Evaluation Time Points Research Articles

Abstract P062: The CL2A-SN38 linker-payload system conjugated to trastuzumab results in improved cellular cytotoxicity over time relative to T-DM1

Abstract Background The approved antibody-drug conjugate (ADC) sacituzumab-govitecan (SG) that exploits the topoisomerase I inhibitor SN38, represents a substantial advance in the ADC field. SN38 is the first payload with low nanomolar cytotoxicity. This deviates from current design principles, which utilize ultracytotoxic payloads. The CL2A linker has a short non-cleavable seven polyethylene glycol segment that enables a higher number of hydrophobic SN38 molecules to be attached to reduced cysteines. CL2A is also designed to permit the release of SN38 in an acidic environment via a pH-sensitive benzyl carbonate bond to SN38’s lactone ring. There is no cathepsin B cleavage site. Key to the performance of SG is the SN38 release half-life of 1-2 days. This also deviates from very stable linker systems that require full ADC internalization and lysosomal processing for payload release. As a result of these novel ADC properties, SG is given in higher and repeated doses, which results in slow release at the tumor site and enhanced uptake by target cancer cells and reduced toxicity on healthy cells due to low potency SN38 alone. Our goal is to further evaluate the CL2A-SN38 system when conjugated to trastuzumab. Material and methods Trastuzumab was conjugated to CL2A-SN38 to reduced cysteines (T-SN38). Monitoring the changes in DAR over time was performed to determine the stability of T-SN38 in PBS at pH values of 7.4, 5.72, and 4.58, to mimic circulating blood, early endosomes, and lysosomes, respectively. Cytotoxicity assays for 72 h on HER2-positive ovarian cancer SKOV3.ip and HER2-negative CHO cells were performed and compared to the approved anti-HER2 ADC trastuzumab-emtansine (T-DM1). Cytotoxicity assays were also performed between T-SN38 and T-DM1 at their respective IC50 values and the percent of cell survival determined daily from 24-96 h. Results T-SN38 was generated with a DAR of 6.97. Surprisingly, the half-life of SN38 release in acidic pH was extremely slow (t1/2=~120 h) and at the final evaluated time point (120 h) 69% of SN38 remained conjugated to trastuzumab. As anticipated, as a function of concentration T-DM1 was significantly more potent than T-SN38 (IC50=0.0013 vs 0.0832 mg/mL). However, when cytotoxicity was evaluated as a function of time T-SN38 switched to the more potent ADC at the late time points. T-SN38 killed SKOV3.ip cells 36% more effectively than T-DM1 at 96 h. Conclusions Our data from SN38 release experiments in acidic buffer suggest that pH-induced cleavage of the CL2A linker is not a contributable release mechanism of SN38 when bound to trastuzumab and is counterintuitive for what is currently described for SG. However, traceless release of hydrophobic SN38 capable of traversing cell membranes is only possible by hydrolysis of the benzyl carbonate bond. Our cytotoxicity studies over time suggest that pH-dependent release does occur. Further investigations are ongoing to more precisely determine the contribution of the carbonate bond for SN38 release and cytotoxic potency. Citation Format: Hardeep Singh, Victor Jeffrey Leyton. The CL2A-SN38 linker-payload system conjugated to trastuzumab results in improved cellular cytotoxicity over time relative to T-DM1 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P062.

Prediction of Clinical Response to Venetoclax Plus Decitabine in AML Using a 7-Day Ex Vivo Assay

Prediction of Clinical Response to Venetoclax Plus Decitabine in AML Using a 7-Day Ex Vivo Assay

A pilot study of multiple time points and multidomain assessment in cerebrospinal fluid tap test for patients with idiopathic normal pressure hydrocephalus

ObjectiveOur study aimed to identify the appropriate evaluation time point and assessment forthe CSF tap test(TT) to predict the shunting responsiveness of patients with idiopathic normal-pressure hydrocephalus (iNPH). MethodsEighty-eight inpatients with clinically possible iNPH who underwent CSF TT at multiple time points (baseline, 8 hours, 24 hours, and 72 hours after CSF TT) at Peking Union Medical College Hospital were recruited. The multidomain assessment included the timed up and go test(TUG), 10-meter walking tests, and a brief executive function battery. Performance in multidomain assessment at the indicated time points were compared. The positive response rate and cumulative positive rate of multidomain assessment at multiple time points were calculated. And their corresponding specificity and sensitivity of predicting shunting response were calculated according to the follow-up results after shunting. ResultsThe multidomain assessment performance except TUG at 8 hours were significantly improved at each time point after CSF TT compared with baseline (P<0.01). Reduction more than 10% in the 10-meter walking time and number of steps at 24 hours showed the highest specificity (both 85.7%) and sensitivity (37.5% and 46.7%, respectively) for predicting shunting response. Additionally, an improvement of more than 20% in the composite z score at 72 hours showed 100% specificity and 80% sensitivity for predicting shunting response. ConclusionMultiple time points and multidomain assessment were helpful to identify more shunting responders. Executive function evaluation might be a candidate tool to increase the effectiveness of CSF TT.

Application of Suspension Fixation with Button Plates for Patients with Distal Radioulnar Joint Dislocation: A Case Series.

ObjectiveThe aim of the present study was to assess the effect of suspension fixation with button plates on the reconstruction of the distal radioulnar joint dislocation (DRUJ).MethodsThis was a case series of six patients (two men and four women) who underwent suspension fixation with button plates for DRUJ dislocation between January 2015 and May 2017. Physical examination, radiography, MRI, functional activity of the wrist joint, grip strength of the wrist joint, Garland–Werley wrist score, Mayo wrist score, and visual analog scale (VAS) score were used to evaluate the effect of this procedure. All patients were followed up every 3 months. The evaluation time point was 12 months after the operation. Comparisons of the functional indexes of wrist function before and after the operation were performed using paired statistical tests.ResultsThe mean range of motion of the affected limb was 70° at forearm pronation and 75° at forearm supination. The subjective assessments and tests of the motor function of the wrist showed improvement after surgery. The Garland–Werley wrist score was 13.50 ± 2.66 preoperatively, the Mayo wrist score was 56.67 ± 18.35, and the VAS score was 4.83 ± 1.17. The Garland–Werley wrist score was 2.83 ± 1.33 postoperatively at 12 months, the Mayo wrist score was 87.5 ± 6.89, and the VAS score was 0.50 ± 0.55. At 12 months, the Garland–Werley wrist score, the Mayo wrist score, and the VAS score showed significant improvements when compared with those before surgery (P = 0.000, P = 0.003, and P = 0.000, respectively). Radiographic examination revealed that the internal fixation device was in place, and no dislocation of the DRUJ could be observed. None of the patients had internal fixation device removal or re‐dislocation of the DRUJ. None of the patients had re‐dislocation of the DRUJ. No secondary ulnar or radial fractures and nerve injury were reported during and after surgery. No tumor recurrence was observed in patients with giant cell tumors of the tendon sheath. No loosening and displacement of screws were reported.ConclusionThe new method of suspension fixation with button plates for the surgical reconstruction of a DRUJ dislocation is simple, with minimal trauma, and maintains the stability of the DRUJ without the need for intra‐articular or extra‐articular reconstruction of the ligament. Furthermore, it allows early functional exercise and achieves satisfactory postoperative functional recovery.

Intravenous methylcobalamin effectively ameliorated painful diabetic neuropathy: A randomized double-blind placebo controlled trial

Objective. Painful diabetic neuropathy (PDN) is a prevalent debilitating consequence of diabetes mellitus with lack of satisfactory therapeutic options. Methylcobalamin (MeCbl) is one of vitamin B12 analogs with known neurotrophic effects. We aimed to determine if MeCbl can relieve PDN. Materials and methods. This was a randomized (1:1) double-blind placebo-controlled trial involving PDN patients. Treatment and control group received daily 12.5 mg oral amitriptyline bid with either 500 µg of intravenous MeCbl or saline injection given on alternating days, respectively, for a 9-consecutive day period. PDN was assessed with douleur neuropathique 4 (DN4) questionnaire. Numeric pain rating scale (NPRS) was used to monitor pain intensity and treatment response. All investigators and patients were kept blinded throughout the study period. Outcomes. 42 patients, 21 on each arm had completed the study. The NPRS reduction can already be observed as early as day 2 post-intervention. Both the treatment and control group demonstrated sustained reduction of NPRS by almost one point per each time point of evaluation in the first three days (p&lt;0.001). NPRS reduction remained until the end of the study period. The treatment group had a significantly lower NPRS score by 1.29 than that of the control group during the entire study period (95% CI -1.84 – -0.75; p &lt; 0.001). Treatment group experienced significantly higher NPRS reduction when compared with control (4.19±1.54 vs. 2.1± 0.83; 95% CI 1.32-2.87; p &lt; 0.001), i.e. 62.6% from baseline. Conclusions. MeCbl significantly and safely relieved PDN in a relatively rapid onset.

Impact of COVID-19 on serum melatonin levels and sleep parameters in children

Background/aim This study aimed to analyze the serum melatonin levels and changes in sleep patterns in pediatric patients with coronavirus disease 2019 (COVID-19).Materials and methods This study was designed as a descriptive, cross-sectional study. Serum melatonin levels and sleep parameters of children with the diagnosis of COVID-19 who had mild and moderate disease (i.e., COVID-19 group) were compared with those of children admitted with non-COVID-19 nonspecific upper respiratory tract infection (i.e., control group). The sleep disturbance scale for children (SDSC) questionnaire was applied to the participants› primary caregivers to analyze their sleep patterns at present and six months before symptom onset and to investigate the impact of COVID-19 on sleep patterns. Results The entire study cohort consisted of 106 patients. The COVID-19 group included 80 patients, while the control group consisted of 26 patients. The mean serum melatonin levels were 136.72 pg/mL and 172.63 pg/mL in the COVID-19 and control groups, respectively (p = 0.16). There was no significant difference between the groups in terms of 6 subcategories of the SDSC questionnaire regarding the present time and 6 months before symptom onset. The total SDSC scores were also similar in two different evaluation time points described above (p = 0.99).ConclusionsWe conclude that COVID-19 did not impact the sleep parameters of children. Serum melatonin levels of all patients were higher than the reference range; however, they were higher in the non-COVID-19 patient group than the COVID-19 group. Since serum melatonin levels were higher than the reference values in children with COVID-19, and this disease is significantly less morbid in children, melatonin may have protective effects against COVID-19.

REGN1908-1909 monoclonal antibodies block Fel d 1 in cat allergic subjects: Translational pharmacokinetics and pharmacodynamics.

REGN1908‐1909, a 1:1 cocktail of two fully human IgG4 monoclonal antibodies (mAbs), REGN1908 and REGN1909, is being evaluated for treatment of cat allergy. Both REGN1908 and REGN1909 bind to the dominant cat allergen, Fel d 1. Adults with cat allergy confirmed by skin prick test (SPT) were randomized to single subcutaneous administration of placebo (n = 6) or REGN1908‐1909 at doses of 150 (n = 6), 300 (n = 6), or 600 mg (n = 6). Blood samples were taken at prespecified time points for pharmacokinetic (PK) analysis and exploratory evaluation of biomarkers (IgE and SPT). Safety was assessed. Drug concentration‐time profiles in serum for ascending doses of REGN1908‐1909 were consistent with linear PKs. Noncompartmental analysis showed that maximum concentration (Cmax) and exposure increased proportionately with dose, with similar time to maximum concentration (Tmax) for REGN1908 and REGN1909 (6.2 to 8.2 days across doses), and a longer terminal half‐life for REGN1908 (~ 30 days) relative to REGN1909 (~ 21 days). Adverse events were not dose dependent; there were no dose‐limiting toxicities. REGN1908‐1909 is characterized by linear and dose‐proportional kinetics of the two individual mAb components. A single 600 mg dose maintains total mAb mean concentrations in serum above the target (mean of ~ 10 mg/L) for 8–12 weeks. Maintaining this mean target concentration resulted in translational pharmacodynamic effects: maximal mast cell degranulation in a passive cutaneous anaphylaxis mouse model, and maintenance of clinical efficacy measured by Total Nasal Symptom Score in a previous proof‐of‐mechanism study.

Analysis of the Outcome and Prognostic Factors of Cyclosporine A in Children with Non-severe Aplastic Anemia

To summarize the long-term efficacy of cyclosporine (CsA) in the treatment of non-severe aplastic anemia (NSAA) in children, and explore the early significant indicators. Data of 36 NSAA children in Department of Hematological Oncology, Wuhan Children's Hospital, Tongji Medical College of Huazhong University of Science and Technology from January 2013 to December 2017 were analyzed retrospectively. All the children received oral CsA immunosuppressive therapy, and CsA trough concentration was checked to maintain at the rage of 200-250 μg/L after 2 weeks. The evaluation time points were at 3, 6, 12, 18 and 24 months, and assessment items were peripheral white blood cell differential count and reticulocyte's percentage and count. The 36 NSAA cases were composed of 16 males and 20 females, whose median age was 5.46 (2.92-7.99) years old, and median follow-up time was 28.00 (10.00-38.25) months. After taking oral CsA for 24 months, the number of cumulative effective cases was 21. There were 4 cases of complete remission (CR), 17 cases of partial remission (PR), and 15 cases of non-remission (NR). The total effective rate was 58.33%, and median effect-acting time of CsA was 3.0 (0.5-10.0) months. Compared with ineffective group, neutrophil (NEU) and red blood cell (RBC) of effective group (CR+PR) began to increase significantly at the 3rd month, and hemoglobin (Hb), platelet (PLT) and white blood cell (WBC) increase significantly at the 6th month after oral CsA administration (P<0.05). Except for 2 cases who received component transfusion within 3-12 months after taking oral CsA for 3 months in effective group, the others did not need. The overall effective rate of oral CsA in children with NSAA was 58.33%. Stopping blood transfusion after the 3 months of treatment may be considered as a turning point for disease outcomes, and levels of NEU, RBC at the 3rd month and Hb, PLT, WBC at the 6th month as indicators for predicting disease prognosis.

Neurophysiological patterns of acute and post-acute foodborne botulism.

Neurophysiological patterns in patients with foodborne botulism are rarely described after the acute phase. We report data from a large Italian outbreak of botulism, with patients evaluated at different timepoints after poisoning. Eighteen male patients (mean age 47 ± 8.4 y) underwent 22 clinical and neurophysiological evaluations (4 patients were re-evaluated). The resting compound muscle action potential (CMAP) amplitude, postexercise CMAP amplitude, CMAP change after high-frequency (50 Hz) repetitive nerve stimulation (HFRNS), and motor unit action potentials (MUAPs) were assessed in the acute (4-8 days after poisoning; 5 patients), early post-acute (32-39 days after poisoning; 5 patients), and late post-acute (66-80 days after poisoning; 12 patients) phases. In the acute, early post-acute, and late post-acute phases, respectively, reduced CMAP amplitudes were found in 100%, 20%, and 17% of patients; abnormal postexercise CMAP facilitation was observed in 100%, 40%, and 0% of patients; and pathological incremental responses to HFRNS were found in 80%, 50%, and 8% of patients. Baseline CMAP amplitudes, postexercise CMAP facilitation, and CMAP increases in response to HFRNS differed significantly between the acute and post-acute phases. Small MUAPs were found in 100% of patients in the acute and early post-acute phases and in 50% of patients in the late post-acute phase. The neurophysiological findings of foodborne botulism vary considerably according to the evaluation time point. In the post-acute phase, different neurophysiological techniques must be applied to support a diagnosis of botulism.

Clinical and biochemical evaluation of oral irrigation in patients with peri-implant mucositis: a randomized clinical trial

This randomized clinical trial aimed to compare the efficacy of an oral irrigator and an interdental brush in patients with peri-implant mucositis clinically and biochemically at different time points (at baseline and at the 2nd, 4th, and 12th weeks). Forty-five patients with at least one implant with peri-implant mucositis were included in the present study (n = 45). The patients were divided into three groups: oral irrigator + toothbrush (OI group, n = 15), interdental brush + toothbrush (IB group, n = 15), and toothbrush only (control) (C group, n = 15). The modified plaque index (mPlI), modified sulcus bleeding index (mSBI), probing pocket depth (PPD), probing attachment level (PAL), and bleeding on probing (BOP) were recorded at baseline and at the 2nd, 4th, and 12th weeks. The levels of interleukin 1 beta (IL-1β), transforming growth factor-beta (TGF-β), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) were also determined in the peri-implant crevicular fluid samples biochemically. The mSBI and t-PA at the 2nd week (p = 0.003; p = 0.003); the mPlI, mSBI, BOP, t-PA, and PAI-1 at the 4th week (p < 0.05; p < 0.001; p < 0.001; p = 0.015; p = 0.011); and the mPlI, mSBI, IL-1β, t-PA, and PAI-1 at the 12th week (p < 0.05; p < 0.001; p = 0.013; p < 0.001; p = 0.002) were significantly lower in the OI group compared with those in the C group. Meanwhile, PAI-1 at the 2nd week, mSBI at the 4th week, and t-PA at the 12th week were significantly lower in the OI group compared with those in the IB group (p < 0.001; p = 0.011; p = 0.003). At the 2nd, 4th, and 12th weeks, all other parameters were not statistically different in the three groups. The clinical indexes (such as mSBI and BOP) that play an important role in the diagnosis of peri-implant mucositis showed the lowest means (although limited) in the OI group at all evaluation time points. Moreover, when the clinical and biochemistry results were interpreted altogether, it became apparent that the OI group exhibited similar or more effective results than the IB group in resolving peri-implant mucositis. In light of the foregoing, this study concluded that the use of an oral irrigator can be as effective as an interdental brush in interdental cleaning. In this study, it is suggested that the regular use of an oral irrigator along with a toothbrush could be an appropriate alternative to other oral hygiene products such as dental floss and interdental brush for the management of peri-implant mucositis by preventing the accumulation of dental plaque (NCT03844035).

Initial Results of KD025-208: A Phase 2a Open Label Trial of KD025 for Steroid-Dependent Chronic Graft Versus Host Disease

Introduction: cGVHD occurs in approximately 50% of patients undergoing allogeneic hematopoietic stem cell transplantation and it remains a leading cause of post-transplant morbidity and mortality. cGVHD typically exhibits features of both autoimmune and fibrotic diseases and can affect single or multiple organ systems. Corticosteroids are the primary treatment modality and while not uniformly effective, often cause additional adverse effects in patients with prolonged use. Despite major advances in the understanding of cGVHD biology, no targeted therapy has been approved for cGVHD. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor currently in Phase 2 clinical development for autoimmune and fibrotic indications. KD025 has been shown to downregulate pro-inflammatory T helper 17 cells and T follicular helper cells while upregulating anti-inflammatory regulatory T cells, which may potentially correct the immunological imbalance seen in cGVHD.Methods: Seventeen adult patients were enrolled in KD025-208, a Phase 2a, open-label study. Enrollment is planned for three cohorts (200 mg QD, 200 mg BID, and 400 mg QD) of 16 steroid-dependent cGVHD patients per cohort. The primary activity endpoint is the percentage of patients who meet the NIH Consensus Conference-defined overall response criteria (Partial Response (PR) + Complete Response (CR)) at 24 weeks. Secondary efficacy endpoints include changes in corticosteroid and calcineurin inhibitor dose and changes in cGVHD severity using the Physician-Reported Global cGVHD Activity Assessment. Exploratory endpoints include changes in symptom burden/bother using the Lee cGVHD Symptom Scale.Results: Seventeen patients with a median age of 50 years, median time from transplant to cGVHD diagnosis of 9.1 months, median time from initial cGVHD diagnosis to KD025 treatment initiation of 25.9 months, and median number of prior treatment regimens of three were enrolled in the 200 mg QD cohort. KD025 demonstrated an overall response rate (PR or CR at any evaluation time point) of 71% (12/17). Three patients discontinued KD025 treatment prior to 24 weeks (one cancer relapse, one cGVHD progression, and one adverse event of headache). Each of the three discontinued patients had demonstrated responses (PR) prior to study discontinuation. Fourteen of 17 (82%) patients remained on treatment at 24 weeks. At week 24, KD025 demonstrated clinical responses (CR or PR) in 57% (8/14) of the remaining evaluable patients. In addition to the eight responders, four patients had stable disease (SD) at 24 weeks; therefore, CR, PR or SD occurred in 86% (12/14) of patients. Importantly, of patients remaining on treatment at 24 weeks, 57% (8/14) had a reduction in steroid dose and 67% (4/6) had a reduction in tacrolimus dose. Moreover, 57% (8/14) of patients had a reduction in symptoms as measured by the Lee cGVHD Symptom Scale score. Patients with PR or SD were permitted to remain on KD025 for an additional 24 weeks. Eleven of 14 patients elected to remain on KD025 treatment after 24 weeks. Two patients were discontinued due to lack of response at 24 weeks and one patient with stable cGVHD was discontinued due to an unrelated adverse event of nephrotic syndrome.In addition, KD025 demonstrated an overall clinical benefit rate (PR or CR at any evaluation time point or SD at 24 weeks) of 88% (15/17) in all cGVHD patients.No treatment-related serious adverse events (SAEs) have been reported and no definitive treatment-related elevations in liver function tests (LFTs) (ALT, AST, ALP, and Bili) have been observed. Elevations in LFTs were commonly observed prior to KD025 dosing and may be attributable to cGVHD liver involvement. KD025 has been well tolerated and the overall adverse event profile appears consistent with cGVHD. Other low-grade treatment emergent adverse events seen in three or more patients were anemia (24%), diarrhea (24%), and nausea (24%).Conclusions: Treatment of cGVHD with KD025 demonstrated encouraging clinical responses and a favorable safety profile in patients with steroid-dependent cGVHD when administered at 200 mg QD. Eight of 14 patients (57%) demonstrated a 2014 NIH Consensus Conference-defined PR. No drug-related SAEs were reported. Enrollment in the dose-escalating cohorts is ongoing. DisclosuresLee:Kadmon: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Amgen: Other: One-time advisory board member; Mallinckrodt: Honoraria. Salhotra:Kadmon: Consultancy. Jagasia:Mallinckrodt: Consultancy; Janssen: Consultancy, Research Funding; Therakos: Consultancy, Research Funding. Schueller:Kadmon: Employment, Equity Ownership.

Measurable Residual Disease (MRD) Testing in Multiple Myeloma Using an Improved Testing Technology: Population Impact

Introduction:The availability of reliable and sensitive methods to assess treatment response is increasingly important in an era of more effective yet costly therapies for patients with Multiple Myeloma (MM). Measurable residual disease (MRD) testing has recently been added to the response evaluation criteria for MM, with NCCN® and IMWG guidelines recommending MRD testing using standardized assays capable of detecting malignant cells at a level of at least 1 in 100,000 cells (1x10-5 sensitivity level). Newer technologies for evaluating MRD testing have demonstrated the ability to detect malignant cells at more sensitive levels (1x10-6) than flow cytometry, conventionally sensitive to 1x10-4 from reference labs. Different levels of sensitivity all beneath the limits of flow cytometry have been shown to correlate with differences in outcome for patients with MM. Therefore, accurate MRD assessment has important implications for patient prognosis and management. Our objective was to evaluate the impact of next-generation sequencing (NGS MRD) (clonoSEQ®) versus traditional flow cytometry techniques (flow) on the number of MM patients with accurate MRD categorization in the United States.Methods:We developed a population model to estimate the number of newly diagnosed MM patients accurately assessed for MRD status over a 1-year time horizon using data from SEER, U.S. census, clinical studies, NCCN guidelines, and expert opinion. We used SEER and U.S. census data to estimate the number of newly diagnosed MM patients expected in 2017. We used NCCN guidelines, a recently completed clinical trial (IFM 2009 trial), publicly available literature and expert opinion to estimate the timing, treatment sequence, and response evaluation time points in the first year after initial diagnosis including the induction, consolidation, stem cell transplant, and maintenance treatment phases. We used the IFM study and published literature to estimate the proportion of patients expected to transition to each treatment phase. We used clinical studies (IFM) comparing the test characteristics of NGS MRD vs. flow to estimate the comparative accuracy of the tests, using NGS MRD as the gold standard for accurate categorization. Finally, we evaluated three market penetration levels in the first year, 25%, 50%, 100%. The primary model outcome was the number of accurately categorized patients in the United States over a one year timeframe.Results:We found that in 1-year, 17,919 (77% accurate with 11,852 True positive and 6,067 True negative) MM patients would be accurately categorized and 5,504 would be inaccurately categorized (402 false positives and 5,102 false negatives) using flow alone. If NGS MRD was used for 25%, 50%, or 100% of the testing, an additional 1,376, 2,752, or 5,504 patients would be appropriately categorized, respectively.Conclusions:Our analysis demonstrates that MRD with NGS with significantly improved depth of measurement could substantially increase the number of patients appropriately assessed for MRD status in the U.S. With clinical decisions, e.g. treatment switching, treatment continuation, and use of SCT, increasingly being tied to MRD evaluation, obtaining accurate MRD status will have important clinical and economic implications for patients and health systems. [Display omitted] DisclosuresZimmermann:Adaptive Biotechnology: Consultancy. Kirsch:Adaptive Biotechnology: Employment. Carlson:Adaptive Biotechnology: Consultancy.

OP31 RESTORE: Interim analysis of a Phase 2 study of QBECO SSI for the induction and maintenance of clinical and endoscopic remission in subjects with Moderate to Severe Crohn’s Disease

Abstract Background Innate immune defects play a role in the pathogenesis of CD. Enhancing innate immune competency and restoring mucosal barrier function provide a novel approach to treat CD. QBECO SSI is a first-in-class immunotherapy designed to correct innate immune dysfunction underlying CD. This analysis is from subjects in the open label portion of a planned controlled trial. Objectives were to assess endoscopic response at Wks 16 and 26, and select the optimal induction timepoint for the RCT. Safety and treatment compliance were also evaluated. Methods 20 pts with moderate-to-severe CD were enrolled and received QBECO SSI by sc injection every other day for up to 52 wks. Minimum eligibility: Simple Endoscopic Score for CD (SES-CD) ≥7 (ileitis ≥4), abdominal pain (AP) score &amp;gt;21 (11-point scale) or liquid/very soft stools (SF) (BFS Type 6 or 7) &amp;gt;10 for 7 consecutive days during screening. Pts were evaluated for clinical symptoms and endoscopy at Wks 16, 26, and 52. After evaluation at the induction period (Wk 26) pts could continue in maintenance up to Wk 52. Endoscopies were evaluated by central blinded read and pts reported daily symptoms. Endoscopic response defined as ≥50% reduction in SES-CD from baseline. Clinical remission defined as AP and SF ≤21. Results Mean age was 43.6 (SD 13.6) yrs; 60% men and 60% previously treated with biologics. Mean yrs since CD diagnosis was 14.4 (10.1), AP score 30.4 (15.8), SF score 36.2 (19.1) and mean SES-CD at baseline was 12.5 (6.7) indicating a more difficult to treat population. Endoscopic response rate by central read during the induction period was 30% (6/20) overall, 38% (3/8) for biologic naïve and 25% (3/12) biologic experienced pts (ITT analysis). Similar number of pts achieved endoscopic response at Wk 16 (4 pts) as 26 (3 pts). Mean SES-CD improved through Wk 26 with a 0.6 point greater reduction at Wk 26 compared to 16. Change in SES-CD from baseline in biologic naïve pts was -2.9 (5.8) at Wk 16 and -4.1 (6.7) at 26. Clinical remission was achieved by 45% (9/20) of pts at Wk 16 and 40% (8/20) at Wk 26; 16 pts continued into the maintenance phase of the study. By central evaluation, 13% (2/16) were in endoscopic response at Wk 52. QBECO SSI was very well tolerated. 8/20 (40%) pts reported AEs related to treatment. Most frequency reported related AE was injection site erythema (2/20, 10% pts). Majority of AEs were mild and no other related AE was reported by more than 1 patient. Conclusion Week 26 was the optimal endoscopic evaluation timepoint for QBECO SSI treatment and will be utilized in the larger RCT. Both biologics naïve and experienced patients showed response to QBECO SSI treatment by Weeks 26 and 52, with higher response rates in biologics naïve patients. QBECO SSI was well tolerated.

POS1043 NETAKIMAB REDUCES PSORIATIC ARTHRITIS ACTIVITY IN PATIENTS WITH OR WITHOUT AXIAL DISEASE: SUBANALYSIS OF THE PATERA STUDY

Background:PATERA is an ongoing phase 3 international double-blind, placebo-controlled clinical study of netakimab (NTK) in psoriatic arthritis (PsA) (NCT03598751). Netakimab (NTK) is an anti-interleukin-17A monoclonal antibody approved for psoriasis, ankylosing spondylitis, PsA in Russia and Belarus.Objectives:A subanalysis was performed to define the impact of NTK on PsA activity depending on the presence of axial disease: a subset of patients with inflammatory back pain (IBP) according to self-reported ASAS IBP criteria, 2009 (IBP(+) was compared to those without IBP (IBP(-)).Methods:194 eligible adult patients with PsA fulfilling the CASPAR criteria, with inadequate response to csDMARD or one TNFi, were randomly assigned to receive NTK 120mg or placebo at weeks 0,1,2,4,6,8,10,14,18,22. Patients with missing values for categorical variables were considered as non-responders in the analysis. For quantitative variables, missing values were replaced using the multiple imputation method.Results:97 PsA patients (N=54 IBP(+), N=43 IBP(-)) received NTK. Both subpopulations were comparable in gender, age and PsA activity at baseline. The treatment led to a pronounced decline in PsA activity in both subpopulations, significant differences between arms were observed only in DAPSA remission and very low disease activity (VLDA) at week 24 (Figure 1A). Changes from baseline in DAS28-CRP were consistent between IBP(+) and IBP(-) patients with a rapid decline during the first month with further improvement up to week 24 (Figure 1B). A similar trend was observed PsA-specific composite responder index (PSARC) (data not shown). A comparable percentage of IBP(+) and IBP(-) patients achieved PSARC at each timepoint of evaluation with 87% and 86% of responders respectively at week 24.Conclusion:NTK significantly improved PsA activity regardless of the presence of IBP.Figure 1.PsA activity after 24-week treatment with NTK. (A) Percentage of patients with DAPSA remission (0-4), very low disease activity (VLDA), minimal disease activity (MDA) at week 24; (B) change from baseline in DAS28-CRPAcknowledgements:This study was sponsored by JSC BIOCAD.Disclosure of Interests:Tatiana Korotaeva Speakers bureau: Abbvie, Biocad, Eli Lilly, Johnson &amp; Johnson, Janssen, Novartis, Pfizer, UCB, Inna Gaydukova Speakers bureau: Abbvie, Biocad, Eli Lilly, MSD, Novartis, Pfizer, Sandoz, V Mazurov: None declared, Aleksey Samtsov: None declared, Vladislav Khayrutdinov: None declared, Andrey Bakulev: None declared, Alena Kundzer: None declared, Nikolaj Soroka: None declared, Anna Eremeeva Employee of: Biocad.

Association rule learning in neuropsychological data analysis for Alzheimer's disease.

Efficient methods of analysis readily available for clinicians continue to be limited within neuropsychological assessment at the raw data level. Here, a novel approach for generating predictive response patterns and analysing neuropsychological raw data is offered. In order to assess the usefulness of association rule learning as an analysis tool for neuropsychological raw data, Frequent Pattern Growth (FP-Growth) was used to mine patterns from the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) database. Complete assessment data for 84 post-mortem confirmed Alzheimer's disease (AD) cases and 294 age, race, and education matched controls were analysed across baseline and one-year follow-up using FP-Growth, for the purpose of assessing the clinical utility of a finer analysis at the raw data level and the feasibility of predicting response patterns for clinical/control groups. Output from FP-Growth, in terms of the number of frequent itemsets retained across both evaluation timepoints, was discernable between controls, mild, and moderate to severe Alzheimer's disease cases (p < .001, and η2 = .488). Patterns within raw data scores, both in terms of frequent itemsets and predictive association rules, appear to be differentiable across groups within neuropsychological analysis, which indicates that FP-Growth is applicable as a supplementary analysis tool for neuropsychological assessment by means of offering an additional level of data analysis, predictive item response capabilities, and aiding in clinical decision making.

Simvastatin loaded chitosan guided bone regeneration membranes stimulate bone healing.

Electrospun chitosan membranes (ESCM) modified with short-chain fatty acids have the ability to control the release of simvastatin (SMV), an anti-cholesterol drug with osteogenic potential, for guided bone regeneration (GBR) applications. This study evaluated in vivo osteogenic effects of rapid short release of SMV (4weeks) vs long sustained release (8weeks) from acetic anhydride (AA)-and hexanoic anhydride (HA)-modified ESCMs, respectively. AA ESCMs loaded with 10 or 50µg SMV and HA ESCMs loaded with 50µg SMV were evaluated for biocompatibility and bone formation at 4 and 8weeks, in 5mm critical size rat calvarial defects, using histological evaluation and micro-CT analysis. No severe inflammatory response was noticed around the ESCMs. Less hydrophobic AA membranes showed signs of resorption by week 4 and were almost completely resorbed by week 8 whereas the more hydrophobic HA membranes resorbed slowly, remaining intact over 8weeks. In micro-CT analysis, 10µg SMV-loaded AA membranes did not show significant bone formation as compared to non-loaded AA membranes at either evaluation time points. 50µg SMV-loaded AA membranes stimulated significantly more bone formation than non-loaded AA membranes by week 4 (%bone=31.0±5.9% (AA50) vs 18.5±13.7% (AA0)) but showed no difference at week 8. HA membranes with 50µg SMV showed significantly more bone formation as compared to corresponding non-loaded membranes by week 8 (%bone=61.7±8.9% (HA50) vs 33.9±29.7% (HA0)), though such an effect was not significant at week 4. These results indicate that modified ESCMs may be used to control the release of SMV and promote bone healing in GBR applications.

Strength and awareness in action: Feasibility of a yoga-based intervention for post-acute mild TBI headaches among veterans

BackgroundMild traumatic brain injury (mTBI) is a signature injury sustained by Veterans during recent conflicts. For some, mTBI/concussion is associated with disabling symptoms, including post-concussive headaches (PCH). However, there are limited evidence-based treatments for persistent PCH. ObjectiveInvestigators assessed the feasibility of design elements of a yoga-based interventional trial for PCH among Veterans, as well as the acceptability of the intervention. MethodsThis randomized controlled acceptability and feasibility trial was implemented using a waitlist-control design. Design elements of interest included: an exercise run-in class; recruitment and retention strategies; and, ecological momentary assessment (EMA) modalities to track headaches and yoga practice. Veteran satisfaction regarding the intervention was also evaluated. A descriptive analysis was conducted on candidate outcomes including PCH, post-concussive symptoms, pain, and daily functioning. ResultsTwenty-seven participants (out of 70 consented and eligible after Study Visit 1) completed each evaluation timepoint and regularly attended yoga sessions, with 89% of these Veterans reporting moderate to high levels of satisfaction with the intervention at study completion. Qualitatively, participants endorsed improvements in headaches, chronic pain, and mood. Feasibility results were mixed. Initial feasibility criterion regarding yoga attendance was not met; however, modifications, such as expansion to an additional clinic site and reduction of in-person yoga sessions with increased encouragement to use study-created online yoga videos improved feasibility of the study design. Participants most frequently used mobile and web-based EMA modalities to track yoga practice. ConclusionsAlthough challenges with feasibility of the study design elements were noted, results suggested acceptability of the yoga-based intervention for Veterans with persistent PCH. Additional exploration regarding the frequency and modality of yoga delivery (e.g., in-person, telehealth) is warranted. ImpactVeterans found the yoga-based intervention acceptable, however exploration of novel modalities of intervention delivery will likely be necessary to enhance the feasibility of intervention implementation during future trials.

Prognostic value of measurable residual disease after venetoclax and decitabine in acute myeloid leukemia

Assessment of measurable residual disease (MRD) provides prognostic information in acute myeloid leukemia (AML). However, the utility of MRD with venetoclax-based lower intensity regimens is unknown. We analyzed the prognostic value of achieving a negative MRD in older/“unfit” patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. MRD was evaluated in bone marrow specimens using multicolor flow cytometry (sensitivity 0.1%). Ninety-seven patients achieving either a complete remission (CR) or CR with incomplete hematologic recovery (CRi) or morphologic leukemia-free state were included. Median age was 72 years (interquartile range, 68-78 years), and 64% had adverse-risk AML. Eighty-three patients achieved CR/CRi, and 52 (54%) became MRD negative. Median time to becoming MRD negative was 2.0 months (interquartile range, 0.9-3.1 months). Patients becoming MRD negative by 2 months had longer relapse-free survival (RFS) compared with those remaining MRD positive (median RFS, not reached vs 5.2 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.12-0.78; P = .004), longer event-free survival (EFS) (median EFS, not reached vs 5.8 months; HR, 0.25; 95% CI, 0.12-0.55; P < .001), as well as longer overall survival (OS) (median OS, 25.1 vs 7.1 months; HR, 0.23; 95% CI, 0.11-0.51; P < .001). Patients achieving an MRD-negative CR had longer OS compared with those with an inferior response (median OS, 25.1 vs 11.6 months; HR, 0.33; 95% CI, 0.19-0.58; P < .0005). Patients becoming MRD negative within 1 month had an improved OS compared with MRD-positive patients (median OS, 25.1 vs 3.4 months; HR, 0.15; 95% CI, 0.03-0.64; P < .0001). Differential impact of MRD status on survival outcomes persisted at a later 4-month time point of evaluation. In conclusion, MRD-negative status at 1, 2, and 4 months after starting therapy confers significantly better survival in older/unfit patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT03404193.

SIMPLE: A Novel Scoring System for Predicting Hemodynamically Significant Patent Ductus Arteriosus Without Echocardiographic Evaluation in Extremely Low Birth Weight Infants.

Aim: To develop a novel clinical scoring system for predicting hemodynamically significant patent ductus arteriosus (hsPDA) in extremely low birth weight (ELBW) infants.Methods: A prospective observational study was conducted among ELBW infants born in the study center during a 6-month period. Fourteen items were selected on a literature review basis and weighed by severity on an arbitrary 1–4 scale, the sum of which represented the Scoring preterm Infants for PDA cLinically without Echocardiographic evaluation (SIMPLE) score. The SIMPLE scores were compared at several time points during the first 3 days of life between two groups of patients: those with an hsPDA at echocardiography and those without.Results: A total of 48 ELBW infants were enrolled, of which 30 infants developed hsPDA. The SIMPLE scores of the infants with hsPDA were significantly greater than those of the infants who did not develop hsPDA. Cut-off SIMPLE scores that were significantly associated with detection of symptomatic hsPDA at each evaluation time point were identified.Conclusions: SIMPLE is the first scoring system that depends on the risk factors and clinical findings of ELBW infants for early prediction of hsPDA. It is simple, objective and easy to perform, and it does not require any additional tests and/or echocardiographic evaluation. We suggest that SIMPLE can be used as a screening tool for determining the need for echocardiographic evaluation in ELBW infants in order to minimize the number of unnecessary pediatric cardiology consultations.

Circulating AQP4 Levels in Patients with Cerebral Amyloid Angiopathy-Associated Intracerebral Hemorrhage.

Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage (ICH) in elderly patients. Growing evidence suggests a potential role of aquaporin 4 (AQP4) in amyloid-beta-associated diseases, including CAA pathology. Our aim was to investigate the circulating levels of AQP4 in a cohort of patients who had suffered a lobar ICH with a clinical diagnosis of CAA. AQP4 levels were analyzed in the serum of 60 CAA-related ICH patients and 19 non-stroke subjects by enzyme-linked immunosorbent assay (ELISA). The CAA–ICH cohort was divided according to the time point of the functional outcome evaluation: mid-term (12 ± 18.6 months) and long-term (38.5 ± 32.9 months) after the last ICH. Although no differences were found in AQP4 serum levels between cases and controls, lower levels were found in CAA patients presenting specific hemorrhagic features such as ≥2 lobar ICHs and ≥5 lobar microbleeds detected by magnetic resonance imaging (MRI). In addition, CAA-related ICH patients who presented a long-term good functional outcome had higher circulating AQP4 levels than subjects with a poor outcome or controls. Our data suggest that AQP4 could potentially predict a long-term functional outcome and may play a protective role after a lobar ICH.