disease or progression, the patient will undergo surgery. In case of major or complete clinical response, conservative approaches may be chosen. Patients will be followed up to evaluate toxicity and quality of life.The number of cases to be enrolled will be 63: all the patients will be treated at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome.DiscussionThis clinical trial investigates the impact of RT dose escalation in poor responder LARC patients identified using ERI, with the aim of increasing the probability of CR and consequently an organ preservation benefit in this group of patients.Trial registrationClinicalTrials.gov Identifier: NCT04815694 (25/03/2021).

ASO Author Reflections: Rectal Preservation After Major or Complete Clinical Response to Neoadjuvant Therapy-The Safety of Integrated Approaches.

ASO Author Reflections: Rectal Preservation After Major or Complete Clinical Response to Neoadjuvant Therapy-The Safety of Integrated Approaches.

Rectal Sparing Approach After Neoadjuvant Therapy in Patients with Rectal Cancer: The Preliminary Results of the ReSARCh Trial.

Rectum-preservation for locally advanced rectal cancer has been proposed as an alternative to total mesorectal excision (TME) in patients with major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The purpose of this study was to report on the short-term outcomes of ReSARCh (Rectal Sparing Approach after preoperative Radio- and/or Chemotherapy) trial, which is a prospective, multicenter, observational trial that investigated the role of transanal local excision (LE) and watch-and-wait (WW) as integrated approaches after neoadjuvant therapy for rectal cancer. Patients with mid-low rectal cancer who achieved mCR or cCR after neoadjuvant therapy and were fit for major surgery were enrolled. Clinical response was evaluated at 8 and 12weeks after completion of chemoradiotherapy. Treatment approach, incidence, and reasons for subsequent TME were recorded. From 2016 to 2019, 160 patients were enrolled; mCR or cCR at 12weeks was achieved in 64 and 96 of patients, respectively. Overall, 98 patients were managed with LE and 62 with WW. In the LE group, Clavien-Dindo 3+ complications occurred in three patients. The rate of cCR increased from 8- to 12-week restaging. Thirty-three (94.3%) of 35 patients with cCR had ypT0-1 tumor. At a median 24months follow-up, a tumor regrowth was found in 15 (24.2%) patients undergoing WW. LE for patients achieving cCR or mCR is safe. A 12-week interval from chemoradiotherapy completion to LE is correlated with an increased cCR rate. The risk of ypT > is reduced when LE is performed after cCR.

Siremadlin (HDM201) Is Well Tolerated and Demonstrates Clinical Activity in Patients with Acute Myeloid Leukemia Who Have Relapsed after Allogeneic Stem Cell Transplantation: A Subset Analysis of Safety and Preliminary Efficacy

Siremadlin (HDM201) Is Well Tolerated and Demonstrates Clinical Activity in Patients with Acute Myeloid Leukemia Who Have Relapsed after Allogeneic Stem Cell Transplantation: A Subset Analysis of Safety and Preliminary Efficacy

Effectiveness and Safety of Physical Therapy Intervention in Adult Dermatomyositis: A Case Report and Review

BACKGROUND The evidence for positive effects of exercise is insufficient in dermatomyositis. This article aims to outline the effects of physical exercise with regard to structure (Disease activity, inflammation, metabolic milieu and muscle structure) as well as clinical outcome in terms of impairment, activity limitation, participation restriction according to the ICF; and QOL in an adult patient with dermatomyositis. CASE DESCRIPTION A 47-years old female diagnosed with definite DM since last 10 months was referred by a Rheumatologist for physical therapy intervention. INTERVENTION 12 weeks (Three days a week) of Physiotherapy (Moderate intensity, individualized, closely monitored) along with a structured home exercise program (Low intensity, 5 days - 6 days a week). OUTCOME MEASURES Assessment of muscular pain, muscle strength, endurance, balance, functional evaluation, and QOL along with serological investigations. RESULTS Effectiveness Patient continued to show meaningful and clinically significant improvement on standardized outcome measures: 1. A major clinical response (total improvement score of 77) on IMAC S core set measures. 2. Improvement across all domains of ICF viz. muscle strength; endurance; movement coordination; balance; aerobic endurance; confidence and performance in activities of daily living; participation in social activities. 3. Probable disease-modifying effect: Progressively tapering dose of prescribed corticosteroids medication and improvement in disease-specific biochemical markers. 4. Patient reported measures: Reduction in muscular pain, shortness of breath &amp; fatigue; and improvement in Healthrelated QOL. SAFETY (As evident clinically and from the investigations): 1. No adverse reaction to exercises or physical activity. 2. Remained in remission - stable disease activity. CONCLUSION Moderate intensity of physiotherapy intervention along with home exercise program is effective and safe in improving functional outcomes for dermatomyositis in a stable disease activity state. This case report enhances our understanding of the effects of physical exercise and may improve treatment and outcome in patients with dermatomyositis.