Transient Elevation Of Liver Enzymes Research Articles

Leflunomide with prednisone or nonsteroidal anti-inflammatory drug therapy is safe and tolerated for long-term treatment of immune-mediated polyarthritis in 27 dogs.

To retrospectively evaluate safety and tolerance of leflunomide for long-term treatment of canine idiopathic immune-mediated polyarthritis (IMPA). 27 dogs with clinical signs and synovial fluid cytology supportive of IMPA with ≥ 6 months' follow-up after starting leflunomide. Medical records were reviewed to identify dogs prescribed leflunomide for treatment of IMPA from February 2012 to May 2022. Initial leflunomide doses of 2 to 4 mg/kg once daily were prescribed and were titrated to the lowest effective dose with concurrent anti-inflammatory therapy. Complete blood count, serum chemistry, and clinical signs were monitored throughout the course of treatment. Adverse effects potentially attributable to leflunomide noted in 9 of 27 dogs (33%) included vomiting, diarrhea, lethargy, decreased or absent appetite, polyuria and polydipsia, and secondary antibiotic responsive infection and were self-limiting or resolved with outpatient therapy. Alkaline phosphatase (ALP) and alanine aminotransferase (ALT) elevation were documented in all dogs prescribed leflunomide plus prednisone, with persistent liver enzyme elevation in 6 of 9 dogs (67%) and normalization after antibiotic therapy in 3 of 9 dogs (33%). The majority of dogs prescribed leflunomide plus NSAID (11/17 [65%] dogs) did not experience liver enzyme elevation; 2 of 17 (12%) dogs developed transient antibiotic-responsive liver enzyme elevations, and 4 of 17 (23%) dogs had persistent liver enzyme elevation. Leflunomide was well tolerated for long-term management of IMPA. A significant difference in liver enzyme elevation was identified between dogs prescribed prednisone versus NSAID in combination with leflunomide. Leflunomide with NSAID therapy resulted in less hepatotoxicity compared with leflunomide with prednisone.

A228 RISANKIZUMAB - DRUG INDUCED LIVER INJURY; A CASE REPORT

Abstract Background Risankizumab is a humanized monoclonal antibody to IL-23. It was initially used in the treatment of plaque psoriasis with recent approval to extend use to treat moderate to severe Crohn’s disease with evidence of endoscopic healing and clinical remission of disease. In the drugs safety manual, it has been reported to have transient liver enzyme elevation that is asymptomatic and not to a degree requiring drug discontinuation. No reported data on steatohepatitis. In this article we describe a 28 year old female, who had no evidence of liver disease in the past who underwent treatment with Risankizumab and within several months developed evidence of steatohepatitis with radiological evidence of significant hepatomegaly. Aims Case report details Drug induced liver injury to Risankizumab. Methods Case Report Results Drug induced liver injury with elevated liver enzyme levels and liver biopsy showing drug related liver changes likely in the setting of Risankizumab use. Conclusions Risankizumab is a newly approved drug in the setting of Crohn's disease, although described in the drug assessment report that it may cause transient hepatitis or eleveted liver enzymes in the setting of lower drug dose for Psoriasis use, the higher drug level used in the setting of Crohn's disease has not been formally evaluated and no previous known case reports of Drug induced Liver Injury to Risankizumab causing severe steatohepatitis Funding Agencies None

Possible cholestatic hepatitis with clindamycin therapy: A case report

Introduction: Clindamycin is a lincosamide antibiotic that is effective against streptococci, staphylococci, and anaerobic bacteria. Though it predominantly undergoes hepatic metabolism, no dose adjustments are recommended for patients with hepatic dysfunction. Hepatotoxicity is a rare side effect and even though transient elevation of liver enzymes has been reported, there are very few cases of acute idiosyncratic liver injury. Case Presentation: A 49-year-old male from Sri Lanka, with no knowncomorbidities, was treated with oral clindamycin for left lower limb cellulitis. He was investigated for a low platelet count and was diagnosed to have chronic liver cell disease (CLCD) on day two of admission following an ultrasound scan of the liver. On day four of treatment, the patient developed deep icterus and asterixis. The serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels rose from normal levels to 681 U/L and 1100 U/L respectively. Total bilirubin had risen to 158.5 micromole/L with a high direct fraction of 116.1 micromole/L and alkaline phosphatase (ALP) was 108 U/L. Drug induced liver injury (DILI) was suspected immediately and clindamycin treatment was withheld. The patient’s symptoms improved over the next few days and the AST, ALT levels dropped immediately and returned to normal within three weeks. Serum anti-nuclear antibody and anti-mitochondrial antibody were negative. IgM antibodies for hepatitis A, C, E, and Epstein-Barr virus were negative and the test for hepatitis B surface antigen was negative. The serum ferritin and transferrin saturation were normal and there were no Kayser–Fleischer rings in the eyes. The urine toxicology screen was negative. Conclusion: This case highlights a rare but important complication of clindamycin treatment. Clinicians should be vigilant when starting clindamycin in a patient diagnosedor suspected to have CLCD and such patients should be monitored for DILI. Early recognition of DILI is essential and immediate discontinuation of drug is the most important intervention which alone can lead to resolution of the injury.
 Keywords: Clindamycin, Cholestasis, Hepatitis

Time Limited Exposure to a ROR1 Targeting Bispecific T Cell Engager (NVG-111) Leads to Durable Responses in Subjects with Relapsed Refractory Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL)

Background: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is absent or expressed at low levels in normal adult tissues but overexpressed in a range of malignancies including CLL and MCL. NVG-111 is a humanized first in class, tandem scFv, ROR1xCD3 bispecific T cell engager. NVG-111 mediates potent killing of ROR1 + tumors by engaging a unique epitope on the Frizzled domain of ROR1 and redirecting T cell activity via the CD3 binder engineered for attenuated cytokine release. Methods: In this phase 1, first-in-human, dose-escalation study (ClinicalTrials.gov identifier: NCT04763083), NVG-111 was evaluated in relapsed/refractory CLL and MCL subjects with an ECOG PS of 0-2 who received ≥2 prior lines of treatment including a Bruton tyrosine kinase inhibitor (BTKi). Bayesian continual reassessment method with overdose control was implemented to guide escalation over a dose range of 0.3-45ug/day. Each subject received at least one dose of NVG-111, administered as a continuous intravenous infusion (cIV) over 21 days followed by 7 days off drug (=1 cycle). NVG-111 was administered in combination (N=8) with ibrutinib to subjects who had achieved a partial response to >1 year of ibrutinib therapy, or as monotherapy in subjects that progressed after covalent BTKi/B-cell lymphoma 2 inhibitor (BCL2i) (N=4). Primary objective was safety, with the secondary objectives being efficacy (overall response rates [ORR], minimal residual disease (MRD) measured by ERIC-compliant flow cytometry and duration of response [DoR]). Serum cytokine levels were determined using a human high sensitivity cytokine premixed magnetic Luminex assay and T cell function was longitudinally evaluated using cytometry by time of flight (CyTOF) analysis. Results: Between May 2021 and July 2023 12 subjects (10 males and 2 females, median age 60 years) completed a maximum of 6 cycles of treatment with NVG-111 (median=3 cycles [range 1-6 cycles]). Pharmacokinetic and pharmacodynamic data demonstrated systemic NVG-111 exposure and exposure-dependent NVG-111 targeting of ROR1 on circulating tumor cells. Adverse events (AEs) related to NVG-111 occurred in 10 subjects (83%), with the most common being nausea (58%), headaches (67%), and fatigue (33%), majority of which were grade 1 or 2. Grade 1(71%) or 2(29%) cytokine release syndrome (CRS) occurred in 58% of subjects during week 1 of cycle 1 except in one subject who had a second grade 1 CRS in cycle 2. Grade 3 dose limiting toxicities (DLTs) occurred in three subjects (25%) consisting of transient elevation of liver enzymes (ALT and AST) in one subject dosed at 3ug/day, immune effector cell-associated neurotoxicity syndrome-like symptoms (ICANS) in one subject dosed at 30ug/day and headache in one subject dosed at 45ug/day. All AEs were fully reversible with no late emergent grade 3 or greater toxicities. Evidence of T cell activation was observed in all 12 subjects with peak cytokine levels at the 30µg/day dose levels (mean±SEM): TNFα, 43±17pg/ml; IL6, 566±541pg/ml; IFNɣ, 18±12pg/ml; and IL10, 103±56pg/ml. Furthermore, T cell profiling showed an increase in cytotoxic CD8 + T cell activation marker expression during each NVG-111 treatment cycle without evidence of T cell exhaustion. Efficacy was evaluable in 11 subjects with objective clinical responses observed in 55% (6/11), including two subjects with clear evidence of single agent activity. Amongst these, three CLL subjects were rendered MRD negative in peripheral blood and one MCL subject achieved complete metabolic response by the Lugano criteria. Two subjects had stable disease but in one of these subjects there was a >50% reduction in peripheral blood lymphocytosis and a 40% reduction in lymphadenopathy. Despite time limited exposure to NVG-111, the restricted mean survival time for DoR is currently 13.6 months (SEM 3.07), the median is not yet calculable with response ongoing in four subjects. The median progression-free survival currently is 18.7 months (95% CI 2.6 - not calculable). Conclusion: These data provide clinical proof of concept for selective targeting of ROR1 with a TCE leading to objective evidence of antitumor activity with encouraging response durability even in CLL patients known to have defective T cell function. The safety profile was consistent with the mechanism of action. Further evaluation of this promising molecule is ongoing.

Abstract 17013: CTX320: An Investigational in vivo CRISPR-Based Therapy Efficiently and Durably Reduces Lipoprotein (a) Levels in Non-Human Primates After a Single Dose

Background: Genetic and epidemiological studies have identified elevated levels of lipoprotein (a) (Lp(a)) as a direct cause of atherosclerosis and related diseases. CTX320™ is an investigational in vivo CRISPR/Cas9 gene editing therapy designed to knock out the apolipoprotein (a) component of Lp(a) in the liver. CTX320 contains Cas9 mRNA and guide RNA (gRNA) formulated for efficient encapsulation into LNPs for in vivo administration . Here we assessed the efficacy, safety, and durability of CTX320 in primary human cells and non-human primates (NHPs). Methods: For in vitro studies, primary human hepatocytes were plated and dosed with CTX320 one day later. Cells were harvested after three days and analyzed via Sanger and next-generation sequencing. For NHP studies, cynomolgus monkeys were dosed with either vehicle control or CTX320 at doses ranging from 0.5 to 3 mg/kg. Baseline levels of plasma Lp(a) were established via ELISA prior to dosing and plasma Lp(a) levels were measured at multiple intervals after dosing until the end of each study. Results: In primary human hepatocytes, potent, dose-dependent editing of up to >80% was observed with CTX320. In NHPs, dose-dependent editing in the liver of ~10%, ~45%, and ~65% at the 0.5, 1.5, and 3 mg/kg doses, respectively, was observed after treatment with CTX320. Plasma Lp(a) levels were reduced by ~20%, ~80%, and ~90% from baseline in each of these respective groups. These reduced Lp(a) levels were attained by Day 15 and lasted for the duration of the study (Day 84). As is commonly observed with LNP delivery, transient elevation in liver enzymes was observed and resolved within 14 days without intervention. In a separate durability study in NHPs, a single infusion of CTX320 at 2 mg/kg led to significant and durable decreases in plasma Lp(a) levels. By Day 14, plasma Lp(a) levels had decreased by an average of 94% from baseline, which persisted through Day 224. The study is ongoing. Conclusion: CTX320 was well-tolerated in NHPs and resulted in high levels of editing in the liver that led to long-lasting reduction in plasma Lp(a). This data suggests CTX320 could be used to reduce plasma Lp(a) levels in humans.

Abstract 16908: CTX310: An Investigational in vivo CRISPR-Based Therapy Efficiently and Durably Reduces ANGPTL3 Protein and Triglyceride Levels in Non-Human Primates After a Single Dose

Background: Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipid metabolism. In humans, naturally occurring loss-of-function variants in ANGPTL3 are associated with reduced levels of serum lipids and reduced risk of atherosclerotic cardiovascular disease. CTX310™ is an investigational in vivo CRISPR/Cas9 gene editing therapy designed to knock out hepatic expression of ANGPTL3. CTX310 consists of Cas9 mRNA and guide RNA (gRNA) targeting ANGPTL3 encapsulated into lipid nanoparticles (LNPs). Here we assessed the efficacy, safety, and durability of CTX310 in primary human cells, mice, and non-human primates (NHPs). Methods: CTX310 was evaluated in vitro in primary human hepatocytes (PHHs), in vivo in wildtype C57BL/6J and LDLR-/- mice using a mouse surrogate gRNA, and in vivo in NHPs where the human target sequence is conserved. For the NHP studies, cynomolgus monkeys were infused with a single dose of CTX310 at doses ranging from 0.5 to 3.0 mg/kg to evaluate efficacy (N=32) and durability (N=8). Results: In PHHs, >90% on-target editing was achieved with CTX310, leading to a >90% reduction in ANGPTL3 production. Comprehensive genomic assessment indicated no sign of unintended genomic changes introduced by CTX310. In wildtype mice administered LNPs containing a mouse surrogate gRNA along with the same Cas9 mRNA and lipid components as CTX310, ~50% liver editing yielded a >95% reduction in plasma ANGPTL3 protein and ~40% reduction in triglyceride levels, sustained up to nine months post-dosing. Similar levels of editing and efficacy were observed in LDLR-/- mice, suggesting an LDLR-independent uptake mechanism.In NHPs, dose-dependent editing of ANGPTL3 in the liver of up to 71% was observed, resulting in reduced levels of plasma ANGPTL3 protein (up to 86%) and triglycerides (up to 64%). Reductions in ANGPTL3 protein and triglycerides were durable past 32 weeks. As is commonly observed with LNP delivery, transient elevation of liver enzymes was observed and resolved within 14 days without intervention. Conclusion: CTX310 was well-tolerated in NHPs and led to significant and durable reductions in circulating ANGPTL3 and triglycerides. This data suggests that CTX310 could be used to treat dyslipidemias in humans.

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

P562 Real world effectiveness and safety of ozanimod: One-year follow-up from a large tertiary center

Abstract Background Ozanimod is a first in class sphingosine-1-phosphate receptor modulator approved by the FDA for moderately-to-severely active ulcerative colitis (UC). Real world data describing use of ozanimod are limited. We provide one-year follow up results of our patient cohort treated with ozanimod. Methods This prospective, observational cohort study includes consecutive patients who initiated ozanimod at our center. We collected demographic, clinical, and laboratory data. Clinical disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI). Clinical response was defined as a decrease in ≥3 points in SCCAI from baseline with only patients with clinically active disease included in the analysis, and clinical remission was defined as an SCCAI score of ≤ 2. Results 47 patients have initiated ozanimod therapy at our center: 45 patients with ulcerative colitis (UC), 1 patient with Crohn’s colitis and 1 patient with lymphocytic colitis. Only patients with UC were included in the effectiveness analysis. Demographics are in Table 1: in the UC cohort, the mean age was 40.6 ±16.6 years, mean disease duration was 9.6 ±9.2 years, 26 (58%) were male, 23 (51%) had extensive colitis, and 34 (76%) had previous advanced therapy exposure. 19 had baseline endoscopy with a mean Mayo endoscopic score of 2.6 ±0.5. Clinical response, remission, and corticosteroid free remission (CSFR) rates at weeks 2, 4, 10, 24, and 52 are in Figure 1. At week 10, follow-up was available for 41 patients: 18 patients (55%) achieved clinical response, 24 (59%) clinical remission, and 22 (54%) achieved CSFR. At week 52, follow-up was available for 30 patients: 5 (17%) achieved clinical response, 5 (17%) clinical remission, and 4 (13%) achieved CSFR. There were no significant differences between advanced therapy naïve and experienced patients, including when stratified by the number of previous advanced therapies or prior use of vedolizumab (Figures 2A+B and 3). Patients with a > 75% reduction in absolute lymphocytes had numerically greater induction clinical response and remission rates (80% vs 54%, p=0.4 and 75% vs 53%, p=0.4, respectively). 13 patients experienced adverse events (AEs): hypertension (n=2), transient nausea (n=2), fatigue (n=3), dry skin (n=2), transient liver enzyme elevation (n=2) and transient headache (n=3). Two AEs required discontinuation – hypertensive crisis in a patient with a prior dx of hypertension, and fatigue. There were no episodes of symptomatic bradycardia. Conclusion We present one-year real world follow-up of ozanimod in a largely treatment-refractory cohort of patients with UC, and describe modest one-year effectiveness and a safety profile that is not different from that described in the clinical trials.

Nilotinib: from animal-based studies to clinical investigation in Alzheimer's disease patients.

Nilotinib: from animal-based studies to clinical investigation in Alzheimer's disease patients.

S3194 The Search for Chest Pain and Shortness of Breath: Drug-Induced Liver Injury

Introduction: Patients with drug-induced liver injury (DILI) are often asymptomatic and have undetected increases in their liver function tests (LFTs). Symptoms of DILI, if present, are vague, mimic a host of diseases, and are attributable to other etiologies before DILI is considered. In our case, we present a series of overlapping and vague symptoms that ultimately were attributed to DILI. Case Description/Methods: We describe the case of a 43-year-old male who presented to his cardiologist office with complaints of chest pain followed by shortness of breath (SOB). The patient has a past history for coronary artery disease and two kidney transplants on tacrolimus. Due to the patient's cardiac history, cardiac catheterization was performed which did not show any signs of re-stenosis or obstructive disease. He underwent evaluation for possible pulmonary cause as well including pulmonary function testing and diagnostic imaging which were normal. Laboratories drawn showed elevated liver enzymes (ALT 154, AST 56) and gamma-glutamyl transferase (GGT) of 382 with a normal total bilirubin. Abdominal ultrasound showed no evidence of biliary dilation, choledocholithiasis, or structural abnormality. On further review, patient had recently started a second immunosuppressant, mycophenolate, around the time he started to experience these unexplained symptoms. Additionally, on thorough physical exam, it was noted that the patient’s subjectively stated chest pain was isolated to the epigastrium on palpation. Liver enzymes were continually monitored with eventual return to normal ranges with resolution of reported pain and SOB without having to hold any immunosuppressant agents. Discussion: This case illustrates the unusual clinical presentation of hepatic injury secondary to an unusual cause of DILI. It was surmised that the mild transient elevation in liver enzymes and GGT was due to the initiation of mycophenolate. Mycophenolate is known to cause liver injury in rare cases and in the setting of inflamed liver tissue irritating Glisson’s capsule, abdominal tenderness can develop. It is important to perform an encompassing physical examination to correlate patients’ subjective complaints with objective findings. For patients taking hepatotoxic medications, widening one’s differential diagnosis to include DILI can ensure minimalization of liver damage.

RANDOMIZED CONTROLLED TRIAL OF THE EFFICACY AND SAFETY OF DEFERIPRONE: SUBGROUP ANALYSIS OF PEDIATRIC PATIENTS IN IRON-OVERLOADED PATIENTS WITH SICKLE CELL DISEASE AND OTHER ANEMIAS

Deferiprone (DFP), an oral iron chelator, has recently been approved as the first-line treatment for transfusional iron overload in pediatric and adult patients with Sickle Cell Disease (SCD) and other anemias. The FIRST study (NCT02041299) reported that DFP is noninferior to Deferoxamine (DFO) in patients with SCD and iron overload (as assessed by Liver Iron Concentration [LIC]) and has an acceptable safety profile. Here, we report a subgroup analysis of FIRST to assess whether the efficacy and safety of DFP are comparable to DFO in children with SCD. In this multicenter, 2-arm, randomized, open-label study, eligible patients were randomized 2:1 to receive DFP or DFO for 12 months. The subgroup analysis included children (2–16 years of age) with SCD or another rare anemia who were treated for transfusional iron overload. The primary efficacy endpoint was the change in LIC from baseline to month 12. Safety was assessed by Adverse Events (AEs) in the study period. The safety analysis was composed of 128 (DFP, n = 86; DFO, n = 42) children; most (DFP, 76%; DFO, 81%) had a primary diagnosis of SCD (HbS). Mean age (SD) in the DFP and DFO arms were 9.9 (3.7) and 10.9 (3.0) years (p = 0.09), respectively. 5 children in the DFP arm withdrew due to AEs and 19 (DFP, n = 14; DFO, n = 5) for other reasons. Children treated with DFP or DFO showed no difference in the number of AEs (p = 0.77; including neutropenia [p = 0.30]), severe AEs (p = 0.10), serious AEs (p = 0.16), or withdrawals due to AEs (p = 0.17). Overall incidence of nonserious AEs possibly related to treatment was higher with DFP than DFO (59% vs. 33%; p = 0.01). Transient elevation of liver enzymes was significantly higher with DFP (p = 0.03). 1 child developed agranulocytosis during parvovirus infection, which resolved the following day. In the efficacy population, there was no significant difference in mean (SD) LIC decrease from baseline to 12 months with DFP compared to DFO (-3.39 ± 4.24 mg/g vs. -2.99 ± 3.16 mg/g, respectively; p = 0.57). This pediatric subgroup analysis corroborates previous findings that DFP is comparable to DFO in safely reducing LIC in children with transfusion-dependent anemias. No new safety concerns were observed in children that have not been previously noted in other populations. The present findings on DFP may benefit children with SCD and their healthcare providers when considering effective iron chelation therapy that may also address treatment-adherence concerns.

Toll-Like Receptor 7 Agonist RG7854 Mediates Therapeutic Efficacy and Seroconversion in Woodchucks With Chronic Hepatitis B.

Conventional treatment of chronic hepatitis B (CHB) is rarely curative due to the immunotolerant status of patients. RG7854 is an oral double prodrug of a toll-like receptor 7 (TLR7) agonist that is developed for the treatment of CHB. The therapeutic efficacy, host immune response, and safety of RG7854 were evaluated in the woodchuck model of CHB. Monotreatment with the two highest RG7854 doses and combination treatment with the highest RG7854 dose and entecavir (ETV) suppressed viral replication, led to loss of viral antigens, and induced seroconversion in responder woodchucks. Since viral suppression and high-titer antibodies persisted after treatment ended, this suggested that a sustained antiviral response (SVR) was induced by RG7854 in a subset of animals. The SVR rate, however, was comparable between both treatment regimens, suggesting that the addition of ETV did not enhance the therapeutic efficacy of RG7854 although it augmented the proliferation of blood cells in response to viral antigens and magnitude of antibody titers. The induction of interferon-stimulated genes in blood by RG7854/ETV combination treatment demonstrated on-target activation of TLR7. Together with the virus-specific blood cell proliferation and the transient elevations in liver enzymes and inflammation, this suggested that cytokine-mediated non-cytolytic and T-cell mediated cytolytic mechanisms contributed to the SVR, in addition to the virus-neutralizing effects by antibody-producing plasma cells. Both RG7854 regimens were not associated with treatment-limiting adverse effects but accompanied by dose-dependent, transient neutropenia and thrombocytopenia. The study concluded that finite, oral RG7854 treatment can induce a SVR in woodchucks that is based on the retrieval of antiviral innate and adaptive immune responses. This supports future investigation of the TLR7 agonist as an immunotherapeutic approach for achieving functional cure in patients with CHB.

Liver Pathology in Children with Diagnosed Inflammatory Bowel Disease-A Single Center Experience.

Background: Inflammatory bowel disease (IBD) in children is frequently associated with liver pathology manifested as transient elevation of liver enzymes or specified liver diseases. The aim of the study was to evaluate the prevalence and the type of liver pathology in children with IBD within 2 years’ follow-up after the IBD diagnosis. Methods: We retrospectively reviewed records of children with IBD. Liver pathology was defined as elevated activity of liver enzymes (alanine transaminase (ALT) and/or gamma-glutamyl transpeptidase (GGT)) and bilirubin concentration in serum and/or as pathological changes of the organ on imaging tests (abdominal ultrasound and/or magnetic resonance cholangiopancreatography) or on liver histology performed when indicated. Results: Liver pathology was detected in 21 from 119 children (18%), including 7 (17%) with Crohn’s disease (CD) and 14 (18%) with ulcerative colitis (UC). Specified diagnosis for liver abnormality was found in 14 of 21 children (67%), including primary sclerosing cholangitis (PSC, 19%), non-alcoholic fatty liver disease (NAFLD, 19%), autoimmune sclerosing cholangitis (ASC, 5%), autoimmune hepatitis (AIH, 5%), cholelithiasis (5%), drug-induced liver disease (9%) and viral infection (herpes simplex virus, 5%). Most patients manifested mild IBD or were in clinical remission at the time of liver pathology diagnosis. 14% of patients with liver disease (including only cases with PSC) were diagnosed before IBD, 33% at the same time, and 52% in the later period. Patients with the specified diagnosis of liver pathology were younger, had higher ALT activity and more often demonstrated liver abnormalities on imaging tests. UC patients with idiopathic elevation of liver enzymes had higher pediatric ulcerative colitis activity index scores compared to children with specified liver disease. Conclusions: Liver pathology was observed in a significant percentage of children with IBD in our study. The majority of cases of hepatobiliary abnormalities were detected after diagnosis of IBD; therefore, children with IBD should undergo routine monitoring of liver enzymes.

Acute Liver Failure in a Healthy Young Female With COVID-19

Several well-described manifestations of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported. Among them, a transient elevation of liver enzymes is the typical presentation of coronavirus disease 2019 (COVID-19) liver-related injury. The mechanism of liver involvement is likely a combination of viral injury and immune-mediated inflammation. In contrast, acute liver failure in the setting of COVID-19 has rarely been reported. Herein, we report a case of pediatric acute liver failure in a previously healthy female adolescent infected with SARS-CoV-2 with biopsy evidence of replicating virus in hepatocytes, which has not been previously reported.

Safety and Efficacy of Adoptively Transferred Donor-Derived Tumor-Directed T Cells with Relapsed AML Post-Allogeneic HSCT

Acute myeloid leukemia (AML) relapse post-allogeneic transplant (HSCT) has a dismal prognosis with a median survival of just 4.5 months. Conventional chemotherapy has limited efficacy in treating relapsed AML and is also poorly tolerated by allogeneic HSCT recipients. Similarly, the adoptive transfer of unmanipulated donor lymphocytes (DLIs) to provide a graft versus leukemia (GvL) effect has demonstrated clinical benefit in only a minority (~10%) of patients but frequently (>50%) induces debilitating graft versus host disease (GVHD). Thus, the goal of this project was to enhance both the safety and efficacy associated with adoptively-transferred donor-derived T cells by selectively enriching and infusing leukemia-directed populations that lack alloreactive potential.To date we have generated 18 clinical grade T cell lines by stimulating donor PBMCs with dendritic cells loaded with overlapping peptide libraries spanning the leukemia-associated antigens (LAA) - WT1, PRAME, NY-ESO1 and Survivin. The lines were polyclonal, comprising both CD4+ (26.7±3.5%) and CD8+ (44±2.9%) cells and expressed memory markers CD45RO+/CD62L-/CCR7- (29.3±4%) associated with long term in vivo persistence. The lines were specific for the targeted antigens WT1, PRAME, NY-ESO1 and Survivin by IFNg ELIspot, and did not exhibit any activity against non-malignant patient-derived cells (3±3.5%, E:T 20:1) - a study release criterion.To test the safety and clinical effects of these donor-derived multiLAA T cells, we developed a phase I clinical trial - ADSPAM (IND #16700) to infuse escalating doses of cells (ranging from 0.5 to 2x107 cells/m2) asadjuvant therapy for those with adverse prognosis AML (Arm A) or to treat active, relapsed disease (Arm B). To date, 12 patients (prior histories summarized in Table 1) have been infused with multiLAA T cells (7 on Arm A and 5 on Arm B). Of note, pt1, was treated on both Arms A and B and except for this patient, who had a transient elevation of liver enzymes (AST and ALT) 2 weeks after the infusion of T cells (on Arm A at 0.5 x 107 cells/m2), there were no other infusion-related adverse events.Of the 7 patients who were infused on the adjuvant arm (Arm A), 2 (pts 1 and 4) developed relapsed disease. Pt4 developed brain parenchymal and leptomeningeal relapse 8 months post-multiLAA T cells and 10 months post-allogeneic HSCT, while pt1 relapsed in the bone 4 months post-multiLAA T cells (9 months post-allogeneic-HSCT) while receiving prednisone. Given the potential impact of the steroids on circulating T cells this patient was subsequently re-enrolled and treated on our active disease arm.Among 5 patients infused with multiLAA T cells to treat relapsed disease, 1 is still too early, 2 developed disease progression (months 1 and 3 post-multiLAA T cells, respectively) and 2 (pts 1 and 10) had clinical responses. Pt10, with a history of chemotherapy- and DLI-refractory AML and 30-40% bone marrow blasts at the time of infusion had a 50% reduction in disease burden within 1 month of infusion and remains in active follow-up (currently month 2 post-infusion) with additional multiLAA infusions planned. Pt1, who developed an extramedullary AML relapse at multiple sites within the axial skeleton, had a complete resolution of all disease-related symptoms (back and hip pain and limited range of motion at the shoulder) and a near complete resolution of all bony lesions, based on imaging studies, within 1 month of infusion. Currently, this patient remains disease-free 5 months post-reinfusion on Arm B and 1.5 years from transplant. Interestingly, in this patient whose blasts expressed WT1, we detected a marked and sustained increase in the circulating frequency of WT1-directed T cells in both peripheral blood and marrow that were confirmed of multiLAA origin based on TCR deep sequencing. In summary, infusion of donor multi-LAA-specific T cells to patients with AML post allogeneic HSCT is safe and associated with clinical benefit in individuals with highly treatment-resistant leukemias. [Display omitted] DisclosuresLulla:Leukemia Texas Research grant: Research Funding; Junior Faculty sees funding-Baylor College of Medicine: Research Funding; ASH Scholar Award: Research Funding; Lymphoma SPORE: Research Funding; ASBMT Young Investigator Award: Research Funding; Leukemia Texas: Membership on an entity's Board of Directors or advisory committees. Tzannou:ViraCyte LLC: Consultancy. Heslop:Viracyte: Equity Ownership; Cell Medica: Patents & Royalties: EBV specific T cells, Research Funding; Marker Therapeutics: Equity Ownership; Celgene: Research Funding. Vera:ViraCyte LLC: Equity Ownership; Wilson Wolf Manufacturing: Consultancy; Marker Therapeutics: Equity Ownership. Leen:ViraCyte LLC: Equity Ownership.

Efficacy and safety of eltrombopag in the first-line therapy of severe aplastic anemia in children

Eltrombopag is being investigated for the treatment of aplastic anemia (AA) by stimulating hematopoietic stem cell (HSC) proliferation. To evaluate the efficacy and safety of eltrombopag in the first-line therapy of pediatric AA. The present retrospective study assessed pediatric patients with newly diagnosed AA administered immunosuppressive therapy (IST) (rabbit ATG combined with CSA) with eltrombopag at a single center from March to September 2017. All patients were followed up for >2 years. A total of 14 patients (8 males), averagely aged 86 months, were enrolled in this study. Eltrombopag was administered with a median time to initiation of 19.5 days after IST; the median course of treatment was 253 days. Complete and overall response rates at 6 months were 64.3% (9/14 case) and 78.6% (11/14 cases), respectively. The survival rate was 100%, and no relapse occurred in responders. Eltrombopag was well-tolerated; however, the most common adverse events included indirect bilirubin elevation, jaundice, and transient liver-enzyme elevation. By the end of follow-up, bone marrow chromosomes were normal, and no abnormal myelodysplastic syndrome (MDS)-related clones appeared. Addition of eltrombopag to IST is associated with markedly increased complete response with respect to hematology in pediatric patients with SAA compared with a historical cohort, without intolerable side effects.

Bilateral Lung Transplantation for End-Stage Respiratory Failure from COVID-19 Pneumonia

IntroductionThe SARS-CoV-2 virus is causing severe end-stage fibrosis and respiratory failure in otherwise healthy individuals. Lung transplant (LTX) has been performed internationally in select patients for this indication, but there is limited evidence on its role in COVID-19. We describe a patient who received a bilateral LTX 12 weeks after an initial diagnosis of COVID-19 pneumonia.Case ReportA 51-year-old male with hypertension and presented to an outlying hospital with dyspnea, fever and exposure to SARS-CoV-2. He was hypoxic and a diagnosis of COVID-19 pneumonia was made by nasopharyngeal swab. He was treated with dexamethasone, remdesivir, and convalescent plasma, mechanical ventilation and eventually femoral VV-ECMO cannulation to maintain oxygenation. He was extubated and was transitioned to a left subclavian dual-limb 30 Fr VV-ECMO cannula for improved rehabilitation. He was then transferred to our center for LTX consideration given refractory ARDS. Evaluation for LTX revealed pulmonary hypertension, negative SARS-CoV-2 PCR and deconditioning but no absolute contraindications. He participated in intensive rehabilitation and progressed to assisted steps despite severe deconditioning and hypoxia. He was listed for a bilateral lung transplant with a lung allocation score of 90 and received a donor offer 7 days after listing and after 82 days on ECMO. He underwent bilateral LTX via clamshell exposure with central VA ECMO support. Intraoperatively, the lungs were densely consolidated with severe hilar adenopathy without peripheral adhesions. Post-operatively, he was transitioned back to his original VV ECMO circuit and then decannulated on post-op day 3. Standard induction with basiliximab and immunosuppression with IV methylprednisolone, mycophenolate and tacrolimus was administered. He had a transient elevation of liver enzymes on post-operative day 1 and an early planned tracheostomy was performed due to deconditioning. He has since, been progressing well on oxygen via tracheostomy collar and is able to speak with a one-way valve and participate in rehabilitation.SummaryFor patients with irreversible end-stage lung disease after COVID-19 pneumonia, LTX is a viable option. Timely transfer to a lung transplant center and intensive rehabilitation are essential. Standard established immunosuppression and post-transplant protocols should be followed.

Hepatic Involvement in Aicardi-Goutières Syndrome.

Aicardi-Goutières syndrome (AGS) is a monogenic type-I interferonopathy that results in neurologic injury. The systemic impact of sustained interferon activation is less well characterized. Liver inflammation is known to be associated with the neonatal form of AGS, but the incidence of AGS-related hepatitis across lifespan is unknown.We compared natural history data including liver enzyme levels with markers of inflammation, (liver-specific autoantibodies and interferon signaling gene expression[ISG] scores). Liver enzymes were classified as normal or elevated by the fold increase over the upper limit of normal (ULN). The highest increases were designated as hepatitis, defined as aspartate-aminotransferase or alanine-aminotransferase threefold ULN, or gamma-glutamyl transferase 2.5-fold ULN. A larger cohort was used to further characterize the longitudinal incidence of liver abnormalities and the association with age and genotype.Across the AGS cohort (n = 102), elevated liver enzymes were identified in 76 individuals (74.5%) with abnormalities at a level consistent with hepatitis in 29 individuals (28.4%). SAMHD1 mutations were less likely to be associated with hepatitis (log-rank test; p = 0.011). Hepatitis was associated with early-onset disease and microcephaly (log-rank test; microcephaly p = 0.0401, age onset p = 0.0355). While most subjects (n = 20/33) were found to have liver-specific autoantibodies, there was no association between the presence of autoantibodies or ISG scores with hepatitis-level enzyme elevations.In conclusion, all genotypes of AGS are associated with transient elevations of liver enzymes and the presence of liver-associated autoantibodies. This adds to our growing understanding of the systemic pathology AGS.

Efficacy and Safety of Sirolimus for Blue Rubber Bleb Nevus Syndrome: A Prospective Study.

Blue rubber bleb nevus syndrome (BRBNS) is a rare systemic venous malformation (VM) disease. The characteristic gastrointestinal (GI) bleeding from multiple VM lesions causes severe chronic anemia which renders most patients depend on lifelong blood transfusion and frequent endoscopic treatment with dismayed outcomes. Although recent case reports suggest that oral sirolimus (rapamycin) is effective, a comprehensive evaluation of its efficacy and safety is in need. A prospective study was conducted for both pediatric and adult BRBNS patients with administration of sirolimus at the dose of 1.0 mg/m2 to maintain a trough concentration of 3-10 ng/mL. Laboratory tests including complete blood count, biochemical profile, D-dimer, and whole-body magnetic resonance imaging were performed at baseline and 3, 6, and 12 months after treatment. Clinical indicators such as hemoglobin level, lesion size, and transfusion need were evaluated. Adverse effects were recorded regularly. A total of 11 patients (4 males and 7 females) with median age of 14 (range, 5-49) years were recruited. The average lesion size was reduced by 7.4% (P < 0.001), 9.3% (P < 0.001), and 13.0% (P < 0.05) at 3, 6, and 12 months of sirolimus treatment, respectively. Hemoglobin increased significantly after 6- and 12-month treatment (P = 0.006 and 0.019, respectively). Only 1 patient received blood transfusion once during the study. Patients' quality of life and coagulation function were improved. Grade 1-2 adverse effects including oral ulcers (81.8%), acne (27.3%), transient elevation of liver enzymes (18.2%), and hair loss (9.1%) were observed. Sirolimus reduces the size of VMs, alleviates GI bleeding, and eliminates transfusion dependence of patients with BRBNS. The drug-related adverse effects are mild and mostly self-limited. These findings support sirolimus as a first-line treatment for GI and cutaneous VMs of BRBNS (see Visual abstract, Supplementary Digital Content, http://links.lww.com/AJG/B819).

SURG-10. SPECTROSCOPIC MEASUREMENT OF 5-ALA-INDUCED INTRACELLULAR PROTOPORPHYRIN IX IN PEDIATRIC BRAIN TUMORS

OBJECTIVE5-ALA guided resection of glioma in adults enables better delineation between tumor and normal brain, allowing improved resection and improved patients’ outcome. Recently, several reports were published regarding 5-ALA for resection of pediatric brain tumors. The aim of the study was to determine the intracellular fluorescence of PPIX in pediatric brain tumors by hyperspectral imaging and to compare it with visually observed intraoperative fluorescence.METHODS5-ALA was administered orally four hours prior to surgery. During tumor resection the surgeon assessed the fluorescence signal to be strong, weak or absent. Subsequently, fluorescence intensity of samples was measured via spectroscopy. In addition, clinical data, imaging and laboratory data were analyzed.RESULTSEleven children (1–16 years) were operated. Tumor entities included: three medulloblastomas, two pilocytic astrocytomas (PA), two anaplastic ependymomas and one diffuse astrocytoma, anaplastic astrocytoma, pilomyxoid astrocytoma and anaplastic pleomorphic xanthoastrocytoma. Strong fluorescence was visible in all anaplastic tumors and one PA; one PA demonstrated weak fluorescence. Visible fluorescence was strongly associated with intracellular fluorescence intensity and PPIX concentration (P<0.05). Within all tumors with visible fluorescence the intracellular PPIX concentration was greater than 4 µg/ml. Except for moderate and transient elevation of liver enzymes, no 5-ALA related adverse events were reported.CONCLUSIONWe demonstrate a strong association between intraoperative observations and spectrometric measurements of PPIX fluorescence in tumor tissue. As in former studies, fluorescence signal was more commonly observed in malignant glial tumors. Further prospective controlled trials should be conducted to investigate the feasibility of 5-ALA guided resection of pediatric brain tumors.