Refractory Patients Research Articles

Tofacitinib for the treatment of chronic pouchitis: A pilot study.

Up to 15% of ulcerative colitis (UC) patients with an ileo-anal pouch will develop chronic or antibiotic refractory pouchitis. We aimed to evaluate the efficacy and safety of tofacitinib in these refractory patients. In this prospective single center study, adult UC patients with chronic or antibiotic refractory pouchitis (pouchitis disease activity index [PDAI]≥7) were treated with tofacitinib 10mg twice daily for 8weeks. Clinical, biochemical, endoscopic and histologic disease activity was assessed at baseline and at week 8. The primary endpoint was the proportion of patients achieving clinical remission (PDAI<7 and a reduction of ≥3 points from baseline) or clinical response (decrease ≥2 points from baseline). Thirteen patients were included and treated with tofacitinib. After 8weeks, 31% achieved PDAI-defined remission (4/13) and 54% achieved response (7/13). Both the total PDAI score (11 [interquartile range 9-12.75] vs. 8 [4.5-9.75], p=0.033) and the clinical PDAI subscore (4 [3-4] vs. 2 [0.25-3.75], p=0.014) decreased significantly from baseline compared to week 8 or early withdrawal, respectively. We did not observe a change in endoscopic or histological PDAI subscores. In this pilot study, clinical remission in patients with chronic pouchitis was achieved in 31% of patients after 8weeks of treatment with tofacitinib. Total and clinical PDAI dropped significantly compared with baseline, but we did not observe a significant change in endoscopic or histologic disease activity. Presumably, a treatment duration of 8weeks is insufficient to induce mucosal healing in these refractory patients.

Phase II single-arm, single-center clinical trial of all-trans-retinoic acid, bevacizumab, and atezolizumab in refractory microsatellite stable colorectal cancer.

TPS324 Background: A critical clinical challenge in microsatellite stable (MSS) metastatic colorectal (mCRC) patients is to identify strategies to overcome lack of response to immune checkpoint inhibitors. An immunosuppressive tumor microenvironment comprising myeloid-derived suppressor cells (MDSC), endothelial cells, regulatory T cells, tumor associated macrophages, and cancer associated fibroblasts promotes immune evasion and resistance to these agents. MDSCs are bone marrow derived myeloid cells that suppress T-cell function and promote tumor growth. Among all cancers, mCRC patients have one of the highest frequency of MDSC (CD11b+, CD33+, CD14+ HLA-DRneg) in blood (1). It was demonstrated that altering the MDSC% in the tumor microenvironment by ATRA and anti-VEGF therapy (bevacizumab) can enhance the effects of immune checkpoint inhibitors (2-4). The hypothesis of the current clinical trial is that the combination of ATRA, bevacizumab and atezolizumab will lead to a decrease in MDSC population in tumor microenvironment leading to a clinically meaningful improvement in response rates among refractory MSS mCRC patients. Methods: This is a single-arm, open-label, phase 2 clinical trial combining ATRA, bevacizumab, and atezolizumab in refractory MSS mCRC patients. It will enroll a total of 21 patients over 24 months at UT Southwestern Medical Center that are MSS by PCR or NGS testing or are proficient in immunohistochemical expression of all four mismatch repair enzymes (MLH1, MSH2, MSH6, PMS2). ATRA will be administered orally at 45 mg/m2/day in 2 divided doses on days 1-7 and repeated every 14 days; atezolizumab will be given intravenously on day 1 at 840 mg dose every 14 days, and bevacizumab will be administered intravenously on day 1 at 10 mg/kg dose every 14 days. The first six patients enrolled on this study will contribute to the safety lead-in phase of this study. The primary outcome is to assess the overall response rate by RECIST v1.1. Secondary outcomes include assessment of disease control rate and frequency of adverse events using CTCAE v5.0. Exploratory outcomes include assessment of PFS and OS and collecting blood and tissue samples at defined timelines to study the changes in the MDSC population among responders and non-responders (NCT05999812). 1. Kobayashi, M. et. al., Clin Cancer Res, 2019. 2. Mirza, N., et al., Cancer Res, 2006. 3. Tobin, R.P., et al., Int Immunopharmacol, 2018. 4. Tobin, R.P., et. al., Clin Can Res, 2023. Clinical trial information: NCT05999812 .

Phase II study of trifluridine/tipiracil (TAS-102) plus irinotecan in combination with bevacizumab as a second‐line therapy for patients with metastatic colorectal cancer.

155 Background: Metastatic colorectal cancer (mCRC) patients have poor prognoses with limited response to second-line chemotherapy. Therefore, it is urgent to refine and design an optimal second-line treatment regimen to improve the response rate and prolong the survival of patients with mCRC. This study assessed the safety and efficacy of the trifluridine/tipiracil (TAS-102), irinotecan, and bevacizumab regimen in second-line settings for mCRC patients. Methods: This was a multicenter, single-arm, phase II trial. The mCRC patients who are refractory to standard first-line treatment, including fluoropyrimidine and oxaliplatin, are eligible. Based on the recommended phase II dose established in phase I, enrolled patients received TAS-102 (30 mg/m2 twice daily on days 1-5) and irinotecan (150 mg/m2 on day 1) combined with bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the objective response rate (ORR). Results: Between October 1, 2023, and August 31, 2024, 60 patients were enrolled, and all of them were evaluated for efficacy. As of August 31, 2024, efficacy was assessed in all 60 participants with an ORR of 18.3% (2 had complete response, CR; 9 had partial response, PR; 39 had stable disease, SD). Among the 39 patients with SD, 29 patients experienced tumor shrinkage. The disease control rate (DCR) was 83.3%. The median follow-up was 8.6 months (95% confidence interval [CI], 6.743-10.457). The six-month progression-free survival (PFS) was 59.6%. The median PFS was 6.9 months (95% CI 5.016-8.784), whereas the median overall survival (OS) was not reached. The 1-year OS rate was 92%. At the time of analysis, four patients have died, and 56 patients are still alive. All patients were evaluable for safety assessment. The most common treatment-related adverse events (TRAE) were nausea (100%), neutropenia (86.7%), and anemia (83.3%). The most frequent grade 3/4 TRAE were neutropenia (48.3%), febrile neutropenia (8.3%), nausea (3.3%), and anemia (3.3%). No treatment-related death occurred. Conclusions: The regimen of irinotecan, TAS-102, plus bevacizumab preliminarily demonstrated promising efficacy with tolerable toxicity for mCRC patients as second‐line treatment. This regimen warrants further exploration in refractory mCRC patients. Clinical trial information: NCT06202001 .

Adverse events (AEs) –derived biomarker in predicting clinical outcomes in patients with colorectal cancer (CRC) treated with immunotherapy (IC).

132 Background: There are insufficient studies evaluating the role of AEs in CRC patients treated with IC. This study aims to transform AEs from traditional toxicity evaluation tools to informative biomarkers for assessing treatment efficacy by utilizing modern analytical strategies. Methods: We analyzed a single arm study of 51 mismatch repair proficient, refractory CRC patients (NCT03712943) treated with regorafenib and nivolumab. Data for analysis included CTCAE version 5 AE data, RECIST treatment response, progression-free survival (PFS), and overall survival (OS). Analytic approach leveraged multiple AE parameters to develop a set of innovative AE biomarkers. One AE biomarker of interest was treatment related low-grade early AEs (TR-LG-AE) which was defined as frequency of all TR-LG-AEs occurring between the 1st day and day 30 after the 1st treatment. Results: TR-LG-AE was associated with treatment response (p&lt;0.001 by ANOVA trend test). Patients with higher AE events tended to be a responder, compared to PD patients with a lower frequency of AE events. The TR-LG-AE also correlated with improved PFS and OS with hazard ratio of 0.83 (p=0.01) and 0.89 (p=0.03), respectively. Accordingly, patients were grouped into high versus low TR-LG-AE based on optimal cutoff of 6 events for further analysis. The dichotomized TR-LG-AE (high vs low) showed significant association with survival outcomes (median PFS: 15.3 vs 3.7 months; p&lt;0.001; median OS: 21.9 vs 9 months; p=0.02). Further interaction analysis showed patients with high TR-LG-AE had improved PFS regardless of occurrence of high-grade AE (HG-AE) (p=0.01), suggesting its independence of HG-AE. Individual AE analysis identified patients experienced with early low-grade rash maculo-papular, lipase increased, or hypertension had improved PFS (p&lt;0.001). In biomarker analysis, one key mutation biomarker, RAS, did not show significant association with survival outcomes (PFS: p=0.66; OS: p=0.81). In contrast, integration with TR-LG-AE led to remarkable improvement. Specifically, the TR-LG-AE was able to help improve RAS classification by identifying patients with better treatment benefit. Specifically, patients with RAS mutation and high TR-LG-AE experiences had a median PFS of 15.3 months compared to others (median PFS of 3.7 months; p=0.007), and a median OS of 21.9 months compared to others (median OS of 9.4 months; p=0.04). Conclusions: The study demonstrated utility of AE in predicting clinical outcomes in CRC, similar to our previous findings in lung cancer. Moreover, it discovered that integration of AE-derived biomarkers with molecular biomarkers could produce a more robust classifier than when considered individually. This analysis is the first of its kind to identify subgroups of CRC patients that benefit from IC treatment.

Bone marrow stromal cells protect myeloma cells from ferroptosis through GPX4 deSUMOylation.

Bone marrow stromal cells (BMSCs) are vital for preventing chemotherapy induced apoptosis of multiple myeloma (MM), but roles and machinery in other forms of cell death have not been well elucidated. Here, using an in vitro BMSC-MM interacting model, we observed BMSCs protected MM cells from labile iron pool (LIP) and reactive oxygen species (ROS) triggered ferroptosis by elevating glutathione peroxidase 4 (GPX4). Mechanistically, direct interaction with BMSCs upregulated the expression of SUMO-specific protease 3 (SENP3) in MM cells through CD40/CD40L signaling pathway, and SENP3 de-conjugated SUMO2 at lysine 75 residue to stabilize GPX4 protein, thereby consuming ROS to obviate ferroptosis in MM cells from the Vk∗MYC mouse model, as well as in CD138+B220- cells separated from the Cd40lfl/fl;Prx1Cre/+ mice (CD40-CKO) and Sumo2 knock out (SUMO2-KO) mice. Using the NOD-scid IL2Rgammanull (NSG) mouse based xenograft model and intra-bone MM growth model, we validated that target SENP3 enhanced the killing effect of GPX4 inhibitor RSL3, thereby reduced tumor burden, prolonged survival of mice, and alleviated bone disruption of mice bearing MM tumors. Our study deciphers the mechanism of BMSCs preventing MM cells from spontaneous ferroptosis, and clarifies the therapeutic potential of non-apoptosis strategies in managing refractory or relapsed MM patients.

Exploring Novel Therapeutics for Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive obliteration of pulmonary arteries. Dysregulated bone morphogenetic protein (BMP) signaling pathway contributes to the development of PAH, and pulmonary vasodilators including endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostaglandins and soluble guanylate cyclase stimulators, dramatically improve the long-term prognosis. However, there still exist refractory patients who require continuous catecholamine support or lung transplantation, and the development of new treatment strategies targeting molecular mechanisms of PAH is highly anticipated. Sotatercept, a first-in-class activin signaling inhibitor, has recently been approved for the treatment of PAH, and it targets and restores an imbalance in activin-growth differentiation factor and BMP pathway signaling. In addition, treatment strategies targeting peroxisome proliferator-activated receptor-γ signaling, inflammatory and immune systems, DNA damage response and cellular senescence, and growth factor receptors including vascular endothelial growth factor and platelet-derived growth factor receptors, are being devised. In this review, we briefly summarize the recent advances in basic research paving the way for the development of more effective treatments for PAH and their potential in clinical therapeutic applications.

Tumor Lesion Uptake of [177Lu]Lu-DOTA-Rituximab in Skeletal and Splenic Disease in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and a sizable fraction of the DLBCL patients presents with advanced, relapsed, and refractory disease, demonstrating poor response to standard chemotherapy regimens. Radioimmunotherapy (RIT) has shown to be clinically effective in refractory DLBCL. We present the case of a patient with DLBCL with [18F]FDG-avid widespread skeletal as well as splenic involvement as poor prognostic extranodal disease on FDG PET/CT. RIT based on [177Lu]Lu-DOTA-rituximab was explored to study the biodistribution and dosimetry of [177Lu]Lu-DOTA-rituximab in CD20-positive lymphoma. An exceptionally high tracer concentration in skeletal and splenic disease was observed, supporting its potential RIT application in relapsed and refractory DLBCL patients in the future.

P-1491. Practice variations and clinical outcomes of Intravenous Aminoglycosides in Nontuberculous Mycobacterium infections at three tertiary hospitals in London, Ontario, Canada

Abstract Background The worldwide occurrence of nontuberculous Mycobacterium (NTM) infections is rising. In Canada, there is a continuing surge in infections caused by Mycobacterium avium complex (MAC). Treating NTM infections is challenging and requires multidrug regimens with antimicrobial susceptibilities to guide therapy. Generally, aminoglycosides have moderate in-vitro activity against NTM isolates. However, the synergistic effect with other antimicrobials makes it an attractive choice for clinicians, especially in the management of severe or refractory cases. The recommended duration of intravenous aminoglycosides is debatable due to side effects and the need for therapeutic monitoring. Moreover, NTMs are becoming more resistant to aminoglycosides. This study aims to assess clinical practice variations in aminoglycoside use among NTM infections in terms of duration and monitoring in London, Canada. Patient Characteristics and Clinical Presentation Methods Retrospective study reviewing the characteristics of 30 patients diagnosed with NTM infection between January 1, 2019 and December 31, 2023 in three tertiary care hospitals in London, Ontario, Canada.Table 2:NTM Susceptibility Report Results Mean age at diagnosis was 60.8 years. Seventeen (57%) were male and 13 (43%) were female. The presentations included pulmonary NTM infections in 19 (63%) and skin and soft tissue infections in four (13%). Among all identified species, MAC was the most common. Fifteen (50%) patients received IV aminoglycosides, with 7 (32%) having documented susceptibility to aminoglycosides. Duration of aminoglycoside use varied among patients, ranging from 2 to 24 weeks. Of the patients started on an IV aminoglycoside, 3 (20%) developed ototoxicity and 2 (13%) had acute kidney injury. Serum aminoglycoside levels were checked in 12 (80%), but only 7 patients (47%) had at least one audiology screen. In terms of outcomes, 7 (23%) achieved clinical cure while 9 (30%) had refractory disease, 7 (78%) of which were pulmonary. Two (57%) of the cured patients and 2 (22%) of the refractory patients had received an aminoglycoside. Aminoglycoside Use and Monitoring Conclusion Aminoglycoside use for the treatment of NTMs is variable among clinicians, mostly due to concerns for side effects and the need for consistent drug monitoring, which limits its implementation in outpatient settings. Clinical Outcomes Disclosures Lise Bondy, Assistant Professor, Pfizer: Honoraria|Viiv: Advisor/Consultant Michael Silverman, MD, FRCP, FACP, AAHIVMed, Pfizer: Grant/Research Support

Efficacy of Serum BDNF for the Evaluation of Depressive Neurological Symptoms in Patients with Refractory Ulcerative Colitis

Background/Aims: Numerous patients with ulcerative colitis (UC) become mentally unstable after experiencing a long-standing, physically painful life, and their long-term prognosis is poorer than that of those who are mentally stable. The current study aimed to evaluate serum biomarkers for predicting mental instability, which is challenging to objectively quantify. Methods: In total, 29 refractory UC patients newly treated with filgotinib underwent measurements of blood parameters associated with depression and a quantitative assessment of quality of life using the Inflammatory Bowel Disease Questionnaire (IBDQ) before and after treatment initiation with a 12-week interval. The data collected were examined in relation to each other. Results: The induction of remission treatment with filgotinib resulted in a clinical response rate of 89.7% and a clinical remission rate of 86.2%, with all eight extraintestinal manifestations resolved. No adverse events were observed. The serum zinc, high-density lipoprotein cholesterol, mature brain-derived neurotrophic factor (BDNF) concentrations, and the IBDQ psychiatric subscores increased significantly after treatment (p &lt; 0.05). Among these parameters, the mature-BDNF concentration and the IBDQ psychiatric subscore had the strongest positive correlation (R = 0.29, p = 0.08). Based on the logistic regression analysis, the mature-BDNF concentration (cutoff value: 20.5 ng/mL) had a sensitivity of 68.2%, specificity of 64.7%, and area under the curve of 0.67 for predicting psychiatric remission (subscore &gt; 42.5) (p = 0.04). Conclusions: While it is not easy to objectively predict the degree of psychiatric instability in patients with refractory UC, serum mature-BDNF levels can be a useful biomarker.

Improving Treatment Options for Patients with Double Refractory CLL

The proliferation and survival of chronic lymphocytic leukemia (CLL) cells are heavily dependent on B-cell receptor (BCR) signaling and resistance to apoptosis. Approvals of multiple covalent Bruton’s tyrosine kinas inhibitors (cBTKis) as well as the B-cell lymphoma-2 inhibitor (BCL2i) venetoclax targeting these pathways have revolutionized the treatment of CLL and small lymphocytic lymphoma (SLL). The superiority of these treatments over chemoimmunotherapy has been proven in phase III studies in both treatment-naïve and relapsed refractory settings, leading to the majority of patients with CLL being treated sequentially with cBTKis and the BCL2i venetoclax as their first- and second-line therapies. While most patients with CLL respond for many years to these sequenced treatments, they are unfortunately not curative. There remains an unmet need for effective treatment options for patients who progressed after treatment with both cBTKis and BCL2i, also referred to as double refractory patients. Treatment options for double refractory CLL has improved recently with the approval of the non-covalent BTK inhibitor (ncBTKi) pirtobrutinib as well as the CD19 targeted chimeric antigen receptor T-cell (CAR T-cell) therapy lisocabtagene maraleucel (liso-cel). These recently approved treatment options for patients with CLL with at least two prior lines of therapy have fortunately demonstrated efficacy for double refractory CLL. Additionally, there are several novel treatment options in clinical development, including bi-specific antibodies, second-generation BCL2is, new ncBTKis, and BTK degraders. Understanding resistance mechanisms to existing cBTKis and venetoclax can potentially inform us of the best utilization of available treatment options for double refractory CLL and provide a personalized approach for these patients. In this review, a challenging example of a double refractory patient with CLL will serve as the basis for a review of available literature on the treatment of double refractory CLL/SLL.

P0411 Utility of Intestinal Ultrasound as a predictor of Severe Ulcerative Colitis response to treatment

Abstract Background Severe Acute Ulcerative Colitis (ASUC) is a serious complication of UC that requires an early response to treatment assessment and which clinical and analytical evaluations are often inadequate. In this setting, intestinal ultrasound (IUS) could be helpful, given its accuracy in evaluating inflammatory activity and non-invasiveness. The aim of this study was to determine whether basal IUS findings and index could predict ASUC patients’ response to corticosteroid treatment. Methods A retrospective descriptive study was done including ASUC patients admitted to our hospital between January 2019 and January 2024 whose IUS had been performed before corticosteroid treatment. Variables related to clinical and analytical activity at admission and after treatment, corticosteroids response and second-line therapy requirement were also collected. In addition, the need for colectomy during the episode and at 52 weeks of follow-up was analysed. Results 43 patients were included. Their and IBD baseline characteristics are summarized in Table 1. The 58% (25) of patients responded to corticosteroids. Regarding clinical response, the responders presented lower mean SAI index of 6.6, than non-responders (7.82), finding statistically significant differences (p=0.02). Truelove-Witts severity index was also lower among responders (16.75) than between corticosteroid-refractory patients (18.1), although no statistical significance was observed (p=0.11). Responders showed lower levels of CRP (18.5 mg/L) and FC (2007.5 µg/g) than refractory patients (CRP= 26.2 mg/L, FC=3185.1 µg/g) although the differences found were not significant (CRP, p=0.24; FC, p=0.23). Regarding baseline IUS, the responders had less parietal thickness (5.9 mm) compared to non-responders (5.8 mm), p=0.78. In addition, non-responders obtained major Simple US Score (11.1) than the other group (8.93), finding statistically significance (p=0.04). However, no significant differences (p=0.089) were observed in UCIUS score (responders 8.88, non-responders 8.97) or baseline MUC (p=0.78) between both groups (10.35 responders, 10.2 non-responders). Conclusion ASUC-IUS activity is related with corticosteroid clinical and analytical response, which demonstrates the role of IUS in early response to treatment assessment. Having found statistically significance or very close to significance differences with a limited sample size, statistical power and therefore, a greater risk of committing type 2 error make results even more paramount. Therefore, our study shows that IUS is a useful predictor of ASUC response to treatment. We hope that with this evidence the use of IUS monitoring becomes a closer reality to ASUC patients.

HSP-CAR30 WITH A HIGH PROPORTION OF LESS-DIFFERENTIATED T CELLS PROMOTES DURABLE RESPONSES IN REFRACTORY CD30+ LYMPHOMA.

CD30-directed CART cell therapy (CART30) has limited efficacy in relapsed or refractory patients with CD30+ lymphoma, with a low proportion of durable responses. We have developed an academic CART30 cell product (HSP-CAR30) by combining strategies to improve performance. HSP-CAR30 targets a proximal epitope within the non-soluble part of CD30, and the manufacturing process includes a modulation of ex vivo T cell activation, as well as the addition of interleukin-21 to IL-7 and IL-15 to promote stemness of T cells. We translated HSP-CAR30 to a phase 1 clinical trial of 10 patients with relapsed/refractory classical Hodgkin lymphoma (HL) or CD30+ T cell lymphoma (T-NHL). HSP-CAR30 was mainly composed of memory stem-like (TSCM-LIKE) and central memory (TCM) CAR30+ T cells (87.5%±5%). No dose-limiting toxicities were detected. Six patients had grade 1 cytokine release syndrome, and no patient developed neurotoxicity. The overall response rate was 100%, and 5 out of 8 patients with HL achieved complete remission (CR). An additional HL patient achieved CR after a second HSP-CAR30 infusion. Remarkably, 60% of patients have ongoing CR after a mean follow-up of 34 months. Of note, CAR30+ T cells at expansion peak had a predominance of TSCM and TCM cells, and CAR30+ T cells remained detectable in 3 of 5 evaluable patients at least 12 months after infusion. Our study shows that selection of the epitope targeting CD30 and ex vivo preservation of less-differentiated memory T cells may enhance the efficacy of CART30 in patients with refractory HL. This trial is registered at www.clinicaltrials.gov (NCT04653649).

P1263 Real-World Evidence Needs for Treatment Sequence Disease Modelling in Refractory Inflammatory Bowel Disease

Abstract Background Sequential use of biologics in Inflammatory Bowel Disease (IBD) is often required in clinical practice to restore or maintain long-term remission. Health technology agencies are requiring treatment sequencing models which are more reflective of clinical practice. The accurate modelling of treatment sequences would help better understand expected patient benefit and make more informed decisions. The aim of our targeted literature review (TLR) was to identify real-world evidence (RWE) on the effectiveness of second-line or later treatments for Crohn’s disease (CD) or ulcerative colitis (UC) refractory to initial therapy and assess its suitability for treatment sequence modelling. Methods We identified observational studies from Europe, the United States (US), and Canada via EMBASE, MEDLINE, and MEDLINE-In-Process (searched from 01/01/2018 to 11/12/2023). Study selection was conducted by a senior researcher and quality was checked by a second one. Evidence was analysed to assess the availability of clinical remission and response, and steroid-free remission data by line of therapy and across various time points. We then conducted a gap analysis against the evidence needs of a treatment sequence model Results After screening a total of 145 publications were included for data extraction in the review: 61 in ulcerative colitis (UC), 50 in Crohn’s disease (CD), and 34 in combined IBD. Studies were predominantly conducted in Europe (n=95), followed by the US (n=26), and Canada (n=3). A total of 12 studies reported clinical remission for first line, four for second line, and two each for third and fourth lines of treatments of refractory patients with UC. Additionally, eight studies reported data for first line, seven for second line, eight for third line, three for fourth line, and two for fifth line treatments of refractory patients with CD. The remaining studies combined results for multiple lines of treatment. Clinical remission during maintenance for patients with CD ranged between 47% - 79%, 38% - 87%, 28% - 68%, and 16% - 63%, for first, second, third, and fourth line, respectively and 40%-67%, 35% - 77%, 41% - 47%, and 16% - 21% for patients with UC. Studies lacked granularity in the assessment of clinical remission and response specific to individual treatments, stratified by specific treatment failure history Conclusion Studies identified in our evidence review did not report sufficiently granular data on clinical response or remission to reliably inform a treatment sequence model. Addressing these data gaps is essential for enabling more reliable decision-making in clinical practice, supporting better resource allocation, and ultimately improving long-term outcomes for refractory patients with IBD.

P1158 Patients with refractory and difficult-to-treat Inflammatory Bowel Disease are underrepresented in randomized clinical trials

Abstract Background A significant proportion of patients with inflammatory bowel disease (IBD) do not respond to treatment. Recently, criteria to define difficult-to-treat (DTT) IBD have been proposed1. These include IBD refractory to at least 2 advanced therapies with different mechanisms of action. We aim to review the representation of patients with prior exposure to biologics, DTT-IBD, and other challenging phenotypes in randomized clinical trials (RCTs). Methods A scoping review was performed by reviewing all RCTs of advanced therapies in IBD. We updated the literature searches of two published systematic reviews of ulcerative colitis (UC)2 and Crohn’s disease (CD)3 searching MEDLINE, EMBASE, and the Cochrane Library up to December 2023. Results We included 140 RCTs, 73 in ulcerative colitis (UC), and 67 in Crohn’s disease (CD), comprising 44.799 patients. In UC, 53% (39/73) of studies included patients with prior exposure to other biologics, but only 19% (14/73) included patients exposed to two or more biologics. Moreover, only 5% (4/73) of studies included participants exposed to biologics with multiple mechanisms of action, or DTT, and these accounted for 2% of the total participants of UC RCTs. None of the trials reported efficacy results specific for DTT. In CD, 60% (47/67) of studies included patients with any prior biologic exposure, and 31% (21/67) allowed the participation of patients who received two or more biologics. Only one study (1.5%) reported efficacy results for patients exposed to multiple mechanisms of action, DTT-IBD, which accounted for 7.4% of the study participants and 0.1% of all those in CD trials. In CD, history of prior intestinal surgery was reported only in 28 of 67 studies (42%) for 2977 patients, or 14.5% of the total participants. Similarly, upper gastrointestinal involvement of CD was included only in 21 trials (31%) and present in 808 participants (3.9%). Instead, the majority of trials either excluded patients with locations proximal to the terminal ileum (35 RCTs; 52%) or did not report whether some participants had upper gastrointestinal locations (11 RCTs; 16%) In both UC and CD there was a trend towards greater inclusion of exposed and refractory patients in recent years. Conclusion Patients exposed to multiple advanced therapies and those with phenotypes of CD more challenging to manage remain underrepresented in clinical trials of IBD.

P1110 Results from the UPITA-Colitis Registry on the Effectiveness and Safety of Upadacitinib in the Induction phase in Patients with Ulcerative Colitis

Abstract Background Upadacitinib, a next-generation JAK inhibitor, has shown positive results in phase 3 studies and was recently approved for moderate-to-severe ulcerative colitis. Our objective is to assess its effectiveness and safety in routine clinical practice. Methods Clinical and biochemical data were retrospectively collected from 14 hospitals in Andalusia, Spain. Clinical and analytical data up to week 16 were analyzed for patients who reached that point. Clinical remission (CR) was defined as a Partial Mayo Index ≤ 2 points, clinical-biochemical remission (CBR) as a Partial Mayo Index &amp;lt;3 and Calprotectin &amp;lt;250 μg/g, and remission without steroids (RWS) as a Partial Mayo Index &amp;lt;3 with no corticosteroid use since week 8. An intention-to-treat analysis was performed. Results A total of 70 patients were included, with a mean age of 37 years (range 17-69), 63.4% male. 59.2% had extensive disease, 30.8% left-sided colitis, and 10% proctitis. Of these, 82.1% were non-smokers, and 13.4% were ex-smokers. Extra-intestinal manifestations were present in 36%. The mean number of prior failed advanced treatments was 2. At the start of treatment, 33% were on 5-ASA therapy, 5% on Azathioprine, and 46% were taking corticosteroids. 67% of patients had prior Zoster virus vaccination. Induction with 45 mg for 8 weeks was administered to 57% of patients, 12 weeks to 18.5%, and 16 weeks to 4.1% (Table 1a)). Clinical and biochemical efficacy data are shown in Table 1b. At the time of the study, 6 patients had discontinued treatment before week 16, including two due to primary failure, one due to reactivation of Zoster virus, one due to pneumonia, and one for personal reasons. The following mild and transient adverse effects were reported (8.9% of total patients): 2 cases of cold sores, 2 cases of acne, and 1 case of paresthesia. Conclusion Upadacitinib proves to be an effective and useful treatment for induction of remission in refractory patients with ulcerative colitis, with an acceptable safety profile. References -Danese S, Vermeire S, Zhou W, Pangan AL, Siffledeen J, Greenbloom S, Hébuterne X, D’Haens G, Nakase H, Panés J, Higgins PDR, Juillerat P, Lindsay JO, Loftus EV Jr, Sandborn WJ, Reinisch W, Chen MH, Sanchez Gonzalez Y, Huang B, Xie W, Liu J, Weinreich MA, Panaccione R. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022 Jun 4;399(10341):2113-2128. doi: 10.1016/S0140-6736(22)00581-5. Epub 2022 May 26. Erratum in: Lancet. 2022 Sep 24;400(10357):996 -D’Haens G, Lindsay JO, Panaccione R, Schreiber S. Ulcerative colitis: shifting sands. Drugs R D 2019; 19: 227–34.9- Boland BS, Sandborn WJ, Chang JT. Update on Janus kinase antagonists in inflammatory bowel disease. Gastroenterol Clin North Am 2014; 43: 603–17

P1056 Effectiveness and Safety of Upadacitinib Induction Therapy in Real-World Setting for 234 Patients with Crohn’s Disease: A GETAID Multicentre Cohort Study

Abstract Background While upadacitinib has demonstrated its efficacy as an induction treatment for Crohn’s disease (CD) in two phase 3 randomized, placebo-controlled trials1, real-world data remain limited. Methods From September 2022 to September 2024, all consecutive patients with refractory CD treated with once-daily upadacitinib 45 mg in 30 French and Belgian GETAID centres were retrospectively included. The primary endpoint was steroid-free clinical remission (SFCR) at week 12, defined as a Harvey-Bradshaw Index (HBI) score of &amp;lt; 4. Secondary endpoints included clinical response (decrease of ≥ 3 points in the HBI score and/or an HBI score &amp;lt; 4), clinical remission, biological remission (calprotectin ≤ 250 µg/g, or CRP ≤ 5 if calprotectin was unavailable), endoscopic or radiological (IUS and/or MRI) response, and adverse events (AEs). Results 234 patients were included, all of whom had been previously exposed to at least one biologic (median 4, IQR[3-4]), and 125 (53.9%) had undergone prior intestinal resection (Table 1). At week 12, SFCR was observed in 107 patients (n=107/197, 54%), clinical response in 120 (n=120/190, 63%) and clinical remission in 111 (n=111/197, 56%). Ninety-two (n=92/179, 51%) achieved biological remission and endoscopic or radiological response was observed in 19 (n=19/40, 48%) patients (Figure 1). Respectively 28 (n=28/37, 76%) and 20 (n=20/37, 54%) of patients with articular EIMs achieved clinical response and remission. For cutaneous EIM, clinical response was achieved in 10 patients (n=10/11, 91%), and clinical remission was achieved in nine patients (n=9/11, 82%). In multivariate analysis, body mass index &amp;lt; 18.5 kg/m2 (OR=0.09, 95%CI: 0.01-0.33, p=0.002) and HBI &amp;gt; 7 (OR=0.24, 95%CI: 0.12-0.47, p&amp;lt;0.0001) were associated with lower rates of SFCR at W12 while the number of prior biologics did not influence SFCR (OR = 0.72, 95% CI: 0.35-1.48; p = 0.36). At week 12, 35 (15%) patients discontinued upadacitinib (lack of effectiveness, n=31; AEs, n=2 and other, n=2). CD-related hospitalization was needed in 18 (7.7%) patients, and 4 (1.7%) underwent intestinal resection. Sixty-eight AEs occurred in 61 patients (26%), including 19 serious AEs, corresponding to 18 cases of CD exacerbation and one case of colonic EBV-associated lymphoproliferative disorder. Acne was observed in 25 (10.7%), justifying treatment discontinuation in one (0.4%). Conclusion In this real-world cohort of highly refractory CD patients, upadacitinib induction resulted in a clinical response in about two-thirds of patients and SFCR in half of patients.

P1130 Real-life histological remission in Ulcerative Colitis patients treated with Ustekinumab: results from the Belgian SULTAN trial

Abstract Background Histological remission is an aspirational therapeutic target in Ulcerative Colitis (UC) associated with lower relapse rates.1Ustekinumab (UST), a monoclonal antibody against the p40 subunit of interleukin (IL) 12 and 23 has shown in the UNIFI trials to be effective and safe in patients with moderate-to-severe UC. However, real-life data on histological remission rates are sparse. The aim of the study was to assess the real-life histological response and remission rates of UST in patients with UC across Belgian hospitals. Methods In this multicentric, retrospective observational study, patients with UC who initialised UST treatment between September 2020 and July 2023 were included. Histological remission was defined as Nancy score = 0, response as Nancy ≤ 1 and assessed at week 16 and 52 by the local pathologist. Other endpoints included steroid-free clinical remission (partial Mayo ≤ 2 with no subscore &amp;gt;1), endoscopic remission (endoscopic Mayo = 0), endoscopic response (Mayo score ≤ 1) and clinical response (decrease in partial Mayo score ≥ 3 points and ≥ 30% plus a decrease in rectal bleeding score ≥ 1 or an absolute rectal bleeding score ≤ 1). UST drug persistence was analyzed by Cox regression analysis, predictors of other endpoints by logistic regression. Results 120 patients with moderate to severe UC (86% patients with ≥S2 severity) were included across 16 participating centers. Median disease duration was 11 years (IQR 9) and 81 (68%) of patients had previously failed 2 or more biologicals. Histological remission was achieved in 3/37 (8%) and 5/45 (11%) at W16 and W52, while histological response was seen in 10.8% (4/37) and 26.7% (12/45) respectively. Steroid-free clinical remission rates were 41/120 (34%) and 38/85 (44%) while endoscopic remission was seen in 23/120 (19%) and 13/52 (25%) at W16 and 52 respectively. Two patients (40%) in histological remission at W52 had an endoscopic Mayo 0 score, while 3 had a Mayo 1 (60%) at the time of evaluation. Active smoking was a negative predictor for achieving steroid-free remission (OR 0.412, p=0.011). No significant predictors for histological remission or response could be identified. UST drug persistence by week 52 was 70.8%. Active smoking (OR 3.058, p=0.02), vedolizumab non-response (OR 2.592, p=0.03) and a high Nancy baseline score (OR 2.46, p=0.04)) were associated with UST failure Conclusion In this multi-centric, real-life cohort with highly refractory UC patients, UST shows acceptable clinical and endoscopic remission rates, but histological remission rates remain low after one year of treatment.

P0949 Long term real-world effectiveness and safety of upadacitinib in patients with moderate to severe Crohn’s disease: A Belgian multi-centric refractory cohort

Abstract Background The therapeutic options for Inflammatory Bowel Disease (IBD) have expanded with the introduction of JAK inhibitors. However, real-world data on upadacitinib (UPA) in patients with moderate to severe Crohn’s disease (CD) are scarce. Our aim was to assess the long-term effectiveness and safety of UPA in multi-refractory Belgian patients. Methods Data from all patients with active CD initiating UPA between September 2022 and January 2024 were retrospectively collected from 17 Belgian centres. Effectiveness endpoints were evaluated at week 24 and 52. Steroid-free clinical response and remission were defined using the two-component patient-reported outcome. Endoscopic response was defined as a decrease in baseline Simple Endoscopic Score (SES-CD) with ≥50%, and endoscopic remission as SES- CD ≤ 4 or absence of ulcers. Adverse events (AE), treatment discontinuation, CD-related hospitalization and surgery were assessed throughout follow-up. Non-response imputation was applied for clinical evaluation. Results A total of 140 patients were included (Table 1) with a median follow-up of 33 weeks (IQR: 3-97). The majority of patients (89%) were exposed to at least 3 biologics. At week 24, 53% and 40% of patients achieved steroid-free clinical response and remission, respectively (Figure 1). At week 52, these numbers were 37% and 29%. Endoscopic data were available in 48/140 patients at week 24, of whom 52% and 27% reached endoscopic response and remission. At week 52, these numbers were 63% and 37%. Of patients with active articular extra-intestinal manifestations at baseline 37% and 34% had a quiescent articular disease by week 24 and 52, respectively. 5 out of 9 patients with active perianal disease at baseline and on UPA by week 52, had persistent perianal active disease. Overall, 66 patients (47%) discontinued UPA during follow-up: 23 due to primary non response, 13 due to secondary loss of response, 16 due to AE, 3 due to patient’s choice and 11 due to CD-related surgery. 16 patients required CD-related hospitalization within 52 weeks. AE occurred in 60% of patients (84/140). Of these patients, 11% experienced serious AE of which 2 cardiovascular events: 1 transit ischemic attack and 1 deep venous thrombosis. The most common reported AE were herpes simplex reactivation (5/140), respiratory tract infection (7/140), cutaneous reactions (7/140) and acne (17/140). Only 3 patients had reactivation of herpes zoster infection. Conclusion In this real-world cohort of highly refractory CD patients, UPA effectively induced both steroid-free clinical remission and endoscopic remission by week 52. UPA was relatively well tolerated with respect to adverse events.

OP05 Efficacy and safety of autologous hematopoietic stem cell transplantation in refractory Crohn’s disease: outcomes from the international stem cell transplant consortium

Abstract Background Autologous hematopoietic stem cell transplant (HSCT) emerged as a treatment for refractory CD after several clinical studies including a randomized clinical trial (ASTIC).1,2 In CD patients at risk for bowel failure these studies demonstrated an endoscopic response in over 80% of patients with two transplant related deaths. A recent randomized trial using an alternative fludarabine-based conditioning regimen had unexpected safety outcomes with 2 deaths and renal failure secondary to thrombotic microangiopathy.3 Here we report recent long-term clinical and safety outcomes of HSCT for refractory CD using a cyclophosphamide-ATG conditioning regimen from 3 international centers. Methods Data from 100 patients was reviewed from 3 international centers (Barts Health, UK; Hospital Clinic Barcelona, Spain and Mount Sinai, US) for subjects with medically refractory CD that underwent HSCT. We compiled clinical (CDAI) and endoscopic (SES-CD) evaluations at baseline and the last documented follow-up after HSCT for 68 patients that underwent HSCT since the ASTIC trial. We further compiled additional outcomes including new initiation of advanced therapy, IBD-related surgery, need for parental nutrition, hospitalizations and death. Results As of the last follow-up (median 2 years) post-HSCT, 75% of patients had endoscopic improvement (SES CD↓50%) and 53% endoscopic remission (SESCD&amp;lt;4 ulcer sub-score&amp;lt;1) (N = 56)(Figure 1). 65% of patients were in clinical remission. 46% did not require advanced therapy following HSCT and of patients that started an advanced therapy 84% required a single therapy over 120 patient-years of follow-up (Figure 2). After HSCT there were 7 CD-related surgeries of which 2 were ileostomy reversals. No patients progressed to bowel failure and there were no long-term (&amp;gt;100 days post-HSCT) complications related to transplant including hospitalization, renal failure, death or malignancy. Conclusion In this multicenter international study, the majority of patients demonstrated sustained endoscopic and clinical improvement without progression to bowel failure or with long-term transplant related adverse events over 120 patient-years of follow up. These results support HSCT as a therapy for highly refractory CD patients and the need to refer these patients to international centers of expertise to prevent CD-related morbidity and mortality.

P0799 Efficacy and Safety of Dual Therapy for Refractory Inflammatory Bowel Disease in a Danish Cohort

Abstract Background Patients with Crohn’s disease (CD) and ulcerative colitis (UC) may become refractory to monotherapy with biologics or small molecules. Dual therapy, combining biologics and small molecules, has been proposed for this challenging population. While awaiting randomized studies, real-world data on its efficacy and safety are crucial. This study contributes to the evidence on dual therapy in a Danish adult IBD cohort. Methods Medical records from May 2018 to May 2023 were reviewed for CD and UC patients undergoing dual therapy with biologics and/or small molecules in outpatient gastroenterology clinics at Aarhus University Hospital and Regional Hospital Randers. Patients treated for at least three months were included and followed until treatment discontinuation or the end of the study period. Patient characteristics, clinical outcomes, adverse events, and efficacy data were collected at baseline and follow-up. Results Seventy-four patients (47 with CD and 27 with UC) received a total of 79 dual therapies. The median duration of dual therapy was 488 days for CD and 412 days for UC. The most common combinations were adalimumab and ustekinumab in CD (46%) and adalimumab and vedolizumab in UC (35%). Clinical remission was achieved in 56% of CD patients and 62% of UC patients. Steroid-free follow-up was observed in 81% of CD patients and 52% of UC patients (Table 1). In CD, dual therapy significantly reduced stool frequency, bloody stools, calprotectin levels, and Harvey-Bradshaw Index (HBI) scores. In UC, stool frequency, nighttime stools, abdominal pain, CRP, calprotectin, and Simple Clinical Colitis Activity Index (SCCAI) scores significantly decreased, while hemoglobin and albumin levels significantly improved. Serious adverse events (SAEs) occurred in 12% of UC patients and 14% of CD patients, consistent with prior studies of adult and pediatric cohorts [1, 2]. No UC patients required colectomy during the study period. Conclusion This retrospective study demonstrates a substantial rate of clinical remission and acceptable safety in refractory IBD patients receiving dual therapy. The findings highlight prolonged treatment duration, significant clinical improvements, and a manageable SAE profile. Dual therapy represents a promising approach for refractory and complex IBD, though the risk of SAEs must always be balanced against therapeutic benefits.