Suboptimal Responders Research Articles

Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized-trial.

Carvedilol is a non-selective β-blocker (NSBBs) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal-pressure (HVPG). However, 35%-45% of patients still have insufficient HVPG-decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal-hypertension and suboptimal response to traditional-NSBBs. Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v.propranolol. Suboptimal responders (HVPG-decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4-6-weeks, repeating HVPG-measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters. Of 184 eligible patients, 82 were randomized to carvedilol+simvastatin (N=41) or carvedilol+placebo (N=41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol+simvastatin (18.6±4-to-15.7±4mm Hg, p<0.001) and carvedilol+placebo (18.9±3-to-16.9±3mm Hg, p<0.001). The decrease was greater with carvedilol+simvastatin (2.97±2.5 vs. 2.05±1.6mm Hg, p=0.031). An HVPG-decrease ≥20% occurred in 37% versus 15% patients respectively (OR:3.37, 95% CI=1.15-9.85; p=0.021). With test-meal, HVPG increased in both groups (p<0.01), although carvedilol+simvastatin attenuated such increment (12±8% vs. 23±16%, p<0.001). Cytokine levels (IL-6,MCP-1,MDA) decreased significantly more with carvedilol+simvastatin (p<0.01). Incidence of adverse events was similar. In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal-pressure reduction achieved with carvedilol-monotherapy, improves endothelial dysfunction and reduces pro-inflammatory cytokines.

Correlation of T Regulatory Cells, Cytotoxic T-lymphocyte-associated Antigen 4, and Transforming Growth Factor-β1 with Treatment Response in Patients with Chronic Myeloid Leukemia Receiving Dasatinib Therapy.

Tyrosine kinase inhibitors improve chronic myeloid leukemia (CML) outcomes. Dasatinib inhibits breakpoint cluster region-Abelson 1 proto-oncogene tyrosine kinase better than imatinib in CML. T-regulatory cells prevent autoimmune diseases and aberrant immune responses by reducing oncoprotein antigen reactivity. They also reduce self-antigen-induced immune responses to maintain peripheral tolerance. In this study, T-regulatory cells in peripheral blood of chronic myeloid leukemia-chronic phase patients were measured, together with serum levels of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and transforming growth factor (TGF)-β1 at diagnosis and 3 months postdasatinib therapy. The Pathology and Clinical Haematology Departments at King George's Medical University, Lucknow, India, conducted this prospective analytical study. Forty CML-chronic patients and 10 healthy controls were analyzed. Flow cytometry was used to determine T-regulatory cell percentage in peripheral blood mononuclear cells of newly diagnosed CML patients before and after 3 months of dasatinib treatment; ELISA was used to measure serum levels of CTLA-4 and TGF-β1. T-regulatory cells, CTLA-4, and TGF-β1 significantly decreased in CML-chronic phase patients after 3 months of dasatinib therapy compared to the initial diagnosis. No significant change in T-regulatory cell, CTLA-4, or TGF-β1 percentages were seen between responders and poor responders. However, responders had a lower percentage of T-regulatory cells than suboptimal responders. The study concluded that dasatinib treatment improved response in CML patients with decreased Treg cells. Dasatinib reduces Treg-mediated immunological suppression, reducing CTLA-4 and TGF-β1 levels.

Effect of follicle-stimulating hormone dose on the risk of being classified as suboptimal responders according to the POSEIDON criteria.

The purpose of this study is to investigate the impact of daily follicle-stimulating-hormone (FSH) dose on the likelihood of suboptimal response to ovarian stimulation (OS) for in vitro fertilization (IVF) according to POSEIDON's criteria. A tri-center retrospective cohort study (2015-2017) including women with normal anti-Müllerian hormone (AMH ≥ 1.2ng/mL) and antral follicle count (AFC ≥ 5) values per POSEIDON's criteria, undergoing their first IVF/ICSI cycle using conventional OS (FSH ≥ 150IU/day). Suboptimal response was the retrieval of 4-9 oocytes. In previous research, we detected an AMH ≤ 2.97ng/mL and AFC ≤ 12 as the optimal cut-offs predicting suboptimal response. Therefore, we examined the effect of daily FSH dose (≤ 300IU versus > 300IU) on suboptimal response risk for each AMH and AFC value within these thresholds (AMH between 1.20 and 2.97ng/mL, by 0.01ng/mL increments; and an AFC between 5 and 12, by unit increments). Analysis involved contingency tables and multivariable logistic regression. Included were 4005 patients with AMH and AFC values in the specific range, among whom 2131 (53.2%) were suboptimal responders. Among 177 AMH groups analyzed, apart from three distributed irregularly, daily FSH doses > 300IU versus lower doses (≤ 300IU) did not decrease suboptimal response risk; similarly, higher doses did not decrease risk at the eight AFC values examined (p > 0.05 for all). Using multivariable logistic regression, FSH doses were not associated with suboptimal response risk. Conversely, female age, AMH, AFC, and gonadotropin type were associated with suboptimal response. In women with AMH values between 1.20 and 2.97ng/mL and/or AFC between 5 and 12, FSH dose increase did not decrease suboptimal response risk. Individualizing the gonadotropin regimen and considering LH activity supplementation to FSH may mitigate risks.

Impact of treat and extend criteria on proportions that can be extended after loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration: PRECISE Report 5.

To study the impact of definitions of various treatment extension criteria on the proportion of patients who could be extended at their first visit after the loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration (nAMD). Patients with nAMD initiated on the loading phase of three intravitreal doses of 2 mg aflibercept in routine clinical practice were recruited from December 2019 to August 2021. The response to the loading phase was assessed at approximately 8 weeks post-loading (up to 140 days from first injection) based on different definitions of response. The proportion of patients that qualify for interval extension based on different clinical trial criteria was also evaluated. A total of 722 patients with visual acuity (VA) and optical coherence tomography (OCT) scans done at all 4 visits were included. Of these 32.4% of eyes responded with complete macular fluid resolution after the first injection with no recurrence through the loading phase (super-responders) while 26.9% had persistent macular fluid in all 4 visits (true non-responders). The rest were considered suboptimal responders. Change in VA showed marked variations within each of these categories of fluid resolution. For extension of next treatment interval, if presence of any macular fluid at the post-loading visit is the only criteria considered, about 50% could be extended to 8 weeks. If both VA worsening by ≥5 letters and a > 25 μm increase in central sub-field thickness (CST)are considered, 90% will be eligible for interval extension. Clinical trial designs and pre-defined treatment extension/shortening criteria determine the proportion of patients requiring treatment in the post-loading visit. The short and long-term impact of interval extension immediate post-loading on visual outcome in clinical practice is unknown.

Vaginal Progesterone Gel versus Intramuscular Progesterone for Luteal Phase Support in Suboptimal Responders Undergoing Assisted Reproductive Cycles

Background: The purpose of this research is to compare the efficacy of 8% micronized vaginal progesterone gel (VAG) at 180 mg daily versus intramuscular progesterone (IMP) in oil at 100 mg daily for luteal phase support (LPS) after fresh single embryo transfer (SET) in Patient-Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) Group 1b patients, and to ascertain whether the type of LPS predicts live birth in these patients. Methods: A total of 2420 assisted reproductive technology (ART) cycles performed in Ondokuz Mayıs University IVF Unit were analysed retrospectively. The data of POSEIDON Group 1b (unexpected suboptimal responders) who underwent antagonist in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles were included. All patients were categorized into groups according to the form of LPS, specifically VAG and IMP. Pregnancy, clinical pregnancy rate (CPR), live birth rate (LBR), spontaneous abortion rate and predictors of live birth (age, infertility duration, body mass index (BMI), type of progesterone used for luteal support, serum day 3 estradiol, serum progesterone on the day of human coryonic gonadotrophin (HCG), total duration of induction, serum estradiol on the day of HCG, the total number of oocytes retrieved, number of mature oocytes obtained, average gonadotropin dose per day, total gonadotropin dose administered and total number of embryos retrieved) were analyzed. Results: There was no statistically significant difference between the micronized VAG and IMP groups in terms of age (31 (23–35) vs. 27 (23–35), p = 0.319). There were no statistically significant differences in pregnancy outcomes between the two groups concerning CPR per transfer (70.6% vs. 75.6%; p = 0.364), ongoing pregnancy per cycle (36.2% vs. 39.5%; p = 0.577), and LBR per cycle (34.4% vs. 36.1%; p = 0.785). The spontaneous abortion rates (36.2% vs. 36.8%; p = 0.921) were similar between VAG and IMP groups. The type of LPS did not emerge as a parameter predicting pregnancy (odds ratio (OR): 0.718, 95% confidence interval (95% CI): 0.652–1.313, p = 0.451), clinical pregnancy (OR: 0.598, 95% CI: 0.592–1.289, p = 0.562) and live birth (OR: 0.802, 95% CI: 0.661–1.202, p = 0.580). The logistic regression analysis aimed at assessing the influence of confounding factors, namely age, BMI, and duration of infertility on pregnancy rate, CPR and LBR, did not reveal statistically significant results (p &gt; 0.05). Conclusions: VAG 180 mg daily provide similar pregnancy outcomes compared to 100 mg daily IMP in POSEIDON Group 1b patients undergoing antagonist fresh IVF/ICSI cycles.

O-009 Comparison of the flexible Progestin-Primed Ovarian Stimulation with the GnRH antagonist protocol in predicted suboptimal responders: a freeze-all randomized controlled trial

Abstract Study question Is the Flexible Progestin-Primed Ovarian Stimulation (fPPOS) non-inferior to GnRH antagonist regarding fertility outcomes in women with a suboptimal response scheduled for freeze-all cycles? Summary answer In predicted suboptimal responders, who do not contemplate a fresh embryo transfer, the ongoing pregnancy outcomes of fPPOS was comparable to that of GnRH-antagonist protocol. What is known already Recent retrospective cohort studies involving donor cycles have demonstrated that Medroxyprogesterone Acetate (MPA) can be effectively and flexibly employed during the mid-follicular phase of the PPOS protocol. This approach prevents premature ovulation without compromising oocyte yields. Given its lesser degree of pituitary suppression, the fPPOS protocol may be particularly relevant for women predicted to have a suboptimal response (defined as AFC &amp;lt; 10) where accumulation of more oocytes could enhance cumulative success rates. Study design, size, duration This is a open-label RCT, performed in a single IVF centre Between July 2019 and June 2023. A total of 484 women scheduled for freeze-all strategy were randomly assigned to fPPOS or GnRH-antagonist protocol. The primary outcome was live birth per woman starting stimulation following18 months of randomization. In this abstract, we present fertility outcomes following the initial frozen embryo transfer (FET) and ongoing pregnancy rates per women within a period of 6 months. Participants/materials, setting, methods Women (AFC&amp;lt;10) referred for IVF/ICSI and did not intend to undergo a fresh transfer, were recruited for this study. MPA (10 mg/day) and Cetrotide (0.25 mg/day) were initiated either when the leading follicle reached 14 mm or on the sixth day of stimulation, whichever occurred first. Due to the COVID-19 pandemic, 22 women withdrew from the study at the stimulation commencement, resulting in 462 women included in the analysis. Data underwent intention-to-treat and per-protocol analyses. Main results and the role of chance No significant difference was observed between the two groups in terms of serum endocrine profiles and stimulation parameters, including the consumption of gonadotropins. Within the 6-month period, 79.5% of women in the fPPOS group and 84.02% in the GnRH antagonist group had undergone at least one cycle of FET (P = 0.234).The ongoing pregnancy rates per women were 48.20% (107/222) in the fPPOS group versus 52.92% (127/240) in the GnRH-anta group (RR: 0.91, 95%CI, 0.76 to 1.09, P = 0.311). There are 62 women who are ongoing pregnancy but do not reached live birth during the follow-up period. Regarding the outcomes of the initial FET cycle, there was no difference in the ongoing pregnancy rate between the two groups (49.01% vs 48.37%, RR: 1.03, 95% CI, 0.81 to 1.26, P = 0.908). Other outcomes including biochemical pregnancy rate (62.25% vs 63.59%), clinical pregnancy rate (60.26% vs 57.61%), and miscarriage rate per pregnancy (16.48% vs 15.09%), also exhibited no significant differences. The number of oocytes retrieved, two-pronuclear oocytes, viable and high-quality embryos, as well as the total number of embryos cryopreserved were also similar between groups. There was one case of premature ovulation in the fPPOS group and none in the GnRH-ant group. Limitations, reasons for caution Due to the distinct administration routes of the medications, blinding was not feasible in this open-label trial, which may affect the assessment of outcomes. All participants were recruited in a single center from one country, limiting the generalizability. In this abstract, we only report on the ongoing pregnancy outcomes. Wider implications of the findings This is the first freeze-all RCT comparing the long-term outcomes of fPPOS and GnRH antagonist in autologous ovarian stimulation cycles. Eliminating the variability of fresh and frozen transfers, the fPPOS seems an efficacious alternative for women with predicted suboptimal response, when a GnRH antagonist would have been the preferred regimen. Trial registration number ChiCTR2000030356

A two-years real-word study with fingolimod: early predictors of efficacy and an association between EBNA-1 IgG titers and multiple sclerosis progression.

Although fingolimod, a sphingosine 1-phosphate receptor agonist, has shown to be an effective treatment reducing relapse rate and also slowing down the disability progression in relapsing-remitting multiple sclerosis (RRMS) patients, it is important to quickly identify those suboptimal responders. The main objective was to assess different clinical, radiological, genetic and environmental factors as possible early predictors of response in MS patients treated with fingolimod for 24 months. The secondary objective was to analyze the possible contribution of the environmental factors analyzed to the progression and activity of the disease along the 2-years of follow-up. A retrospective study with 151 patients diagnosed with MS, under fingolimod treatment for 24 months, with serum samples at initiation and six months later, and with clinical and radiological data at initiation and 24 months later, were included in the study. Clinical and radiological variables were collected to establish NEDA-3 (no evidence of disease activity: patients without relapses, disability progression and new T2 lesions or Gd+ lesions) and EDA (evidence of disease activity: patients with relapses and/or progression and/or new T2 lesions or gadolinium-positive [Gd+] lesions) conditions. Human leukocyte antigen II (HLA-II), EBNA-1 IgG and VCA IgG from Epstein-Barr virus (EBV) and antibody titers against Human herpesvirus 6A/B (HHV-6A/B) were also analyzed. A total of 151 MS patients fulfilled the inclusion criteria: 27.8% was NEDA-3 (37.5% among those previously treated with high efficacy therapies >24 months). The following early predictors were statistically significantly associated with NEDA-3 condition: sex (male; p=0.002), age at baseline (older; p=0.009), relapses 2-years before fingolimod initiation ≤1 (p=0.010), and absence of Gd+ lesions at baseline (p=0.006). Regarding the possible contribution of the environmental factors included in the study to the activity or the progression of the disease, we only found that EBNA-1 IgG titers decreased in 20.0% of PIRA (progression independent from relapse activity) patients vs. 73.3% of RAW (relapse-associated worsening) patients (p=0.006; O.R. = 11.0). MS patients that are male, older, and with a low clinical and radiological activity at fingolimod initiation have a greater probability to reach NEDA-3 condition after two years with this therapy. An intriguing association of EBV with the progression of the disease has also been described, but it should be further study in a larger cohort to confirm these results.

Phase II study of neoadjuvant ipilimumab and nivolumab in combination with paclitaxel following anthracycline-based chemotherapy in patients with treatment resistant stage III triple negative breast cancer (TNBC): BCT1702—Survival results.

608 Background: We examined the efficacy and safety of neoadjuvant ipilimumab and nivolumab combined with paclitaxel following suboptimal response to anthracycline-based chemotherapy in patients with early-stage TNBC. Methods: This single arm phase 2 study enrolled 34 patients at 8 sites. Patients had stage 3 TNBC, after 4 cycles of anthracycline-based therapy, with ≥15mm of tumor remaining or ≥10mm of tumor with ≥1 positive lymph node. A suboptimal response at baseline was defined as &lt;50% reduction in tumor volume after anthracycline-based therapy. Patients received neoadjuvant ipilimumab 1mg/kg IV 6 weekly for 2 doses and nivolumab 240mg every 2 weeks for 6 doses, with weekly paclitaxel at 80mg/m2 for 12 weeks, followed by surgery. Nivolumab (480mg 4-weekly) continued post operatively for a further 9 months. Primary endpoint was pathological complete response (pCR: ypT0/is, ypN0) in breast and axilla, with secondary endpoints pCR in the suboptimal responders, pCR in PD-L1 positive (≥1% by SP142) or TIL% high (≥30%), event-free (EFS) and overall survival (OS). Results: Between December 2018 and April 2020, 34 patients were enrolled, 33 were evaluable for the primary endpoint. Median age was 46.6yrs. At diagnosis, 97% patients were clinical stage III, 24/34 (70.5%) were clinically node positive, 9/31 (27%) were PD-L1 positive and 6/30 (20%) were TILs% high. At study entry (after anthracycline-based chemo), the median tumor size by ultrasound was 28mm (12-62). The pCR rate was 24.2% (95% CI, 11.09-42.26) in all evaluable, 44.4% [4/9] in PD-L1+ and 9.5% [2/21] in PD-L1- patients. In suboptimal responders, the pCR rate was 25% (95% CI,8.6-49.1) (3/16). At a median follow up of 36.6 months, 9 patients have died. The KM estimates for EFS and OS at 12 months were 96.8% and 93.7%, at 24 months were 84.4% and 84.4% and at 36 months 61.2% and 71.9%, respectively. Patients who achieved a pCR had numerically better EFS (HR 3.61 (0.47-28.2, p=0.2) and OS (HR 2.6 (0.33-21.08); p=0.34). Patients with PD-L1+ tumors vs PD-L1- had a 3-year EFS of 100% vs 52% (p=0.01) and 100% vs 67% OS (p=0.05). Results were similarly favorable for TIL high vs low. Conclusions: The addition of ipilimumab and nivolumab to neoadjuvant chemotherapy resulted in 100% survival for high-risk patients with PD-L1+ and/or TIL% high tumors. Combination CTLA4 and PD-1 targeting agents should be further investigated in Stage 3 TNBC patients. Translational research is ongoing. Clinical trial information: ACTRN12617000651381. [Table: see text]

Development and validation of a prediction model for suboptimal ovarian response in polycystic ovary syndrome (PCOS) patients undergoing GnRH-antagonist protocol in IVF/ICSI cycles

BackgroundPCOS patients with unexpectedly low oocyte yield following conventional ovarian stimulation are referred to as suboptimal responders. However, identifying suboptimal responders presents a significant challenge within reproductive medicine and limited research exists on the occurrence of suboptimal response. This analysis aimed to develop a predictive model of suboptimal response during in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatments in PCOS patients.MethodsThis retrospective study involved a cohort of 313 PCOS patients undergoing their first IVF/ICSI cycle from 2019 to 2022. Univariate logistic regression analyses, least absolute shrinkage, selection operator regression analysis, and recursive feature elimination were employed to identify relevant characteristics and construct predictive models. Moreover, a nomogram was constructed based on the best model. Receiver operating characteristic curves, decision curve analysis (DCA), and calibration curves were used to evaluate the model.ResultsThe predictors included in the model were age, Anti-Mullerian hormone, antral follicle count, and basal follicle-stimulating hormone. The area under the receiver operating characteristic curve (AUC) was 0.7702 (95% confidence interval 0.7157–0.8191). The AUC, along with the DCA curve and calibration curve, demonstrated a satisfactory level of congruence and discrimination ability.ConclusionThe nomogram effectively predicted the probability of suboptimal response in PCOS patients undergoing gonadotropin-releasing hormone antagonist protocol during IVF/ICSI treatment.

A Multicentre, Randomized Trial in Adults with de novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia to Assess the Efficacy of Ponatinib versus Imatinib in Combination with Low-Intensity Chemotherapy, to Compare End of Therapy with Indication for Stem Cell Transplantation versus Tyrosine Kinase Inhibitor, Blinatumomab, and Chemotherapy in Optimal Responders, and to Evaluate Blinatumomab in Suboptimal Responders (GMALL-EVOLVE)

Introduction: Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL) is treated as standard of care (SoC) by imatinib-based treatment combined with induction and consolidation chemotherapy followed by allogeneic stem cell transplantation (SCT) in first remission. The German Multicenter ALL Study Group for Adult ALL (GMALL) reports about a trial to evaluate the impact of ponatinib-based therapy, blinatumomab treatment for suboptimal responders, and the possibility of omission of SoC Allo SCT in optimal responders entitled GMALL-EVOLVE. Methods: Herein, imatinib is randomized versus ponatinib as frontline treatment combined with chemotherapy, optimal responders also get randomized between SCT and chemo-immunotherapy, and suboptimal responders receive immunotherapy before SCT. The trial is registered under the EudraCT number 2022-000760-21. Conclusion: This trial will answer several major questions in the treatment of Ph+ALL.

Exposure-response relationship of guselkumab and the potential of serum proteomics in identifying predictive biomarker candidates in psoriasis.

Response to biologics in psoriasis varies in real-world settings. Serum biomarkers could aid biologic selection and dose modifications to improve patient outcomes while encouraging cost-effective care. To explore the exposure-response relationship for guselkumab (GUS), to define a GUS concentration target for optimal response and to evaluate the potential of serum protein levels as predictive biomarker candidates. This is a prospective, multicentric, cohort study in psoriasis patients treated with GUS. Serum GUS trough concentrations (TCs) collected at multiple timepoints were measured using an in-house immunoassay. Next, proximity extension assay technology (Target 96 Inflammation Panel Olink®) was used to measure serum protein levels in a subcohort including 38 GUS patients (week 0 and week 4), six psoriasis patients naive for systemic treatment and four healthy controls. Seventy-five patients participated and 400 samples were collected. Guselkumab TCs and clinical response were correlated at week 4, week 12 and in steady-state (≥20 weeks). Optimal responders (Psoriasis Area and Severity Index [PASI] ≤ 2) had significantly higher TCs than suboptimal responders from week 4 onwards in treatment. An optimal steady-state TC of 1.6 μg/mL was defined. Although TC and absolute PASI were lower and worse, respectively, in patients weighing ≥90 kg, clinical outcomes referred to desirable to excellent PASI ranges. Therefore, we do not recommend systematically higher GUS doses in obese patients. We could not reveal early differentially expressed proteins to distinguish future optimal from suboptimal responders. We demonstrated an exposure-response relationship for GUS and an optimal steady-state TC of 1.6 μg/mL in real-world psoriasis patients. Hereby, we deliver more evidence that therapeutic drug monitoring poses a promising strategy in optimizing GUS treatment. No biomarker candidates were identified through serum proteomics. We propose protein screening should be repeated in larger cohorts to continue the quest for predictive biomarkers.

Iraqi experts consensus on the management of relapsing remitting multiple sclerosis in adults

Objective In Iraq, a lack of evidence-based management protocols for diagnosing, treating, and managing multiple sclerosis (MS) poses risks of suboptimal outcomes and clinical practice variability and potential harm to the patients. This study aimed to develop consensus recommendations regarding the diagnosis and management of MS in Iraq, specifically focusing on treatment-naïve patients, suboptimal responders, and women of childbearing age during preconception, pregnancy planning, and lactation. Methods A survey was conducted to collect feedback from a panel of ten key opinion leaders (KOLs), who evaluated and discussed the statements to determine agreement levels. The mini-Delphi method was employed to establish a consensus on the management recommendations, and a meeting was held to analyze the responses and ensure that the recommendations were based on current evidence and followed a consensus-driven approach. Results The Revised McDonald Criteria is recommended for MS diagnosis, which includes evidence of dissemination of disease characteristics in space and time. Disease activity and progression can be monitored using relapses, MRI activity, and short-term disability progression. Experts suggest initiating treatment at diagnosis using higher efficacy medications, such as cladribine, ocrelizumab, natalizumab, or rituximab, for patients with high disease activity after careful risk stratification. Injectable interferon preparations have a tolerable risk profile but have drawbacks, such as the route and frequency of administration. Overall, disease-modifying therapies (DMTs) have shown efficacy in reducing relapse rates and short-term disability. Conclusion This article presents expert panel recommendations for managing MS in Iraq, taking into account international guidelines, medication updates, and local resources. However, practical questions remain regarding the real-world use of disease-modifying therapies (DMTs). Personalizing treatment based on disease severity, prognosis, and individual risk factors while adhering to guidelines is crucial. A collaborative approach between healthcare providers and patients, considering individual preferences, is vital for achieving treatment goals.

P053 Sub-optimal response to first biologic in axial spondyloarthritis: real world data showing clinician decisions in a tertiary centre

Abstract Background/Aims Up to 50% of patients respond inadequately to their first biologic treatment for axial spondyloarthritis (axSpA). Whilst NICE advises that if the BASDAI improves by ≤ 2 or ≤ 50% in 12 weeks the treatment should be discontinued, we were interested to assess the real-world application of this, and particularly how clinicians manage sub-optimal response: namely patients whose BASDAI decreases by two points but remains moderately raised above four. Methods We retrospectively assessed clinical records of axSpA patients attending the Royal National Hospital for Rheumatic Diseases, Bath who started a biologic for axSpA between 2016 and 2018. Based on their post-biologic BASDAI, patients were divided into excellent-, sub-optimal- (drop of ≥ 2 in the BASDAI but the score remained ≥4) and non-responders. Results 93 patients were included, of which 55% of patients were male with a mean age of 42 at the time of starting their first biologic. There was a 65:35 split in diagnosis between radiographic and non-radiographic axial spondyloarthritis. 50/93 (54%) patients had an excellent response. 31/93 (33%) patients were non-responders, with post-biologic BASDAI dropping &amp;lt;2 from baseline. Of the non-responders, 13/31 (42%) patients switched or stopped biologic due to primary inefficacy at the first review after an average of 6.4 months, while the remaining 18/31 (58%) patients were kept under review for another 6-12 weeks. 9/18 (50%) improved on average 8.1 months after baseline and met NICE criteria to continue treatment; and 9/18 (50%) switched on average 29.9 months later with primary or secondary inefficacy, almost five times longer than those switched immediately (p=0.0009). 7/13 (54%) who switched due to primary inefficacy switched between anti-TNF and anti-IL-17 classes, whereas all five patients with secondary inefficacy switched between biologic classes. Notably, 19% of poor responders were current smokers compared to 8% of excellent responders (p=0.0004). The remaining 12/93 (13%) patients were classified as sub-optimal responders. Of these, 5/12 (42%) patients switched to a second anti-TNF after an average 12.4 months. 7/12 (58%) patients continued with their first biologic. Pre-biologic, four patients had high CRPs (≥5mg/L) and eight had normal CRPs (&amp;lt;5mg/L). There was no change between these categories for seven patients who had CRP checked during their sub-optimal response. Conclusion Our research shows that clinicians’ decisions with sub-optimal biologic response vary, with a 42:58 split between patients switching or persevering with their biologic treatment. It appears that if patients are going to respond, they should do so within eight months and non-responders should be switched at that point to avoid poor outcomes. Smoking is a known poor prognostic factor which might suggest we should switch sooner with sub-optimal response, but we have been unable to show any benefit of the CRP in guiding management of sub-optimal responders. Disclosure E. Gates: None. M. Ho: None. C. Cavill: Honoraria; Abbvie, Eli Lilly, Novartis, Pfizer. R. Sengupta: Honoraria; Abbvie, Biogen, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB.

Complement inhibition in paroxysmal nocturnal hemoglobinuria: From biology to therapy.

Complement inhibitors are the mainstay of paroxysmal nocturnal hemoglobinuria (PNH) treatment. The anti-C5 monoclonal antibody eculizumab was the first treatment to improve hemolysis, thrombotic risk, and survival in PNH although at the price of a life-long intravenous fortnightly drug. Additionally, suboptimal response may occur in up to 2/3 of patients with persistent anemia due to incomplete control of intravascular hemolysis, development of upstream C3-mediated extravascular hemolysis (EVH), or concomitant bone marrow failure. Ravulizumab, a longer half-life anti-C5 developed from eculizumab, administered every 8 weeks, improved patient convenience, and reduced pharmacokinetic breakthrough hemolysis (BTH) by establishing more stable anti-C5 concentrations. More recently, several other anti-C5 compounds (crovalimab, pozelimab, tesidolumab, cemdisiran, zilucoplan, and coversin) are on study in clinical trials. Upstream inhibition of complement cascade was also explored with the anti-C3 pegcetacoplan, and with the alternative pathway inhibitors iptacopan (anti-factor B) and danicopan (anti-factor D). These drugs efficiently target EVH and are able to improve anemia and transfusion need in suboptimal responders to anti-C5. The route and schedule of administration (twice weekly subcutaneously for pegcetacoplan and twice or thrice oral daily dosing for iptacopan and danicopan, respectively) are very convenient but pose novel issues regarding adherence. Additionally, both anti-C5 and upstream inhibitors do not resolve the unmet need of pharmacodynamic BTH events due to complement amplifying conditions such as infections, traumas, and surgery. In this review, we will recapitulate PNH physiopathology, clinical presentation, and diagnosis and describe available and developing drugs that will lead to a precision medicine approach for this rare though heterogenous disease.

Quantifying Fluid and Function in Suboptimal Responders Switched From an Anti-vascular Endothelial Growth Factor (VEGF) to Faricimab.

Background Anti-vascular endothelial growth factor (VEGF) injections have been successful in reducing vision loss from neovascular age-related macular degeneration, a leading cause of blindness. Due to the high treatment burden and suboptimal responses, switching to bi-specific faricimab treatment may lead to improved outcomes. Methods This retrospective chart review evaluated if suboptimal responders to anti-VEGF injections had better outcomes when switched to faricimab. Suboptimal responders were defined as patients with a history of >3 months of injections and the presence of fluid after ≥3 injections. The primary endpoints were best-corrected visual acuity, treatment interval, and fluid levels. Visual acuity measurements and optical coherence tomography were performed before each injection. The total fluid area (TFA) was measured using MATLAB 2023a (MathWorks, Natick, MA, USA). Results Nineteen eyes were included in the analysis. After three faricimab injections, average letters increased from 54.5 to 59.0 (SD: 15.3; p<0.05), and the injection interval was extended from 7.6 to 9.3 weeks (SD: 3.9; p<0.01) after four injections. Patients also experienced anatomical retinal changes, with a reduction in the TFA to 47.3% (p<0.005) after the second injection and a reduction in pigment epithelial detachment height to 82.3% (p<0.005) after one injection. The central subfield thickness was significantly reduced after the second injection (90.6% (SD: 17.6%)p<0.05). Conclusion Switching to faricimab after a suboptimal anti-VEGF response results in improvements in visual acuity, reduced treatment burden, and reduced fluid levels.

Clinical factors associated with unexpected poor or suboptimal response in Poseidon criteria patients

Research questionWhat clinical factors are associated with ‘unexpected’ poor or suboptimal responses to IVF ovarian stimulation per POSEIDON's criteria, and which AMH and AFC threshold values distinguish this population? DesignTri-centre retrospective cohort study (2015–2017) involving first-time IVF and ICSI cycles with conventional ovarian stimulation (≥150 IU/day of FSH). Eligibility criteria included sufficient ovarian reserve markers according to POSEIDON's classification (AMH ≥1.2 ng/ml; AFC ≥5). Ovarian response categories were poor (<4 oocytes), suboptimal (4–9 oocytes) and normal (≥9 oocytes). Primary outcomes included clinical factors associated with an unexpected poor or suboptimal response to conventional ovarian stimulation using logistic regression analyses, and the threshold values of AMH and AFC predicting increased risk of such responses using ROC curves. ResultsA total of 7625 patients met the inclusion criteria: 204 (9.3%) were poor and 1998 (90.7%) were suboptimal responders. Logistic regression identified significant clinical predictors for a poor or suboptimal response, including AFC, AMH, total gonadotrophin dose, gonadotrophin type and trigger type (P ≤ 0.02). The ROC curves indicated that AMH 2.87 ng/ml (AUC 0.740) and AFC 12 (AUC 0.826) were the threshold values predicting a poor or suboptimal response; AMH 2.17 ng/ml (AUC 0.741) and AFC 9 (AUC 0.835) predicted a poor response; and AMH 2.97 ng/ml (AUC 0.722) and AFC 12 (AUC 0.801) predicted a suboptimal response. ConclusionsThe threshold values of AMH and AFC predicting ‘unexpected’ poor or suboptimal response were higher than expected. These findings have critical implications for tailoring IVF stimulation regimens and dosages.

Expert Panel Consensus for Optimizing Outcomes in Neovascular Age-Related Macular Degeneration in the Context of Suboptimal Response to a Biosimilar: The Role of Aflibercept.

The inclusion of ranibizumab biosimilars into National Health Service England commissioning recommendations published in 2022 created a need for expert guidance to optimize treatment outcomes in patients with neovascular age-related macular degeneration (nAMD) who otherwise may not have received first-line ranibizumab. This article provides a consensus treatment pathway supporting timely identification and management of a suboptimal response to these therapies, thereby aiming to facilitate clinically meaningful outcomes and efficient management of service capacity under specific circumstances where ranibizumab biosimilars may be initiated as a first-line treatment. Two structured round-table meetings of UK medical retina specialists were held in person and virtually on September 22 and November 3, 2022, respectively. These meetings were organized and funded by Bayer. The panel provided guidance on the implementation of an early treatment optimization pathway in cases where ranibizumab biosimilars are used as a first-line treatment, including recommendations on patient suitability and capacity requirements, and criteria for identification and strategies for management of a suboptimal response. The panel discussed the role of aflibercept treatment and its potential benefits and outlined recommendations on switching ranibizumab biosimilar suboptimal responders to an aflibercept treat-and-extend regimen, where appropriate. Developed by a retinal expert panel, this early treatment optimization pathway provides guidance to facilitate optimal long-term patient outcomes while addressing capacity and resourcing constraints in circumstances of first-line ranibizumab biosimilar use for nAMD, including how aflibercept may be used in cases with a suboptimal response. Therefore, this fills an important gap in guidance on navigating the new treatment landscape.

Topiramate dosage optimization for effective antiseizure management via population pharmacokinetic modeling.

Despite the suggested topiramate serum level of 5-20 mg/L, numerous institutions have observed substantial drug response at lower levels. We aim to investigate the correlation between topiramate serum levels, drug responsiveness, and adverse events to establish a more accurate and tailored therapeutic range. We retrospectively analyzed clinical data collected between January 2017 and January 2022 at Seoul National University Hospital. Drug responses to topiramate were categorized as "insufficient" or "sufficient" by reduction in seizure frequency ≥ 50%. A population pharmacokinetic model estimated serum levels from spot measurements. ROC curve analysis determined the optimal cutoff values. A total of 389 epilepsy patients were reviewed having a mean dose of 178.4 ± 117.9 mg/day and the serum level, 3.9 ± 2.8 mg/L. Only 5.6% samples exhibited insufficient response, with a mean serum level of 3.6 ± 2.5 mg/L while 94.4% demonstrated sufficient response, with a mean 4.0 ± 2.8 mg/L, having no statistical significance. Among the 69 reported adverse events, logistic regression analysis identified a significant association between ataxia and serum concentration (p = 0.04), with an optimal cutoff value of 6.5 mg/L. This study proposed an optimal therapeutic concentration for topiramate based on patients' responsiveness to the drug and the incidence of adverse effects. We recommended serum levels below 6.5 mg/L to mitigate the risk of ataxia-related side effects while dose elevation was found unnecessary for suboptimal responders, as the drug's effectiveness plateaus at minimal doses.

Predictive biomarkers and specific immune responses of COVID-19 mRNA vaccine in patients with cancer: prospective results from the CACOV-VAC trial

ObjectiveVaccinated patients with cancer in follow-up studies showed a high seropositivity rate but impaired antibody titres and T cell responses following mRNA vaccine against COVID-19. Besides clinical characteristics and the...

High Dimensional Profiling of Patient-Derived Multiple Myeloma Bone Marrow Specimens Treated with an FcRH5-Targeted Bispecific Ex Vivo

Background: Cevostamab is an FcRH5 (Fc receptor-homolog 5) targeted T cell-dependent bispecific (TDB) currently being evaluated in the clinic, with promising activity and favorable safety profile as a monotherapy in patients (pts) with heavily pre-treated Relapsed/Refractory multiple myeloma (MM) (NCT03275103, Trudel et al. ASH 2021). Cevostamab selectively engages and activates T cells in the proximity of MM cells in the bone marrow (BM) to drive tumor cell killing. To dissect the transcriptional and functional impact of cevostamab treatment on the MM BM tumor microenvironment (TME) and identify factors linked to enhanced killing, we established an ex vivo TDB killing assay with MM pt BMMC (BM mononuclear cells) samples followed by detailed characterization of immune and tumor cells. Methods: We tested commercially procured frozen BMMC samples from 7 pts with Stage I or Stage III Newly Diagnosed Multiple Myeloma (NDMM) with no known prior treatments (except a paired, longitudinally collected sample) and median age of 67.5 years. BMMC samples containing endogenous T and MM cells were treated ex vivo with 10 ug/mL of either a non-targeted TDB (considered as baseline) or a research grade cevostamab surrogate (FcRH5 TDB) for 16 to 48 hours (hr). T cell enumeration and MM killing (CD138 + CD38 +) was evaluated at 48 hours by flow cytometry. Ex vivo response was normalized by T cell quantity and defined as % tumor cell killing per 10 3 T cells present in the assay, which was used to classify samples as Responders (R) (&amp;gt;= 10%) or Suboptimal Responders (SoR) (&amp;lt; 10%). Single cell RNA-seq (scRNA-seq) was performed at 16, 24 and 48 hr post treatment. Tumor-specific genes enriched in SoRs at baseline were investigated for prognostic value by examining their bulk gene expression profile in baseline tumor samples (CD138-enriched) from pts (N=1150) treated with immunomodulatory drug, proteasome inhibitors, or combinations thereof (NCT01454297, MMRF CoMMpass IA22). Results: We first examined the T cell compartment by scRNA-seq profiling. Upon FcRH5 TDB treatment, clustering analysis suggested that CD4 and CD8 T cells undergo extensive transcriptional changes compared to control TDB (Fig 1A). A TNF and LTA-expressing CD4 memory cluster was enriched upon treatment in both SoRs and Rs, but to a greater extent in Rs. A similar trend was observed with an IFNG and CCL4-enriched CD8 effector-like proliferating T cell cluster. Transcriptional profiles of MM cells suggested inter- and intra-pt tumor heterogeneity at baseline. MM cells in SoRs at baseline had higher expression of genes like CD44, SRGN, CCND2 and SLAMF1. Of these genes, higher expression of CD44 or SRGN was found to be significantly associated with worse outcome to 1L treatments. Exposure to FcRH5 TDB altered tumor cells from all pts (Figure 1B), resulting in significant upregulation of genes such as HLA-E, SOCS1, and TNFSF10. Increase in CXCL9 expression upon treatment was found to be higher in Rs than SoRs. Discussion: Our work provides a novel ex vivo approach for unbiased, high dimensional pharmacodynamic profiling of functional and transcriptomic changes in pt samples by combining TDB treatment with scRNA-seq. Consistent with the expected mechanism of action and preliminary biomarker analysis reported for cevostamab (Nakamura et al. ASH 2020), FcRH5 TDB led to increased expression of genes in T cells associated with infiltration, activation and effector function. It also induced transcriptional changes in MM cells regardless of the ex vivo response status, including upregulation of genes associated with T and NK cell infiltration and antigen presentation. For certain genes, a greater magnitude of these changes was observed in Rs. These identified genes, and enriched clusters will be examined in clinical RNAseq data from cevostamab-treated pts. It remains to be determined whether our results reflect treatment effects that are applicable to other targeted bispecifics in MM. Overall, our assay setup can serve as a platform to generate novel hypotheses, corroborate clinical observations, identify pt-specific features driving improved or dampened response, and test novel combinations for improved killing. Figure 1 : UMAP (Uniform Manifold Approximation and Projection) plot of all (A) T cells and (B) tumor cells shows distinct clustering of cells by treatment type for all pts (red: FcRH5 TDB; blue: non-targeted TDB)