Years Of Remission Research Articles

7860 Predictors of Remission in Patients with Graves' Disease Treated with Antithyroid Drugs at the University of Santo Tomas Hospital - A Retrospective Cohort Study

Abstract Disclosure: F.E. Sorsona: None. E.C. Cunanan: None. This is a local study with the objective to determine the predictors of remission in Graves’ disease patients who completed 12 to 18 months of antithyroid drug therapy in University of Santo Tomas Hospital (Manila, Philippines) from 2017 to 2022. The study employed a retrospective cohort design. Patients included were all Graves’ disease patients seen at University of Santo Tomas Hospital who were treated with antithyroid drug methimazole. Data were collected via a retrospective review of medical charts. From the 203 Graves’ disease patients, a total of 59 patients met the inclusion criteria and were included in the study. Following completion of antithyroid drug therapy, patients were divided into remission and non-remission groups. Predictive factors analyzed were age, gender, smoking history, presence of orbitopathy and goiter, duration of ATD therapy, and thyroid function tests (TSH, free T3 and free T4) at time of initiation and completion of ATD. Forty-nine patients (83%) were females, and ten patients (17%) were males. The median age at the time of ATD initiation was 35 years old. The median duration of ATD therapy was 24.2 months. Following completion of ATD, 34 patients had remission with incidence of 57.63% (95% CI: 44.07-70.39%). Age, gender, smoking history, presence of goiter and orbitopathy, duration of ATD therapy, thyroid function tests at initiation, and FT3, FT4 and FT3/FT4 ratio at time of completion showed no significant differences between the two groups. After univariate and multivariate analyses, only one factor was significantly associated with 1-year remission which was the TSH at the time of ATD completion, with a median of 1.54 mIU/L, range: 0.001-7.94 mIU/L. Median TSH was significantly higher among patients who had remission than those with non-remission. Compared to patients with normal TSH at the time of ATD completion, the odds of remission was 14 times lower among patients with low TSH, and 7 times lower among patients with high TSH. A normal TSH at the time of ATD completion was associated with 1-year remission from Graves’ disease. Presentation: 6/2/2024

Long-term Outcomes and Prognostic Factors of Gastric MALT Lymphoma.

This study aimed to evaluate the long-term prognosis of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, including overall survival (OS), remission, and factors associated with an aggressive disease course. Medical records of 153 patients diagnosed with gastric MALT lymphoma between 2013 and 2020 were retrospectively reviewed. Patients experiencing relapse, progression, high-grade transformation, or residual diseasewere included in the aggressive group and were compared with those in the indolent group. Additionally, the endoscopic findings of Helicobacter pylori-negative patients were reviewed. Patient characteristics were as follows: mean age (56.9±11.2 years), sex (male, 51.0%), H. pylori infection (positive, 79.7%), endoscopic location (distal, 89.5%), endoscopic feature (superficial, 89.5%), clinical stage (stage I, 92.8%), invasion depth by endoscopic ultrasound (mucosa, n=115, 75.7%), and bone marrow result (no involvement, n=77, 100.0%). The median follow-up period was 59 months (mean, 61; range, 36-124) and the continuous remission period (n=149) was 51 months (mean, 50; range, 3-112). The 5-year survival rate was 97.7% while the 5-year continuous remission was 88.3%. Factors associated with the patients in the aggressive group were old age, sex(male), and clinical stage II or higher. H. pylori-negative patients' endoscopy revealed a high incidence of atrophic gastritis in the antrum. The long-term prognosis of gastric MALT lymphoma appears indolent and is indicated by the 5-year OS and continuous remission rates. Aggressive disease courses are associated with old age, sex (male), and clinical stage II or higher, but are not related to OS.

Pediatric Inflammatory Bowel Disease Type Unclassified: A Nationwide Cohort Study in Scotland With up to 20 Years Follow-up Shows Reclassification in the Majority and Mild Course in Those Whose Diagnosis Is Unchanged.

Given the paucity of long-term longitudinal data for inflammatory bowel disease type unclassified (IBDU), we aimed to clarify IBDU disease course and reclassification rate by presenting nationwide data with up to 20 years of follow-up. We analyzed a prospectively identified 11-year cohort of pediatric patients diagnosed with IBDU between January 1, 2003 and December 31, 2013 at all Scottish pediatric IBD centers and followed up into adult services until December 31, 2022. Data were obtained from electronic medical records at fixed timepoints (5 and 10 years post-diagnosis) and at the final follow-up. Overall, 102 patients were included in the analysis (57/102 [56%] male, median [interquartile range {IQR}] age at diagnosis: 11.5 [9.1-13.2] years) with a median (IQR) follow-up length of 10.5 (8.6-14.0) years. A change of diagnosis was made in 61 of 102 patients (60%); of these, 30 patients (29%) were reclassified to Crohn's disease (CD) and 31 patients (30%) to ulcerative colitis (UC). Patients who remained with IBDU had higher 1- to 5-year remission rates (IBDU 30/39 [77%] vs reclassified 16/57 [28%], P < .05), with lower rates of moderate-to-severe disease (IBDU 3/39 [8%] vs reclassified 31/57 [54%], P < .05) and less need for biologics across all timepoints (IBDU vs reclassified: first timepoint 1/39 [3%] vs 17/57 [30%], second timepoint 1/33 [3%] vs 26/56 [46%], third timepoint 0/18 [0%] vs 16/33 [49%]; all P < .05). Higher rates of surgical resections were observed in reclassified patients (reclassified 11/61 [18%] vs IBDU 1/41 [2%], P = .02). In our nationwide pediatric IBDU cohort, 60% of patients were reclassified to either UC or CD over 10.5 years of median follow-up; those who remained with IBDU had a milder disease course.

Efficacy and safety of rituximab in patients with PLA2R associated membranous nephropathy and resolved HCV infection

Rituximab occasionally induces reactivation of hepatitis C virus (HCV) in patients with resolved HCV infection, sometimes with fatal consequences. As rituximab has become one of the first-line therapies for the treatment of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) and is more widely used, there is a lack of studies reporting the effectiveness and safety of rituximab in patients with PLA2R-associated MN and resolved HCV infection. A single-center retrospective study was conducted on PLA2R-associated membranous nephropathy (MN) patients who were HCVAb positive but HCV-RNA negative and treated with rituximab. A total of 598 adult patients with PLA2R-associated MN who underwent rituximab therapy were screened. General clinical information, including gender, age, pathological data, and previous treatment plans, was collected from medical records. Routine blood tests, liver and kidney function assessments, blood lipid profiles, 24-h urine protein levels, anti-PLA2R antibody titers, circulating B-cell counts, and HCV viral loads were measured at the time of rituximab infusion and repeated at intervals of 1–3 months post-rituximab administration. A total of 8 patients were enrolled, with a median follow-up period of 19.00 (range: 16.00–25.25) months. Among the 8 patients, 5 were male, and the mean age was 50.13 ± 4.29 years. Histological findings indicated that tubuloreticular inclusions, mesangial deposits, intramembranous deposits, and subendothelial deposits were not observed in any of the 8 patients. The overall 1-year remission rate for these patients was 75%, accompanied by a significant reduction in proteinuria. Additionally, blood albumin levels increased significantly, and renal function remained stable. No increase in HCV viral load and stable liver function tests were observed throughout the entire follow-up period. This study suggested that on the basis of successful eradication of HCV virus with antiviral drugs, rituximab can effectively induce clinical remission of patients with PLA2R associated MN and resolved HCV infection, and does not lead to a significant increase in HCV virus load. However, this finding is based on a very small sample size and should be confirmed in larger clinical trials.

A case of posttransplant isolated extramedullary relapse of acute lymphoblastic leukemia achieving durable treatment-free remission with blinatumomab and donor lymphocyte infusion.

Acute lymphoblastic leukemia (ALL) relapsed after allogeneic hematopoietic cell transplantation (allo-HCT) has a catastrophic prognosis. Blinatumomab, a CD3/CD19-directed bispecific T cell engager, is reportedly effective for advanced B-cell ALL (B-ALL), even after allo-HCT. However, the efficacy of blinatumomab in extramedullary relapse (EMR) is controversial. Donor lymphocyte infusion (DLI) is another immunological treatment worth considering for ALL relapsed after allo-HCT. We report the case of a 56-year-old woman with B-ALL. Allo-HCT was performed during the second complete remission (CR). Thirteen months after allo-HCT, isolated EMR (iEMR) of B-ALL developed without bone marrow lesions. A third CR was achieved with 2 cycles of blinatumomab. An additional four cycles each of blinatumomab and DLI were then administered. The patient did not develop graft-versus-host disease and has confirmed 2-year treatment-free remission without a second allo-HCT. Therefore, blinatumomab was considered an effective salvage therapy for iEMR of B-ALL after allo-HCT, because iEMR could have a lower tumor burden than that seen in systemic relapse, and low tumor burden was a prognostic factor for response to blinatumomab. Furthermore, immunological consolidation therapies could only provoke graft-versus-leukemia effects if the imbalanced effector/target ratio was restored and the tumor burden was lowered through immunosurveillance.

Impact of blue-collar vs. white-collar occupations on disease burden in psoriatic arthritis patients: A Swiss clinical quality management in rheumatic diseases cohort study

Biomechanical stress may exacerbate inflammation in psoriatic arthritis (PsA). This study aimed to investigate disease activity, work disability, and drug response/retention rates in PsA patients among two different occupation’s types: blue-collar workers (BCol) with manual labor versus white-collar workers (WCol) with sedentary occupations. PsA patients registered in the Swiss cohort (SCQM) were classified as BCol or WCol workers and assessed at the initiation of a biologic or targeted synthetic disease-modifying anti-rheumatic drug (b-/tsDMARD). We compared the baseline characteristics at treatment start and the DAS28-CRP for the 1-year remission. Treatment retention was investigated using Kaplan–Meier curves and Cox regression analysis. Multivariable models were adjusted for potential confounders. Of 564 patients, 29% were BCol, and 71% were WCol workers. Baseline disease activity was comparable between both groups. BCol workers were predominantly male (79.8%) and more work disabled at baseline (84.0% vs. 27.9%; p < 0.01). One hundred seventy-four treatment courses (TCs) of 165 PsA patients were included for longitudinal analysis. Occupation did not significantly influence the achievement of DAS28-CRP remission at 1 year. Kaplan–Meier analysis (n = 671) indicated longer retention for BCol workers (mean retention duration: 3.15 years vs. 2.15 years, (p = 0.006). However, adjusted Cox regression analysis did not corroborate these findings. This study indicates that physically demanding occupations correlate with increased rates of work disability among PsA patients, while treatment response seems to be unaffected by the patients’ occupation type. Additional research is required to thoroughly comprehend the relationship between physical workload, disease activity, and treatment outcomes.Key Points• This study indicates that physically demanding occupations correlate with increased rates of work disability among PsA patients.• The treatment response among of PsA patients seems unaffected by the patients’ occupation type.

Treatment Patterns and Preferences for Graves' Disease in Korea: Insights from a Nationwide Cohort Study.

Treatment patterns and preferences for patients with Graves' disease (GD) vary across countries. In this study, we assessed the initial therapies and subsequent treatment modalities employed for GD in real-world clinical practice in Korea. We analyzed 452,001 patients with GD from 2004 to 2020, obtained from the Korean National Health Insurance Service database. Initial treatments included antithyroid drug (ATD) therapy (98% of cases), thyroidectomy (1.3%), and radioactive iodine (RAI) therapy (0.7%). The rates of initial treatment failure were 58.5% for ATDs, 21.3% for RAI, and 2.1% for thyroidectomy. Even among cases of ATD treatment failure or recurrence, the rates of RAI therapy remained low. Regarding initial treatment, the 5-year remission rate was 46.8% among patients administered ATDs versus 91.0% among recipients of RAI therapy; at 10 years, these rates were 59.2% and 94.0%, respectively. Our findings highlight a marked disparity in the use of RAI therapy in Korea compared to Western countries. Further research is required to understand the reasons for these differences in treatment patterns.

Early postoperative growth hormone measurement as a predictive marker for acromegaly remission.

Growth hormone (GH) has a short half-life and declines abruptly following somatotropinoma surgery, enabling its prompt measurement as an indicator of surgical success. This study assesses the predictive value of early postoperative GH levels for 3-month and >1-year remission of acromegaly. We conducted a retrospective search in our database of patients who had undergone transsphenoidal surgery of GH-secreting pituitary adenoma from January 2011 to June 2022. Only the patients who underwent the first pituitary surgery and had GH measurements on the fifth postoperative day were included. The 3-month and >1-year remission of acromegaly was defined as achieving the GH nadir of <0.4 μg/L during an oral glucose tolerance test and maintaining normal insulin-like growth factor 1 levels at the initial follow-up visit 3 months after surgery and throughout at least the first year postoperation. We included 63 patients in the analysis, with a median follow-up of 51.8 (13-155) months. The 3-month remission was achieved in 42 (66.7%) patients, and >1-year remission without additional therapy in 38 (60.3%) patients. Those who achieved >1-year remission had significantly lower fifth-day postoperative GH levels (0.59 [0.09-8.92] vs. 2.63 [0.25-24.64] μg/L, p < .001). Receiver-operating characteristic analysis revealed a significant value of fifth-day postoperative GH levels regarding the prediction of 3-month (area under the curve [AUC], 0.834; p < .0001) and >1-year (AUC, 0.783; p < .0001) acromegaly remission. The GH threshold of ≤1.57 μg/L yielded a sensitivity of 90.5% and a specificity of 71.4% at 3 months and 89.5% sensitivity and 60% specificity at the >1-year remission, respectively. Notably, all patients with fifth-day postoperative GH levels ≤0.23 μg/L exhibited remission of acromegaly throughout the follow-up period. Early postoperative GH measurement could be a reliable predictor of both 3-month and >1-year remission of acromegaly.

Identification of gaps in the delivery of high-quality care of patients with eosinophilic esophagitis.

Quality indicators (QIs) are standardized metrics that can be used to quantify health care delivery and identify important areas for practice improvement. Nine QIs pertaining to the diagnosis and management of eosinophilic esophagitis (EoE) were recently established. We therefore aimed to identify existing gaps in care using these QIs. This is a retrospective, multicenter study utilizing recently established EoE QIs to evaluate practice patterns among adult gastroenterologists in the diagnosis and management of EoE. Three patient cohorts of 30 patients each presenting with dysphagia, food impaction, and new diagnosis of EoE, respectively, were obtained, yielding 120 patients per site to assess for every QI. Summary statistics were reported across two main themes: diagnosis and management. Subsequent analysis of gaps in care was then performed. The domain of diagnosis of EoE (QI 1 and 2) had the most notable gap in care with only 55% of the presenting patients undergoing appropriate evaluation for EoE. The domain of management of EoE had overall higher QI fulfillment-however it also contained significant intra-category variation in care. Notably, while 79% of patients had clinical follow-up within 1year from remission, only 54% underwent surveillance endoscopy within 2years of remission. In contrast, 100% of patients with symptomatic strictures independent of histologic response underwent endoscopic dilation (QI 4). Management approaches for EoE are evolving and variation in care delivery exists. We identified significant gaps in both diagnosis of EoE especially amongst patients presenting with index food impaction and long term management of EoE, when retrospectively evaluating care patterns using newly established QIs. This is the first study of its kind to utilize these previously established QIs to objectively identify care gaps that exist in EoE amongst several institutions. These findings also highlight the importance of QIs and standardization of management of complex chronic diseases like EoE to help bridge these gaps and provide a framework to measure adherence to these best practices.

Effect of physical activity on the course of inflammatory bowel disease

The inflammatory bowel disease (IBD) group includes ulcerative colitis (UC), Crohn's disease (CD) and microscopic enteritis. In UC, the lesions involve only the large intestine and do not cross the mucosa, while CD can involve any part of the gastrointestinal tract, from the mouth to the anus. Inflammatory bowel disease usually occurs between the ages of 20-30, with another peak incidence in the seventh decade of life. The etiology of inflammatory bowel disease is not fully understood. Diagnosis is made on the basis of clinical evaluation, endoscopic examination with histopathological evaluation and imaging studies. Treatment involves the introduction of an appropriate diet, and pharmacological, biological and surgical treatments are used. The prognosis is inauspicious, with inflammatory lesions often recurring, even after years of remission of the disease. The purpose of this paper is to describe in detail the two most common diseases in the inflammatory bowel disease group, highlighting the differences and similarities between them at the level of lesion localization, symptoms, diagnosis and treatment. Patients with inflammatory bowel disease, due to the accompanying symptoms that make daily activities difficult, are less active than healthy people. There is ample evidence of the beneficial effects of physical activity on quality and length of life. It is recommended to conduct moderate intensity of both endurance and resistance exercises.

Mortality in relation to diabetes remission in Swedish Obese Subjects -a prospective cohort study.

People with obesity and type 2 diabetes (T2D) have reduced life expectancy, partly explained by increased risk of cardiovascular diseases and cancer. Here, we examined whether 2-year diabetes remission after bariatric surgery or usual care is associated with long-term mortality. This report includes 586 participants with obesity and concomitant T2D from the prospective Swedish Obese Subjects (SOS) cohort study; 338 underwent bariatric surgery and 248 received usual obesity care. At inclusion, age was 37-60 years and BMI ≥34kg/m2 in men and ≥38kg/m2 in women. Median follow-up was 26.2 years (interquartile range 22.7-28.7). Diabetes status was determined using self-reported data on diabetes medication and in-study measures of blood glucose and HbA1c. The study was cross-linked to Swedish national registers for data on morbidity, death, and emigration. Overall, 284 participants, 71.9% of surgery and 16.5% of usual care patients, were in remission at the 2-year examination. During follow-up, mortality rates were 16.6 deaths per 1000 person-years (95% CI:13.7-20.1) in the remission subgroup and 26.0 deaths per 1000 person-years (95% CI:22.2-30.4) in the non-remission subgroup (adjusted hazard ratio (HRadj)=0.71, 95% CI:0.54-0.95, P=0.019). The adjusted median life expectancy in the remission subgroup was 2.5 years (95% CI:0.3-4.7) longer than in the non-remission subgroup. Specifically, remission was associated with decreased cardiovascular mortality (sub-HRadj=0.54, 95% CI:0.35-0.85, P=0.008), but no detectable association with cancer mortality was found (sub-HRadj=1.06, 95% CI:0.60-1.86), P=0.841). In this post-hoc analysis of data from the SOS study, patients who achieved short-term diabetes remission had increased life expectancy and decreased cardiovascular death over up to 32 years of follow-up. Future studies should confirm these findings.

Factors contributing to the improvement in J-HAQ after 3 years of treatment with abatacept in biologic-naïve rheumatoid arthritis patients: Interim results of a long-term, observational, multicentre study in Japan (ORIGAMI).

We investigated the long-term effectiveness, safety, and factors affecting Japanese Health Assessment Questionnaire (J-HAQ) improvement during abatacept treatment in Japanese rheumatoid arthritis (RA) patients. The ORIGAMI study is an ongoing observational study of biologic-naïve RA patients with moderate disease activity treated with subcutaneous abatacept (125 mg, once-weekly). Patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry as an historical, weighted control group. The primary endpoint for this interim analysis was the proportion of patients with J-HAQ remission (score ≤0.5) at 3 years. Among 279 abatacept-treated and 220 csDMARD-treated patients, J-HAQ remission was achieved at 3 years in 40.5% (95% confidence interval [CI] 34.7%-46.2%) and 28.9% (95% CI 9.9%-47.8%), respectively. Age, RA duration <1 year, baseline J-HAQ score, and Simplified Disease Activity Index remission at 6 months were associated with 3-year J-HAQ remission in the abatacept group. Overall, 24/298 patients (8.1%; safety analysis set) experienced serious adverse drug reactions with an incidence of 5.3 per 100 person-years. This study confirmed the 3-year effectiveness and safety, and revealed potential factors associated with J-HAQ remission in biologic-naïve RA patients treated with abatacept in real-world clinical practice.

Five-year outcomes of revisional bariatric surgery: gastric band to sleeve gastrectomy or to Roux-en-Y gastric bypass.

Revisional bariatric surgery after an index adjustable gastric band (AGB) may be indicated to remedy weight relapse or band-related complications. We examined outcomes five years following revision from AGB to laparoscopic sleeve gastrectomy (AGB-LSG) or to Roux-en-Y gastric bypass (AGB-RYGB). We conducted a retrospective review to identify patients (men and women, age 18-80) who underwent one revisional bariatric procedure with AGB as the index procedure at two medical centers in our healthcare system between January 2012 and February 2017. We only included patients with a pre-revision BMI > 30kg/m2 for whom 5-year follow-up data were available. We compared 5-year weight loss and remission of comorbidities in patients undergoing AGB-LSG and AGB-RYGB conversion. A total of 114 patients met inclusion criteria (65 AGB-LSG, 49 AGB-RYGB). At 5-year post-revision, percent total weight loss (3.4% vs 19.9%; p < 0.001), percent excess weight loss (7.0% vs 50.8%; p < 0.001) and decrease in BMI (1.5 vs 8.8; p < 0.001) was greater in AGB-RYGB vs. AGB-LSG. No significant difference in remission or development of new comorbidities was observed. Conversion of AGB to RYGB is associated with superior intermediate-term weight loss compared to conversion of AGB to LSG. Future multicenter studies with larger sample sizes are necessary to further describe the intermediate-term outcomes of revisional bariatric surgery.

Patient Preferences for Lifestyle Management in a Multi-site Randomized Lifestyle Trial for Remission of the Metabolic Syndrome.

Randomized behavioral clinical trials are the gold standard for evaluating efficacy of a behavioral treatment. However, because participants are generally unblinded to treatment, preference for a specific treatment option can lead to biased results and/or reduced treatment efficacy. The purpose was to describe the relative frequency and correlates of existence of a preference and patient preference for either an in-person group-based or a remote self-directed, lifestyle treatment prior to randomization to one of these treatments. The Enhanced Lifestyles for Metabolic Syndrome (ELM) trial is a multi-site behavioral clinical trial that compares efficacy of a group-based vs. a self-directed approach to lifestyle change on 2-year remission of the metabolic syndrome. Prior to randomization, participants were asked whether they had a preference for a particular treatment and, if so, which approach they preferred. Baseline data were used for a series of logistic regression models to determine behavioral correlates of treatment preference, independent of socioeconomic factors. Of the 331 participants, 131 (39.6%) had no preference for either treatment. Among the 200 with a preference, 56 (28.0%) preferred the self-directed program. Strength of a pre-existing habit of eating vegetables on most days was an independent correlate of no preference (adjusted OR, 1.27; 95% CI, 1.01-1.61; p = 0.03) and preference for a self-directed program (adjusted OR, 1.55; 95% CI, 1.09-2.22; p =0.01). A pre-existing habit of eating vegetables was associated with no preference and preference for a less intensive lifestyle treatment. Post-treatment follow-up of the trial results will determine if concordance between preference and treatment assignment influences outcomes.

Endothelial Dysfunction in Children With Nephrotic Syndrome: A Cross-Sectional Study.

Background Children with nephrotic syndrome (NS) have a higher risk of cardiovascular morbidity. Studies on the evaluation of arterial stiffness and endothelial function and its predictive risk factors in these children are limited. Objective The primary objective of the study was to determine arterial stiffness by measuring carotid intimal medial thickness, flow-mediated dilatation, and physiological parameters in children with nephrotic syndrome to predict the risk of premature atherosclerosis as compared to controls. Participants A total numberof 33 children with NS in the age group of 2-14 years in remission and 39 healthy controls were enrolled in the study. Out of 33 children with nephrotic syndrome, five were infrequently relapsing NS, eight were frequently relapsing, 16 were steroid dependent, and four were steroid-resistant NS. Intervention Relevant history, physical examination, anthropometric measurements, and laboratory investigations were done. Carotid intimal medial thickness (cIMT), flow-mediated dilatation (FMD), and other physiological parameters were measured in both children with NS and control groups. Outcome Carotid intimal medial thickness (cIMT), flow-mediated dilatation (FMD), and other physiological parameters were compared between children with NS and healthy controls for detecting arterial stiffness and endothelial dysfunction. Results Dyslipidaemia was seen in more than 50% of children during remission. There was neither significant difference in mean cIMT in the common carotid artery nor FMD between the control and study groups. There was a trend of lower Reactive Hyperemia Index (RHI) in children with NS. Conclusion Dyslipidemia persists even during the remission phase in NS. No statistically significant difference is observed in cIMT and percentage proportionate change in FMD in both the study and control groups. Nevertheless, RHIis notably lower in children with NS. These findings need further validation in future studies.

REAL-WORLD SAFETY AND EFFICACY OF USTEKINUMAB AND VEDOLIZUMAB IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Abstract CONTEXT/PURPOSE Ustekinumab and vedolizumab are approved biologicals to treat adults with inflammatory bowel disease (IBD) but currently administered off-label for children. Aims: (1) assess safety and adverse events during treatment with ustekinumab or vedolizumab in pediatric IBD and (2) assess steroid free clinical remission and mucosal healing at 6 months and 1 year. METHODS Retrospective chart review of pediatric patients (&amp;lt;22 years) with IBD treated at an academic hospital and two affiliated practices. Inclusion: Patients with IBD who received either ustekinumab or vedolizumab between January 2015 to June 2022 with minimum of 6 months follow up. Clinical remission assessed by Pediatric Ulcerative Colitis Activity Index (PUCAI) &amp;lt; 10 and short Pediatric Crohn’s Disease Activity Index (shPCDAI) &amp;lt;15, and mucosal healing by fecal calprotectin &amp;lt;250 mcg/gram. RESULTS Fifty-eight patients received vedolizumab and 55 patients received ustekinumab. Patients with ulcerative colitis (UC) or IBD unclassified (IBDU) on vedolizumab were more likely to be in remission at 6 months (58% vs. 42%, p = 0.3, Table 1) and significantly higher at achieving 1-year steroid free remission (64% vs. 27%, p = 0.019) compared to ustekinumab. Over two thirds of biologic naïve and about half of biologic exposed patients who received vedolizumab achieved 1-year steroid free remission (78% vs. 58%, Figure 1). All patients who received ustekinumab were biologic exposed. In Crohn’s disease (CD), no significant difference was seen in children receiving vedolizumab compared to ustekinumab at 6 months remission (57% vs. 63%, p = 0.7) or 1-year steroid free remission (70% vs. 70%, p &amp;gt;0.9). All biologic naïve patients and half of biologic exposed patients who received vedolizumab achieved 1 year steroid free remission. Both bionaive and two thirds of biologic exposed patients who received ustekinumab achieved 1-year steroid free remission (100% vs. 67%). When comparing vedolizumab and ustekinumab, no significant difference was observed in 6 month remission (73% vs. 59%, p = 0.2) and 1-year steroid free remission based on calprotectin (61% vs. 66%, p = 0.7). Similar to clinical remission rates, biologic naïve patients tended to have higher remission rates based on calprotectin. Five patients each had minor adverse events with ustekinumab and vedolizumab, and 20 were hospitalized mostly for IBD flare. CONCLUSION Both biologicals were safe and effective in achieving clinical remission at 6 months and 1 year. They were more effective when used in bionaive patients, although numbers were very low for ustekinumab. The superior efficacy of vedolizumab in UC and IBDU at 1-year may be attributed to larger cohort of bionaive patients. Larger multicenter prospective studies are needed to validate these findings regarding efficacy and safety of vedolizumab and ustekinumab in pediatric IBD. Table 1 Remission on Vedolizumab and Ustekinumab Figure 1 Remission on Vedolizumab vs. Ustekinumab Stratified by Biologic Exposure

Decreased circulating dipeptidyl peptidase-4 activity after short-term intensive insulin therapy predicts clinical outcomes in patients with newly diagnosed type 2 diabetes.

This study aims to investigate the changes in circulating dipeptidyl peptidase-4 (DPP-4) activity following short-term intensive insulin therapy (SIIT) in newly diagnosed type 2 diabetes (T2D) patients and to assess its potential in predicting long-term remission. Ninety-five patients underwent SIIT for 2-3 weeks to attain and sustain near-normal glycemia. Insulin was then discontinued, and patients were followed for a year to evaluate glycemic outcomes. Biochemical tests, serum DPP-4 activity, and mixed meal tolerance tests were conducted at baseline, post-SIIT, and the 3-month follow-up. DPP-4 activity decreased from 44.08 ± 9.58 to 40.53 ± 8.83 nmol/min/mL after SIIT (P<0.001). After three months post-SIIT, DPP-4 activity remained stable in the remission group (39.63 ± 8.53 nmol/L) but increased in the non-remission group (42.34 ± 6.64 nmol/L). This resulted in a more pronounced decrease in DPP-4 activity from baseline in the remission group (-3.39 ± 8.90 vs.-1.10 ± 8.95, P = 0.035). Logistic regression analyses showed that patients with greater DPP-4 activity reduction had a higher likelihood of 1-year remission (70% vs. 51.1%, OR: 7.939 [1.829, 34.467], P = 0.006 in the fully adjusted model). A non-linear relationship between △DPP-4 and 1-year remission rate was observed, with a clear threshold and saturation effect. Circulating DPP-4 activity significantly decreases after SIIT. The change in circulating DPP-4 activity during the 3-month post-treatment phase has the potential to predict long-term remission.

The Different Impacts of an MRD-Guided Protocol on Relapse of Childhood Acute Lymphoblastic Leukemia: The Report of Taiwan Pediatric Oncology Group (TPOG)-ALL-2013

Taiwan Pediatric Oncology Group (TPOG)-ALL-2013 protocol (TPOG-2013), modifying from St. Jude Total Therapy XV Study and Total Therapy XVI Study, was launched since January 2013. This is the first nationwide minimal residual disease (MRD)-directed protocol for treatment of childhood acute lymphoblastic leukemia (ALL) in Taiwan. According to TPOG-2013, two MRD measurements were scheduled on days 15-19 of induction (MRD1 time point, TP1) and days 35-42, end of induction (MRD2 time point, TP2) to make the definitive risk stratification to guide subsequent therapy. As of April 30, 2023, 814 newly diagnosed ALLs treated with TPOG-2013 and followed up ≥3 years were enrolled in the study. The outcomes were compared with those of TPOG-ALL-2002 protocol (TPOG-2002) (N=1350, between January 2002 and December 2012), which did not integrate the MRD monitoring. The 5-year event-free survival and overall survival were significantly improved from 76% (95% CI, 74-78) and 81% (80-84) of TPOG-2002 to 86% (83-88) and 89% (87-92) of TPOG-2013, respectively ( P&amp;lt; 0.0001). For further analysis of TPOG-2013, 585 (72%) patients with exact adherence (EA) to both TPs were assigned as MRD EA group; 225 patients who were non-adherence (NA) to either one of TPs as MRD NA group; and four patients were excluded for the comparative outcome analysis. For B-cell precursor (BCP) ALL, the 5-year cumulative incidence of relapse (CIR) significantly decreased from TPOG-2002 (N=1194) to TPOG-2013 MRD EA (N=527) ( P &amp;lt;0.0001). However, there was no significant improvement of CIR between TPOG-2002 and MRD NA (N=202) ( P= 0.21) (Figure 1). In MRD EA of BCP-ALL, compared with TPOG-2002, patients with ETV6::RUNX1 or BCR::ABL1 appeared to have significantly lower CIR. Patients without the common genetic subtypes , denoted as “negative” group, also had significant inferior CIR. And the trend of CIR decrease did not attain significant difference in high hyperdiploidy. In contrast, patients with T CF3::PBX1 or infant with KMT2A-rearrangement did not show CIR improvement (Table 1). In T-ALL, compared with TPOG-2002 (N=156), there was a significant decrease of CIR in TPOG-2013 MRD EA (N=58)( P= 0.01)(Table 1), but not in MRD NA (N=23)( P= 0.86). There was a longer duration to relapse in MRD EA of BCP-ALL. However, a delay of relapse was only demonstrated in patients with BCR::ABL1, which could be addressed by the introduction of MRD-monitoring and TKI inhibitor in TPOG-2013 (Table 1). Further, in term of early relapse before 1.5 year of remission, there was no significant difference in MRD EA of BCP-ALL, compared with TPOG-2002. In conclusion, this study demonstrated diffident impacts on relapse according to genetic subtypes and MRD adherence. In the negative group of BCP-ALL without the discovery of novel genetic alternations, the relapse could be much decreased with the MRD-directed treatment protocol.

A Phase II Study of Low-Intensity Chemotherapy (Mini-Hyper-CVD) and Ponatinib Followed By Blinatumomab and Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background Patients with Philadelphia chromosome (Ph)-positive B-cell acute lymphoblastic leukemia (ALL) treated with Hyper-CVAD and ponatinib achieve deep responses and long-term overall survival (OS). We aim to investigate if a reduced intensity regimen of mini-Hyper-CVD (mini-HCVD) with sequential blinatumomab (blina) in combination with ponatinib may further improve outcomes while mitigating the toxicity of intensive chemotherapy and the need for hematopoietic stem cell transplantation (HSCT). Methods Patients age ≥18 years with newly diagnosed (ND) or relapsed/refractory (R/R) Ph-positive ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Other inclusion criteria included adequate liver, renal and cardiac function, and ECOG performance status ≤2. Patients with baseline central nervous system (CNS) involvement were not excluded. All patients had BCR::ABL1 transcripts and fluorescence in situ hybridization (FISH) for t(9;22) done at baseline. Morphological analysis of FISH patterns was performed in ND patients to identify if the BCR::ABL1 signal was observed in myeloid cells (e.g., segmented neutrophils). Four cycles (C) of mini-HCVD alternating with methotrexate (MTX) + cytarabine were followed by blina 28µg/d given for four weeks every six weeks during C5-8. Patients received ponatinib 30mg daily initially, with a dose reduction to 15mg daily once in complete molecular remission (CMR). CMR was defined as undetectable BCR::ABL1 with an assay sensitivity of 0.01%. Rituximab was given for CD20-positive disease. Maintenance ponatinib, vincristine and prednisone for 15 cycles with blina + ponatinib every three cycles was given, followed by ponatinib for at least five years. All patients without CNS disease received 12 intrathecal injections of MTX or cytarabine. Results 20 patients (12 ND, 4 R/R, 4 CML-LBP) were treated between November 2019 and May 2023. Baseline characteristics are shown in Table 1. One patient with CML-LBP had received prior dasatinib while in chronic phase. The predominant BCR::ABL1 transcript was p190 in 7 (58%) ND patients. All patients achieved a complete remission (CR). Among patients in the ND, R/R, and CML-LBP cohorts, CMR was achieved in 10/12 (83%), 3/4 (75%), and 4/4 (100%) patients, respectively. In the ND cohort, six (50%) patients achieved CMR after C1 and eight (67%) after C3. Five (42%) ND patients had documented BCR::ABL1 signal in myeloid cells by FISH. Four of them achieved CMR, after C1, C3, C4 and C3 maintenance respectively. With a median follow-up of 25 months (range, 2-42), the 2-year continuous remission duration (CRD) and OS rates were 93% and 83% for the entire cohort (Figure 1), and 90% and 82% in the ND cohort, respectively. In the ND cohort, one (8%) patient had isolated CNS relapse (during C4 of maintenance with blina and ponatinib), three (25%) patients died (two in CR due to COVID-19 and one of HSCT complications), and eight (67%) patients are in remission without HSCT. No patients relapsed in the R/R cohort; one patient underwent HSCT, one patient died in CR from MTX-associated disseminated necrotizing leukoencephalopathy, and two patients are in remission without HSCT. None of the CML-LBP relapsed; one patient underwent HSCT in CR. Ponatinib dose was reduced in two patients prior to obtaining CMR (one had pancreatitis, one had cardiomyopathy). One patient switched from ponatinib to dasatinib due to a pulmonary embolism in C2. No patients required dose modification of blina. The 60-day mortality rate was 0%. Conclusion In patients with Ph-positive ALL, the combination of mini-HCVD and ponatinib followed by sequential blina and ponatinib yielded excellent outcomes with durable remissions. The toxicity profile was favorable and HSCT was avoided in most patients with ND disease. Longer follow-up is needed to confirm the durability of responses.

Efficacy and Safety of AALL0232 Protocol in Adults with Acute Lymphoblastic Leukemia: Single Institution Experience

Background Over the past few decades, the outcomes for children with ALL have significantly improved with current regimens that yield a 5-year complete remission (CR) and event-free survival (EFS) rates of 98% and 70-80%, respectively. In contrast, the adult population has a CR of 85-90%, with a less satisfactory disease-free survival (DFS) rate of only 30-40% at 5-years. The feasibility of Children's Oncology Group (COG) AALL0232 protocol in older patients has not been established, especially adults older than 40 years and whether they will tolerate such unmodified pediatric based regimen. Therefore, we planned to assess our practice's outcomes in terms of the efficacy and safety of the COG AALL0232 protocol in adult ALL patients. Method This was a retrospective observational study that included patients ≥ 14 years with newly diagnosed ALL. Patients were excluded if they have secondary ALL. Our institute has adopted the AALL0232 protocol for both B-cell and T-cell ALL due to the similarities between the AALL0232 and CALGB 10403 protocols. MRD data was not included in our study since the cut-off for detection has been changed over the study period. Patient demographics and treatment-related outcomes will be reported using descriptive statistics. OS and RFS probabilities will be calculated using the Kaplan-Meier product-limit method from the date of pre-phase initiation. All P-values will be two-sided with P &amp;lt;0.05 indicating significance. Results Between 2014 and 2022, a total of 96 patients were included in our study. 74% had B-cell and 26% had T-cell ALL. The majority of the patients had standard risk ALL (23%). 65% of the patients were receiving AALL0232 protocol. Early death with AALL0232 protocol occurred in 11.1% of our population. The 2-year OS rate was 72.6% (95% CI 61.4-81.1) (Figure 1). The OS rate for B-cell ALL was 78.5% compared to 53.8% for T-cell ALL at 2-years (P =0.0912). The use of AALL0232 protocol was comparable to other protocols in terms of survival with a 2-year OS rate of 77% and 62.3%, respectively (P=0.0761). Adults with favorable cytogenetic risk had an OS rate of 100% compared to 67.6% for standard and 49.2% for poor risk (P =0.047). Adults younger than 40 years had a higher OS rate compared to those older than 40 (76.4% vs. 54.7%, P= 0.0187). RFS rate at 2-years was durable in 68.2% of the patients (95% CI 56.8-77.2) (Figure 2). RFS rates were 72.3% for B-cell and 54.8% for T-cell ALL. The AALL0232 Protocol had a significant impact on RFS compared to other protocols (73.6% vs. 56.5%, P= 0.0277) (Figure 3). Those who were younger than 40 had an RFS rate of 73.9%. The 2-year NRM occurred in 21.7% of the population. The AALL0232 protocol did not result in a higher NRM compared to other protocols (P= 0.492). Conclusion Although the use of AALL0232 protocol in the adult population has a remarkable impact on the rate of relapse, its effect on survival remains questionable especially for patients with T-cell ALL and poor cytogenetic risk. Another point of concern is the early death rate that was observed in our study. Further studies are needed to assess the overall impact of COG protocol in the adult population.