Lost Response Research Articles

Phase II trial of imatinib mesylate in patients with PDGFRA/B-negative hypereosinophilic syndrome.

The role of imatinib in PDGFRA/B-negative hypereosinophilic syndromes (HES) is controversial because of the heterogeneity of HES and the scarcity of prospective studies. We conducted a phase II clinical trial to evaluate the efficacy of imatinib in PDGFRA/B-negative HES. Thirty-two patients were treated with imatinib (100-400 mg daily), and the molecular basis of their response was identified using whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS). The haematological response rate was 46.9%, with a complete haematological response (CHR) rate of 18.8%. The median time to response was 1.5 months. Among the six patients who achieved CHR, five maintained it until the 24th cycle of imatinib and one lost response after 20 months. The median progression-free survival was 4.3 months. WES and WTS were conducted for 11 patients. The number of non-silent mutations did not differ between responders and non-responders. Nine differentially expressed genes, including SNORD15A, were downregulated in responders. STAT5B::RARA, PAK2::PIGX, and FIP1L1::CHIC2 fusions were identified in patients with sustained responses, and RNF130::BRAF and WNK1::KDM5A fusions were identified in non-responders. Imatinib, along with an appropriate biomarker, could be a promising option for PDGFRA/B-negative HES.

Etrasimod (Velsipity)

CADTH recommends that Velsipity be reimbursed by public drug plans for the treatment of adults with moderately to severely active ulcerative colitis (UC) whose disease had an inadequate response or lost response, or who were intolerant, to either conventional therapy or an advanced treatment, if certain conditions are met. Velsipity should only be covered to treat adults with moderately to severely active UC whose disease has had an inadequate response or lost response, or who were intolerant, to either conventional therapy or an advanced treatment provided that it is covered for a similar patient population and in a similar way to other advanced therapies for UC (e.g., biologics, sphingosine 1-phosphate receptor modulators, or Janus kinase [JAK] inhibitors) currently reimbursed by public drug plans. Velsipity should only be reimbursed if it is prescribed by a physician experienced in the diagnosis and management of UC, if it is not used in combination with other advanced therapies for UC, and if the cost is reduced so that it does not cost the drug programs more than the least costly relevant advanced therapy. A patient’s disease must respond to the treatment in the first 12 weeks of starting Velsipity to continue receiving the drug.

Long-Term Outcomes of Intravenous Ustekinumab Maintenance Treatment in Patients With Loss of Response to Subcutaneous Dosing.

Ustekinumab (UST) is commonly used to treat Crohn's disease and ulcerative colitis. However, some patients may experience diminishing response or require increased dosage. Intravenous (IV) UST maintenance is explored as a solution. We sought to evaluate IV UST maintenance effectiveness and safety in inflammatory bowel disease patients with partial or lost subcutaneous UST response. This was a multicenter retrospective study of inflammatory bowel disease patients on IV UST maintenance. Clinical response and remission at weeks 12 and 52, defined as Harvey-Bradshaw Index ≤4 for Crohn's disease or partial Mayo score ≤2 for ulcerative colitis. Objective markers reduction (fecal calprotectin, C-reactive protein), UST trough levels pre- and post-IV maintenance, and adverse events were assessed. A total of 59 patients were included. Clinical remission at weeks 12 and 52 achieved by 47.5% and 64.3% respectively. 96.6% continued IV UST at follow-up. UST serum levels quadrupled. No adverse events reported. IV UST maintenance effectively sustained remission in most patients at 52 weeks.

Sub-lethal effects of the insecticide, imidacloprid, on the responses of damselfly larvae to chemosensory cues indicating predation risk

Insecticides, including the widely used neonicotinoids, can affect both pest and non-target species. In addition to lethal effects, these insecticides at sub-lethal levels may cause disruption to sensory perception and processing leading to behavioural impairments. In this laboratory experiment, we investigated the effects of a 10-day exposure to the neonicotinoid insecticide, imidacloprid, on the behaviour of larvae of the damselfly, Lestes congener. In tests of baseline activity, imidacloprid concentrations of 1.0 and 10.0 μg/L caused significant reductions in foraging behaviour. Moreover, in response to chemical cues that indicate a potential risk to the larvae, imidacloprid caused the loss of an appropriate antipredator response (reduced foraging) depending on the concentration and duration of exposure. Imidacloprid at 0.1 μg/L caused the loss of responses toward the odour of a beetle (Dytiscus spp.) predator after 10 days of exposure, whereas 1.0 μg/L caused lost responses toward both the predator odour and injured conspecific cues (i.e., alarm cues) and after only 2 days of exposure. However, at 10.0 μg/L, larvae responded appropriately to both cues throughout the duration of the study, suggesting compensatory responses to imidacloprid at higher concentrations. Hence, the lack of appropriate responses at 1.0 μg/L likely resulted from a cognitive impairment rather than chemical alteration of these important chemosensory cues. In the natural environment, such effects will likely cause decreased survivorship in predator encounters. Hence, imidacloprid exposure, even at low concentrations, could have adverse consequences for chemosensory ecology of this damselfly species.

Research progress of Ustekinumab in the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic, recurrent gastrointestinal disorder with elusive etiology. Interleukin-12 (IL-12) and IL-23 have emerged as key proinflammatory mediators/cytokines in IBD pathogenesis. Ustekinumab (UST), targeting IL-12 and IL-23, has demonstrated promising efficacy and safety in the treatment of IBD. Recently, UST has become increasingly favored as a potential first-line treatment option. This review delineates UST's mechanism of action, its clinical applications in IBD, including the response rates, strategies for dose optimization for case of partial or lost response, and potential adverse events. This review aims to offer a comprehensive understanding of UST's role as a therapeutic option in IBD management.

Etrasimod: First Approval.

Etrasimod (VELSIPITY™) is an orally available, small-molecule selective sphingosine-1-phosphate (S1P) receptor modulator being developed by Pfizer for the treatment of ulcerative colitis and other immune-mediated inflammatory disorders. Etrasimod is selective for S1P receptor subtypes S1P1, S1P4 and S1P5 while having minimal activity on S1P3 and no activity on S1P2. Etrasimod received its first approval, in the USA, in October 2023 for the treatment of moderately to severely active ulcerative colitis in adults. Subsequently, the European Medicines Agency adopted a positive opinion in December 2023, recommending the granting of marketing authorisation for etrasimod for the treatment of patients aged ≥ 16years with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy, or a biological agent. Etrasimod is also under regulatory review for the treatment of ulcerative colitis in several other countries. Clinical development of etrasimod for use in the treatment of Crohn's disease, atopic dermatitis, eosinophilic oesophagitis and alopecia areata is ongoing worldwide. This article summarises the milestones in the development of etrasimod leading to this first approval for the treatment of ulcerative colitis in adults.

P1008 Efficacy and safety of retreatment with upadacitinib after treatment interruption in ulcerative colitis: Data from the phase 3 open-label extension study U-ACTIVATE

Abstract Background Upadacitinib (UPA) is an oral reversible Janus kinase (JAK) inhibitor designed to preferentially inhibit JAK1 approved for the treatment of moderately to severely active ulcerative colitis (UC). UPA may be temporarily discontinued for many reasons including adverse events (AEs) and lack of efficacy.1 As clinical consequences of discontinuing and restarting UPA are yet to be characterised, here, we assess the efficacy and safety of UPA retreatment in patients (pts) who lost response following UPA treatment withdrawal. Methods Pts with a clinical response to 8 weeks’ (wks) UPA 45 mg once daily (QD; UPA45) induction therapy in the Phase 3 U-ACHIEVE or U-ACCOMPLISH studies were re-randomised to placebo (PBO), UPA 15 mg QD (UPA15) or UPA 30 mg QD (UPA30) for the 52-wk maintenance phase of U-ACHIEVE. Pts randomised to PBO who lost response could enter the long-term extension (LTE), U-ACTIVATE, and be retreated with UPA15. Efficacy was analysed (i) at wk 4 of the LTE and (ii) at wk 48 of the LTE among pts with an inadequate response to UPA15 who dose escalated to UPA30 between wks 2 and 36. Exposure-adjusted event rates (EAERs) of treatment-emergent AE (TEAE) were assessed throughout. Results Of 223 pts with a clinical response to UPA45 induction randomised to PBO during maintenance, 112 (50.2%) lost response (mean [standard deviation (SD)] days to loss of response: 135.4 [84.6]) and 110 subsequently entered the LTE. Pts with loss of response vs those without were more likely to have a history of inadequate response, loss of response, or intolerance to ≥1 biologic (57.1% vs 46.8%, respectively) or corticosteroid use at baseline (42.0% vs 33.3%). After 4 wks of retreatment with UPA15, 75/108 (69.4%) and 39/108 (36.1%) pts achieved clinical response and remission, respectively (Figure A). In total, 38 (34.5%) pts dose escalated to UPA30 (mean [SD] days to escalation: 80.3 [57.8]); 30/31 (96.8%) and 22/31 (71.0%) achieved clinical response and remission at wk 48 of retreatment, respectively (Figure B). For safety during maintenance, 225 pts with 128.7 patient-years (PYs) of exposure (loss of response [n=112], 42.6 PYs; no loss of response [n=113], 86.1 PYs) were analysed. Generally, the EAERs of serious TEAEs were numerically lower in patients with vs without loss of response. However, patient years of exposure were low, restricting interpretation. During the LTE, EAERs were generally similar in pts who underwent dose escalation vs all pts. Conclusion In pts who experience loss of response following UPA withdrawal, efficacy can be recaptured following retreatment with UPA15 and UPA30. No new safety signals were identified. Reference 1. Sandborn WJ, et al. Gastroenterology. 2020;158(8):2139−2149.e14.

DOP16 Safety of long-term ozanimod treatment for up to 4 years in patients with moderately to severely active Ulcerative Colitis: an interim analysis of the True North open-label extension

Abstract Background The 52-week, phase 3 True North (TN) study (NCT02435992) demonstrated the efficacy and safety of ozanimod (OZA), a highly selective sphingosine 1-phosphate receptor 1 and 5 modulator, in patients (pts) with moderately to severely active ulcerative colitis (UC). A prior analysis reported the long-term safety of up to 3 y of OZA in the ongoing TN open-label extension (OLE; NCT02531126; from TN baseline to OLE Week [W] 94). This analysis presents the cumulative long-term safety of OZA in TN and the TN OLE for an additional year (up to OLE W142). Methods The TN study design has been previously described. This analysis included all TN pts who entered the OLE from TN (clinical nonresponders at W10, lost response during maintenance, or completed maintenance at W52). Safety assessments were reported from the first dose of OZA either in TN or OLE up to OLE W142. Lab abnormalities, including absolute lymphocyte count (ALC) reductions, were reported. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated for all treatment-emergent adverse events (TEAEs). Results A total of 823 pts entered the TN OLE (average age: 41.7 y; 59% male); 62% had left-sided UC disease. Total PY exposure to OZA at OLE W142 was 2536 y. Overall, the cumulative safety assessments did not significantly change with an additional year of OZA exposure from OLE W94 to W142 (Table). A decrease in EAIRs per 100 PY was observed in overall TEAEs (85.5 vs 87.6) and serious TEAEs (7.0 vs 7.4) at OLE W142 vs OLE W94, respectively. Notably, with an additional year of OZA exposure, TEAEs leading to treatment discontinuation remained at 2.5 EAIR/100 PY, and there were no new cases of bradycardia or atrioventricular block. One new TEAE each of herpes zoster, macular oedema, cystoid macular oedema, myocardial ischaemia, pulmonary embolism, and deep vein thrombosis were noted. COVID-19 TEAEs increased at OLE W142 (n=103; EAIR: 4.3/100 PY) from OLE W94 (n=66; EAIR: 3.0/100 PY). Reductions in ALC <500 cells/mm3 were common in the OLE (OLE W94, 54.0%; OLE W142, 56.1%); few pts had ALC <200 cells/mm3 (OLE W94, 5.3%; OLE W142, 6.5%), but these pts had no serious infections. No serious hepatic safety events were observed. One new death due to adenocarcinoma, which was unrelated to OZA, was reported. Conclusion The ongoing safety profile of OZA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses. Long-term use of OZA representing 2536 PYs of exposure continues to be well tolerated in pts with moderately to severely active UC.

DOP74 Short and long-term effectiveness and safety of ustekinumab in Ulcerative Colitis in real life: the ULISES study

Abstract Background Primary aim: To assess the durability of ustekinumab treatment in patients with ulcerative colitis (UC). Secondary aims: To assess the short-term effectiveness, the durability of response, and the tolerability of ustekinumab in clinical practice. Methods Retrospective, multicenter study including UC patients who had received the 1st ustekinumab dose at least 16 weeks before inclusion. Patients were followed-up from the 1st ustekinumab dose to treatment discontinuation or last visit. Only patients with active disease [Partial Mayo Score (PMS)>2] at ustekinumab start were considered in the effectiveness analysis. Clinical effectiveness was based on PMS. Patients who stopped ustekinumab before their last visit were considered not in remission at subsequent time points (negative imputation). Results 620 patients were included (table 1). 78% of patients who started ustekinumab maintenance treatment, did it with 90 mg every-8-weeks dose. 155 patients (25%) withdrew ustekinumab during follow-up [median=12 months (m)]. Incidence rate of ustekinumab discontinuation was 20% per patient-year of follow-up. The probability of maintaining ustekinumab is shown in figure 1A. Among patients who withdrew ustekinumab, the main reasons were primary non-response (39%) and loss of response (35%). Anaemia at baseline (HR=1.5, 95%CI=1.1-2.1), steroids at baseline (HR=1.5; 95%CI=1.06-2.08), and more severe clinical activity at baseline (HR=1.5; 95%CI=1.09-2.06) were associated with higher risk of ustekinumab discontinuation. Short and long-term effectiveness of ustekinumab is shown on figure 1B. Moderate-severe vs. mild disease activity at baseline (OR=0.3, 95%CI=0.2-0.5), male sex (OR=0.5; 95%CI=0.4-0.8), and increased number of previous biologics (OR=0.6, 95%CI=0.6-0.8) were associated with lower likelihood of steroid-free remission at week 16. A total of 57 (25%) patients among those with active disease at baseline and with steroid-free remission at week 16, lost response during a median follow-up of 8 m (IQR=3-16 m) (figure 1C). The dose was escalated in 72% of patients with loss of response, and 80% improved (67% remission); an intravenous reinduction was given in 3 patients, and none of them improved. A total of 176 patients (28%) had at least one adverse event, with infections being the most frequent (11%). No negative impact on extraintestinal manifestations and/or immunomediated diseases was seen. Conclusion Ustekinumab was effective in inducing remission even in highly refractory UC patients. A proportion of patients discontinue the treatment, mostly due to primary failure and loss of response. Dose escalation may be effective to regain response after loss of effectiveness. The safety profile was similar to previously reported.

P776 A Prospective, Multicenter, Single-arm, Observational Study to Evaluate the Safety and Effectiveness of Vedolizumab in Real-world Clinical Practice in China: Interim Analysis of Safety results

Abstract Background Crohn's disease (CD) and ulcerative colitis (UC) are categorized as inflammatory bowel disease [IBD] usually treated by corticosteroids, immunomodulators and biologics, etc. Vedolizumab, a gut-selective α4β7 integrin antibody, has been approved in China for IBD patients who are intolerant /lost response to conventional therapies or TNF-α inhibitors. Of late, there is a paucity of data on the safety and effectiveness of vedolizumab in real-world clinical practice in China. This study evaluates the safety and effectiveness of vedolizumab in adult patients with UC or CD Here, we present the first interim analysis. Methods In this multicenter, single arm, prospective, observational, real-world study (NCT04872491), adults (aged >18 years) with UC or CD were administered intravenous vedolizumab 300 mg at week 0, 2, 6, and thereafter every 8 weeks. Incidence of adverse events (AEs), serious AEs (SAEs), Treatment-related AEs (TRAEs) and AEs of special interest (AESIs) were the primary endpoints Patients with administration of at least 1 dose of VDZ were included and observed 18 weeks after completion of the study or early termination, up to maximum of 72 weeks. AESIs included infections, malignancies, infusion-related reactions, and hypersensitivity. The secondary endpoints included the effectiveness of vedolizumab in terms of clinical response, clinical remission and endoscopic remission assessed at week 14 and week 54 after vedolizumab initiation. Results A total of 307 patients (UC, n=245; CD, n=62) with a median age of 41 years (range: 18-86) were included in the interim analysis. Median duration was 883 days (UC: 1035 days; CD: 731 days) and 105 days (UC: 107 days; CD: 99 days) for IBD and vedolizumab exposure, respectively. A total of 105 (34.20%) patients (UC: 35.92%; CD: 27.42%) developed 225 AEs and the most frequent AEs were infections and infestations (16.61%) followed by gastrointestinal disorders (GID) (14.66%) and general disorders (GD) (4.56%). Colitis and pyeria were the most common GID and GD, respectively occurred in 7(2.28%) patients each (Table 1). Forty-one TRAEs were observed and ten AEs lead to study discontinuation. Total 13 AESIs and 34 SAEs were reported and at least one AESI was reported in 10 patients. No deaths were reported during the study (Table 2). A total of 79.19% (118/149) and 34.48% (10/29) patients with UC and CD respectively, achieved clinical response at week 14 (±4 weeks). Clinical remission and endoscopic remission was achieved by 2/2 and 1/1 patients with UC, respectively at week 54 (±4 weeks). Conclusion Vedolizumab demonstrated favorable safety profile and treatment effectiveness among Chinese adult patients with UC or CD in real-world clinical practice.

Interferon-γ/IL-2 ELISpot and mRNA Responses to the SARS-CoV2, Feline Coronavirus Serotypes 1 (FCoV1), and FCoV2 Receptor Binding Domains by the T Cells from COVID-19-Vaccinated Humans and FCoV1-Infected Cats.

The receptor binding domain (RBD) of SARS-CoV-2 (SCoV2) has been used recently to identify the RBD sequences of feline coronavirus serotypes 1 (FCoV1) and 2 (FCoV2). Cats naturally infected with FCoV1 have been shown to possess serum reactivities with FCoV1 and SCoV2 RBDs but not with FCoV2 RBD. In the current study, COVID-19-vaccinated humans and FCoV1-infected laboratory cats were evaluated for interferon-gamma (IFNγ) and interleukin-2 (IL-2 ELISpot responses by their peripheral blood mononuclear cells (PBMC) to SCoV2, FCoV1, and FCoV2 RBDs. Remarkably, the PBMC from COVID-19-vaccinated subjects developed IFNγ responses to SCoV2, FCoV1, and FCoV2 RBDs. The most vaccinated subject (five vaccinations over 2 years) appeared to produce hyperreactive IFNγ responses to all three RBDs, including the PBS media control. This subject lost IFNγ responses to all RBDs at 9months (9 mo) post-last vaccination. However, her IL-2 responses to FCoV1 and FCoV2 RBDs were low but detectable at 10 mo post-last vaccination. This observation suggests that initially robust IFNγ responses to SCoV2 RBD may be an outcome of robust inflammatory IFNγ responses to SCoV2 RBD. Hence, the T-cell responses of vaccine immunity should be monitored by vaccine immunogen-specific IL-2 production. The PBMC from chronically FCoV1-infected cats developed robust IFNγ responses to SCoV2 and FCoV2 RBDs but had the lowest IFNγ responses to FCoV1 RBD. The constant exposure to FCoV1 reinfection may cause the IFNγ responses to be downregulated to the infecting virus FCoV1 but not to the cross-reacting epitopes on the SCoV2 and FCoV2 RBDs.

An Antennae-Enriched Odorant-Binding Protein EonuOBP43 Mediate the Behavioral Response of the Tea Green Leafhopper, Empoasca onukii Matsuda to the Host and Nonhost Volatiles.

Olfaction is crucial for Empoasca onukii Matsuda to recognize odors from the host and nonhost plants, and it has been proposed that odorant binding proteins are directly required for odorant discrimination and represent potential targets of interest for pest control. Here, we cloned EonuOBP43 and expressed the recombinant EonuOBP43 protein. Furthermore, competitive fluorescence binding assays with 19 ligands indicated that terpenoids and alkanes showed a relatively higher than for other classes of chemicals. Additionally, ligand docking and site-directed mutagenesis results revealed that seven hydrophobic residues, including Val-86, Met-89, Phe-90, Ile-104, Ile-105, Leu-130, and Val-134, played a key role in the binding of EonuOBP43 to plant volatiles. In olfactometer tests, E. onukii were significantly attracted to α-farnesene and repelled to β-caryophyllene, and dsOBP43 treated adult lost response to α-farnesene and β-caryophyllene. In summary, our results demonstrated that EonuOBP43 may function as a carrier in the process of sensing plant compounds of E. onukii.

Combinatorial BCL-2/ BCL2L1 Expression Predicts Clinical Response to Ruxolitinib in Myelofibrosis

Introduction: JAK inhibitors (JAKi) marked a revolutionary breakthrough in the treatment of patients (pts) with myelofibrosis (MF). The BCL-2 family of proteins have been implicated in both disease development and mechanisms of response/resistance to JAKi. This is further reinforced by preliminary evidence of therapeutic efficacy of combining JAK2 and BCL-xL inhibition. Aims&Methods: In the current study, we investigated the expression of three major BCL-2 family members in MF pts treated with ruxolitinib (RUX) at baseline and during treatment. Gene expression of BCL-2, BCL2L1 (encoding BCL-xL) and MCL-1 was analyzed by qPCR normalized to endogenous 18S gene using cDNA obtained from peripheral blood (PB) granulocytes; the relative gene expression (expressed as fold-change, FC) was calculated with reference to healthy controls using the Ct (2−ΔΔCt) method. Results: The study included 19 pts (10 males; median age 61 years) with MF (10 primary, 9 secondary) who received treatment with RUX. Sixteen pts were JAK2-mutated, 2 CALR-mutated, and 1 MPL-mutated. Treatment response was fully evaluable across the entire treatment period. After a median treatment time of 67 (range, 6-121) months, 7 (37%) pts achieved a spleen response (defined as a >50% reduction in palpable splenic length lasting >6 months) and were considered as responders, as compared to 12 (63%) non-responders. We did not find any significant correlation of baseline BCL-2/ BCL2L1/ MCL-1 expression with clinical and molecular characteristics, the only exception being the association between EZH2 mutation and higher BCL2L1 expression. First, we ascertained whether BCL2 family protein expression levels at baseline predicted response to RUX. We found that BCL2 and BCL2L1 were significantly more expressed in responders compared to non-responders, with median FC values of 0.14 vs 0.04 ( P=.0130) and 2.46 vs 0.51 ( P=.0096), respectively (Fig. 1A). A similar, not statistically significant, trend was observed for MCL-1 expression. Accordingly, in univariate regression logistic analysis, both BCL2 and BCL2L1 FCs correlated significantly with the probability of response to RUX. Then, we incorporated BCL-2 and BCL2L1 gene expression at baseline into a combinatorial score (CS) resulting from the product of the respective FCs (FC BCL-2 * FC BCL-xL). The CS outperformed the individual BCL2 family proteins expression in predicting RUX response, as confirmed in regression logistic analysis. ROC analysis identified 0.06 as the optimal cut-off value of the CS. In univariate analysis, pts with a baseline CS >0.06 had a significantly higher probability of responding to RUX (OR 27.5, 95% CI 2.1-236.7; P=.0037), with a superior cumulative incidence of RUX response at 24 weeks (50% vs 9%, respectively; P=.0045) (Fig. 1B). Finally, we prospectively assessed the changes in gene expression during treatment with RUX. Six out of seven responder pts had an available PB sample at the time of best response, while all non-responders were evaluated at some point during RUX therapy. Among responders, 5 lost response after a median time of 34 months, and 3/5 had an available sample for analyses at the time of response loss. Although we did not find any significant difference comparing gene expression at baseline and on treatment, we observed a trend for BCL-2 upregulation in responders at the time of best response. Furthermore, non-responders showed a down-regulation of MCL-1 expression during treatment ( P=.05). By comparing gene expression of responder pts at the time of best vs loss of response, we discovered a down-regulation for all the three genes, with a statistical significance that was reached only for BCL-2 ( P=.0471). Conclusion: Despite study limitations (mainly the small cohort), this preliminary data suggests that the expression levels of BCL2 family proteins may represent a predictor of response to RUX. Specifically, we developed a simple, combinatorial score includingbaseline BCL-2 and BCL2L1 expression that accurately discriminated pts who responded to RUX. Moreover, we showed that BCL2 family protein expression changes during RUX treatment, with potential correlations with both response achievement and loss. Further studies are needed in order to confirm and expand our data.

Final Report: Somatic Mutations and HMGCLL1 Haplotype Are Not Associated with Molecular Relapse-Free Survival in Patients with Chronic Myeloid Leukemia Who Attempt Treatment-Free Remission

Background Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder resulting from the BCR::ABL1 rearrangement. Patients with CML have a comparable life expectancy to that of age-matched individuals in the general population when they achieve an optimal response with tyrosine kinase inhibitor (TKI) therapy. With the aim of improving the quality of life of patients who are significantly affected by drug-related adverse events and financial burden, the practical goal of CML treatment has shifted to treatment-free remission (TFR), defined as the successful discontinuation (DISC) of TKI therapy without losing leukemia control. TKI treatment DISC is a safe procedure but requires appropriate candidate selection and frequent molecular monitoring. Several biomarkers were investigated, but no definite biomarker has yet been successfully identified and validated. We have investigated somatic mutations before TKI discontinuation and HMGCLL1 haplotype as a potential biomarker for TFR, given that they were previously described as predictors of CML outcomes. Patients and methods A total of 155 patients who attempted TKI discontinuation for TFR from 5 countries were included: Canada (n=71), Brazil (n=30), Argentina (n=28), Italy (n=23), and the Czech Republic (n=3). We applied our in-house single molecule-molecular inversion probe (smMIP) panel which is a barcoded error-corrected DNA-based sequencing with a limit of detection up to 0.2%. The panel encompasses 40 genes with 332 amplicon probes: epigenetic modifiers (n=7), activation signaling (n=12), myeloid transcription factor (TF; n=5), spliceosome (n=3), tumor suppressor (n=3), cohesion (n=4), miscellaneous (n=3) and 8 HMGCLL1 single nucleotide polymorphisms (SNPs). Two groups were constructed based on these eight SNPs: group 1: CTCAGGCA (C- haplotype) or group 2: ACGTAATG (A-haplotype). Samples were collected prior to TKI DISC when patients met the criteria for TFR attempt. Molecular relapse-free survival (mRFS) was calculated from the date of TKI DISC to the date of confirmed loss of deep molecular response (DMR). Loss of DMR includes single-time loss of major molecular response (MMR) or two consecutive episodes of loss of molecular response 4 log or deeper response (MR4). Kaplan-Meier survival estimate was used to evaluate mRFS and Cox's proportional hazard regression model was applied. Results The median MR4 duration prior to TKI DISC was 7.2 years (range 4.7-9.3), while overall TKI treatment duration was 8.5 years (range 6.0-11.6). With a median follow-up of 831 days (range: 460-1,415), out of the 155 patients, 68 (43.9%) lost response, among whom 6 lost MMR only, 12 lost MR4 only, and 50 lost MMR and MR4, both. Median time to MMR loss was 95 days (range 83.5-137). A total of 71 mutations were detected in 51 patients (32.9%). TET2 mutation was the most frequent mutation, detected in 17 cases (24%) followed by ASXL1 (n=14; 20%) and DNMT3A (n=12; 17%). When grouped by relevant biological pathways involved, mutations in epigenetic genes (n=42, 61%) were the most frequently involved. mRFS rate was 64% (95% CI [55.8-71.1%]) and 56% [48.2-64.0%] at 6 and 12 months, respectively. During the univariate analysis, no significant difference was observed in mRFS according to the presence, number, or type of somatic mutations, or the HMGCLL1 haplotype. Additionally, there were no significant differences in mRFS based on age, sex, Sokal risk group, line of TKI therapy, or TKI drug type prior to TKI DISC. However, MR4 duration prior to TKI DISC was associated with mRFS rate: patients with≥7.3 years (n=71) showed higher mRFS: 74.09% [62.05-82.82%] compared to those <7.3 years (n=74) with mRFS rate of 44.36% [32.54 -55.51] (p <0.01, HR 0.36 [0.21-0.63]). In addition, a longer duration of TKI treatment before TKI DISC was associated with higher mRFS: patients with ≥ 8.3 years of treatment (n=85) showed 71.8% mRFS [60.4-80.4], compared to 42.5% mRFS [30.5-54.0%] in those with <8.3 years (n=71) (p<0.01, HR 0.48 [0.31-0.74]). Multivariate analyses for mRFS confirmed that MR4 duration and the total duration of TKI treatment before TKI DISC were associated with TFR outcomes, but not the presence of epigenetic mutations, any mutation, or HMGCLL1 haplotype (Table1). Conclusion In CML, somatic mutations before attempting TFR are frequently observed. However, our current study does not support their prognostic significance as TFR-predictive biomarkers.

Durability of Near-Complete Skin Clearance in Patients with Psoriasis Using Systemic Biologic Therapies: Real-World Evidence from the CorEvitas Psoriasis Registry.

Near-complete skin clearance has become a rapidly achievable treatment goal for patients with psoriasis receiving systemic biologic therapies. However, real-world evidence for durability of near-complete skin clearance and risk factors associated with loss of near-complete skin clearance is limited. This study described durability of near-complete skin clearance (≥ 90% improvement in Psoriasis Area and Severity Index from initiation; PASI90) and identified clinical factors or patient characteristics associated with loss of PASI90 among patients with psoriasis from the CorEvitas Psoriasis Registry (April 2015-August 2021). Included patients had PASI > 5 at biologic initiation and achieved PASI90 at approximately 6months from initiation (index). A Kaplan-Meier estimate described time to loss of treatment response over 24months follow-up from index. Proportional hazards regression was used to identify independent predictors of loss of treatment response. This study included 687 patient initiations (instances of patients initiating a biologic). Following achievement of PASI90, treatment response was maintained in more than half of patient initiations (54%). Treatment response was maintained at 6, 12, and 18months from index in an estimated 73% (95% [confidence interval] CI 70-77%), 60% (95%CI 56-63%), and 50% (95%CI 47-54%) of patient initiations, respectively. Adjusted hazards regression suggested non-White race, full-time employment, greater body weight, concomitant psoriatic arthritis, prior use of biologics, and clinically meaningful skin symptoms were associated with loss of treatment response. Among real-world patients with psoriasis who achieved PASI90 with biologic therapy, about one-quarter lost response at 6months, and half lost response at 18months. Prior use of a biologic therapy and clinically meaningful skin symptoms at index, including itch and skin pain, were associated with loss of treatment response. Therefore, dermatologists may consider focusing on patient-reported symptoms as part of any intervention designed to reduce the likelihood of loss of response to biologic therapies. ClinicalTrials.gov identifier, NCT02707341.

Multi‐channel response reconstruction using transformer based generative adversarial network

AbstractAccurate measurement data are a basic prerequisite for effective structural health monitoring (SHM). However, data loss are inevitable in the long‐term monitoring of large‐scale structures. To solve this problem, this research proposes a transformer‐based generative adversarial network (GAN) to reconstruct lost measurements from observed measurements. The generator of GAN is an encoder‐decoder structure using transformer as the backbone combined with discrete wavelet transform. Skip connections are used between the encoder part and decoder part to promote multi‐scale information flow. A novel discriminator is designed to assess the reality of wavelet spectra of reconstructed samples. To deceive the discriminator, the generator must generate samples that are accurate over the full frequency band. The developed model is used to reconstruct linear responses of a footbridge under pedestrian excitations and nonlinear responses of a suspension bridge under typhoon events. Experimental results demonstrate that lost responses can be reconstructed accurately, even when a large proportion of data are lost. The effectiveness of the proposed method is further verified by comparing the reconstruction accuracy of the proposed model with those of other three state‐of‐the‐art models. The results demonstrate that an improved performance of applying the proposed approach for dynamic structural response reconstruction is achieved and validated with in‐field testing data under ambient and extreme excitation conditions.

Mirikizumab: First Approval.

Mirikizumab (Omvoh®), a humanized IgG4 anti-human IL-23p19 monoclonal antibody, is being developed by Eli Lilly and Company Ltd for the treatment of ulcerative colitis and Crohn's disease. Mirikizumab was approved in March 2023 in Japan for use as induction and maintenance therapy in patients with moderate to severe ulcerative colitis who have an inadequate response to conventional therapy or therapies and is the first IL-23p19 inhibitor to be approved for this indication. Mirikizumab was granted a positive opinion in the EU in March 2023 for the treatment of adult patients with moderately to severely active UC who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic treatment. This article summarizes the milestones in the development of mirikizumab leading to this first approval for use in ulcerative colitis.

An NlpC/P60 protein catalyzes a key step in peptidoglycan recycling at the intersection of energy recovery, cell division and immune evasion in the intracellular pathogen Chlamydia trachomatis.

The obligate intracellular Chlamydiaceae do not need to resist osmotic challenges and thus lost their cell wall in the course of evolution. Nevertheless, these pathogens maintain a rudimentary peptidoglycan machinery for cell division. They build a transient peptidoglycan ring, which is remodeled during the process of cell division and degraded afterwards. Uncontrolled degradation of peptidoglycan poses risks to the chlamydial cell, as essential building blocks might get lost or trigger host immune response upon release into the host cell. Here, we provide evidence that a primordial enzyme class prevents energy intensive de novo synthesis and uncontrolled release of immunogenic peptidoglycan subunits in Chlamydia trachomatis. Our data indicate that the homolog of a Bacillus NlpC/P60 protein is widely conserved among Chlamydiales. We show that the enzyme is tailored to hydrolyze peptidoglycan-derived peptides, does not interfere with peptidoglycan precursor biosynthesis, and is targeted by cysteine protease inhibitors in vitro and in cell culture. The peptidase plays a key role in the underexplored process of chlamydial peptidoglycan recycling. Our study suggests that chlamydiae orchestrate a closed-loop system of peptidoglycan ring biosynthesis, remodeling, and recycling to support cell division and maintain long-term residence inside the host. Operating at the intersection of energy recovery, cell division and immune evasion, the peptidoglycan recycling NlpC/P60 peptidase could be a promising target for the development of drugs that combine features of classical antibiotics and anti-virulence drugs.

P405 Long-term safety of 3 years of ozanimod in moderately to severely active ulcerative colitis: an interim analysis of the True North open-label extension

Abstract Background The phase 3, randomised True North (TN) study demonstrated the efficacy and safety of ozanimod for up to 52 weeks in patients (pts) with moderately to severely active ulcerative colitis (UC). The ongoing TN open-label extension (OLE) aims to assess the long-term efficacy and safety of ozanimod in UC. This analysis evaluated the cumulative long-term safety of ozanimod in these studies, which included pts with up to ~3 years of treatment exposure. Methods In TN, pts were randomised to once-daily ozanimod 0.92 mg or placebo, or to open-label ozanimod for a 10-week induction period. Ozanimod clinical responders were rerandomised at Week 10 to ozanimod or placebo in the maintenance period through Week 52. TN pts were eligible to enrol in the OLE and receive ozanimod if they did not achieve clinical response at the end of induction (Week 10), lost response during maintenance, or completed maintenance at Week 52. This interim analysis of the TN OLE (data cutoff: 10 January 2022) included all pts who entered the OLE from TN (n=823). Safety was monitored from the first dose of ozanimod in TN and throughout the subsequent OLE. Exposure-adjusted incidence rates per 100 patient-years (PY) were calculated. Results The average age of TN OLE study participants was 41.7 years (±13.6), 41% were female, 62% had left-sided UC disease, and 35% had prior exposure to tumor necrosis factor inhibitors. Total PY exposure to ozanimod was 2219 years (mean [SD] exposure = 2.7 [1.6]). The most frequent treatment-emergent adverse events (TEAEs) reported through OLE Week 94 (up to 146 weeks of continuous treatment) are listed in the Table. Most TEAEs were nonserious; TEAEs leading to discontinuation were uncommon. Bradycardia was reported in 3 pts (0.4%; EAIR 0.1/100 PY; 2 in TN and 1 in OLE; no pts were discontinued from treatment). Macular edema was reported in 2 (0.2%; EAIR 0.1/100 PY) pts. Reductions in ALC were common (470 [57.1%] had ALC < 500 cells/mm3), as previously described, but ALC reductions were not associated with the occurrence of TEAEs. Malignancies were uncommon (n=13 [1.6%]; EAIR 0.6/100 PY), and included 6 basal cell carcinomas and 3 colorectal neoplasms. Two deaths were reported: 1 due to COVID-19 and 1 sudden death. Investigators deemed both to be unrelated to treatment. Ozanimod was not associated with an increased risk of ischemic heart disease or thromboembolic events. Conclusion Long-term exposure to ozanimod for up to 3 years was well tolerated in pts with moderately to severely active UC. No new safety signals were observed with long-term ozanimod use in UC (2219 PY exposure). Safety findings are consistent with previous reports from the UC and multiple sclerosis development programs (>16,512 PY exposure).

Molecular Characterization of Response/Loss-of-Response to Ruxolitinib in Patients with Myelofibrosis

Background. Ruxolitinib (RUX) is standard of care for most patients (pts) with primary (PMF) and secondary (sMF) myelofibrosis. However, about half of responders lose benefits at 3-5y, associated with clonal progression, and have a dismal outcome thereafter. The molecular bases for response/loss of response to RUX have not been clarified yet. Aim. To explore genetic variables associated with response/loss of response to RUX in MF pts. Patients and Methods. All consecutive pts with WHO2016/IWG-MRT diagnosis of PMF/sMF, treated with RUX at our Center, were included. To the purpose of the study, response was stringently defined as achievement of spleen lenght reduction from LCM of >50% at any time point; non-responders (NR) were all the others. Loss-of-response was defined as the reappearance of >5cm splenomegaly, if the nadir under RUX was <5cm, and >50% increase if the nadir was >5cm. A custom NGS panel including complete CDS of 552 genes, selected for putative involvement in RUX response (belonging to JAK/STAT, MAPK, ERK pathways, inflammatory reactions, apoptosis) or associated with myeloid neoplasms, was designed. For RNAseq analysis, we used the R package DOSE and performed Over Representation Analysis (ORA) to identify over-represented biological functions/processes. Results. Baseline characteristics. A total of 171 pts were included, 52.1% PMF (15.8% prePMF, 36.5% overtPMF) and 82 sMF (46.9%; 29.2% PPV-, 17.7% PET-MF). DIPSS at RUX start was Int-1: 43.8%, Int-2: 39.8%, high: 16.4%. Median FU from RUX start was 3.5y (0.8-17.3y), median time on RUX was 2.4y (0.2-12y). Sixty-eight pts (39.8%) died, 39 (22.8%) while on RUX. AML developed in 13 pts (7.6%), 10 of which while on RUX. OS from RUX start was 5.8y (4.4-7.3y). JAK2V617F mut in 72.3%, MPLW515 7.6%, CALR 19.3% (12.8% Type1/like, 6.4% Type2/like), TN 2.3%. 68 pts (39.8%) were High Molecular Risk (HMR; ASXL1, EZH2, IDH1, IDH2, SRSF2, U2AF1). Response to RUX. 93/171 pts (54.4%) were NR. Of the 78 responders (45.6%), 45 (57.7%) lost response (hence, R/L) after a median of 22.7 mo from RUX start, and 33 pts (43.3%) maintained response (hence, R/M) at last FU. Response outcome was influenced by RUX dose: 75.2% of NR and 64.4% of R/L had received <20 mg/die, compared with 63.6% of R/M who had received >30 mg/die. RUX stop (any reason) occurred in 24.2% of R/M, 62.2% R/L, 55% of NR (P=0.02). Baseline molecular predictors. Baseline molecular variables found to correlate with response/loss of response included: (i) HMR status, found in 51.1% R/L vs 24.2% R/M and 40.2% NR (P=0.04); (ii) >1 RAS pathway mutated gene (CBL, NRAS, KRAS, PTPN11), found in 30% NR, 5% R/L and 13.8% R/M (P=0.016); (iii) isolated CBL (n=8, 10.5%; P=0.02) and U2AF1 (n=5,6.7%; P=0.05) mutation, found exclusively in NR pts. Nor type nor variant allele frequency (VAF) of driver mutations impacted on response/loss of response. Serial mutational analysis. Among JAK2V617F mut pts, a partial molecular response (PMR, >50% VAF reduction; IWG-MRT criteria) was achieved by 18.6% of pts, after a median of 1.7y (1-5y). Median VAF reduction under RUX of pts with PMR was 71.3% (51-100%). A PMR occurred in 44.4% of R/M vs 14.8% of (R/L+NR), P=0.03. In 14 responder pts who were on stable dose of RUX since >1y and later became R/L, target NGS sequencing for 552 genes was performed using granulocyte DNA, collected at baseline (T0), at the time (+6mo) of response adjudication (T1) and at R/L (T2). A total of 91 mutated genes were acquired at T2 (mean gene number/pt, 2.5, range 1.0-16). Of these, 22 genes belonged to categories of "transcription regulator", 19 "cytokine mediator signaling", 14 "spliceasome/RNA processing", 11 "EGFR/TKI resistance" and 8 "chromatin regulators" (GO, KEGG, Reactome, Wikipathway). Serial, single cell analysis to interpret clonal hierarchy is ongoing, results will be presented at meeting. Pairwise RNAseq was performed in 4 pts with purified PB CD34+ cells collected at T1 and T2. By using a stringent FDR<0.1 value, enriched transcripts belonged to "RHO-GTPase" (n=88), "spliceasome" (n=40), "Type-2 interferon responses" (n=20), "IL12 stimulated gene and proteins" (n=14) categories. Conclusions. This study adds to the understanding of molecular mechanisms of response/loss of response to RUX by identifying baseline predictors and highlighting a set of involved genes/pathways, that remain to be validated.