Transient Transaminitis Research Articles

Refractory pruritus in cholestatic drug-induced liver injury secondary to androgenic anabolic steroids: Plasmapheresis to the rescue

Abstract: Anabolic androgenic steroids (AASs) have long been misused by professional athletes. Easy online and over-the-counter availability of AASs makes it an alluring option even among amateurs for their desired cosmetic and performance-enhancing effects. AASs have been associated with distinct forms of liver injury including transient transaminitis, peliosis hepatis, and hepatic tumors. An acute cholestatic syndrome with bland histology is another characteristic form of liver injury rarely reported with AASs. Plasmapheresis may provide a long-lasting relief of symptoms when conventional pharmacotherapeutic measures fail. Herein, we report a challenging case of a young male with refractory pruritus secondary to AASs, managed effectively with plasmapheresis.

Phenotypic and genetic spectra of galactose mutarotase deficiency: A nationwide survey conducted in Japan

PurposeGalactose mutarotase (GALM) deficiency was first reported in 2019 as the fourth type of galactosemia. This study aimed to investigate the clinical and genotypic spectra of GALM deficiency. MethodsThis was a questionnaire-based retrospective survey conducted in Japan between February 2022 and March 2023. ResultsWe identified 40 patients with GALM deficiency in Japan (estimated prevalence: 1:181,835). Four of 38 patients (10.5%) developed cataracts, which resolved with lactose restriction in 3 out of 4 patients. Transient transaminitis was the most common symptom (23.1%). All of the patients followed lactose restriction; discontinuation of the restriction after infancy did not cause any complications. Moreover, none of the participants experienced long-term complications. Two variants, GALM NM_138801.3: c.294del and c.424G>A, accounted for 72.5% of the identified pathogenic variants. The patients showed moderately elevated blood galactose levels with lactose intake; however, the elevation was lower than that observed in galactokinase deficiency. ConclusionGALM deficiency is characterized by a similar but milder phenotype and lower blood galactose elevation than in galactokinase deficiency. Diagnosis and initiation of lactose restriction in early infancy should be essential for prevention of cataracts, especially in cases of irreversible opacity.

Systemic VSV-IFNβ-NIS oncolytic virotherapy in patients with relapsed refractory T-cell lymphoma.

7530 Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach currently under study for relapsed refractory (R/R) hematologic malignancies. The engineered Vesicular Stomatitis Virus VSV-IFNβ-NIS used in this study encodes interferon beta (IFNβ) and sodium iodine symporter (NIS). Virally-encoded IFNβ serves as an index of viral proliferation and enhances host anti-tumor immunity. Herein, we report the updated results of the phase 1 clinical trial NCT03017820 of a one-time administration of systemic VSV-IFNβ-NIS among patients (pts) with R/R multiple myeloma (MM), T cell Lymphoma (TCL) and Acute myeloid Leukemia (AML) with particular focus on the TCL cohort treated at the highest dose level (DL4) without Ruxolitinib. Methods: VSV-IFNβ-NIS was administered as a single IV dose following a classical 3+3 phase I trial, starting at 5e9 TCID50 DL1 through 1.7e11 TCID50 DL4. A dose expansion cohort of 8 additional R/R TCL pts was added at DL4 in view of an initial signal of activity. The primary objective was to determine the maximum tolerated dose of VSV-IFNβ-NIS as a single agent. Secondary objectives were determination of safety profile and preliminary efficacy of VSV-IFNβ-NIS. Adverse events (AEs) are reported based on CTCAE V4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014) criteria. Results: To date, a total of 43 pts received VSV-IFNβ-NIS: MM (N=21), TCL (N=21) and AML (N=1). In the TCL cohort: at DL4 Group A (no Ruxolitinib), 12 pts were registered, but only 11 pts were treated (mycosis fungoides (MF) N=3; ALK- ALCL N=1; PTCL-NOS N=2; AITL N=4; Nodal PTCL, TFH N=2; ages 33-79). These pts received a median of 3 lines of therapy (range: 1-5). No dose limiting toxicities were observed. Grades 3 and higher AEs were hematologic with transient lymphopenia (63.6%), neutropenia (36.4%) being the most common. The non-hematologic AEs observed included unique toxicities such as CRS grades 1-2 (81.8%); the transient transaminitis grade 1-2 (36.4%) and grade 3 (27.3%) along with thrombocytopenia grade 1-2 (63.6%) and grade 3 (18.2%) were a reflection IFNβ toxicity. All the AEs observed were short lived. Responses were seen in pts with PTCL. At DL4, in pts with systemic PTCL (N=9), there were 5 responses including 3 complete responses (CR) with two long-lasting at 24 months, an ongoing 15 month CR, and a 5 month CR, and 2 partial responses (PR) lasting 5 months in one pts and 6 months in the other. Conclusions: These updated results of single agent VSV-IFNβ-NIS which include pts with PTCL treated at the highest dose level and a dose expansion cohort demonstrates not only the safety of VSV-IFNβ-NIS but also a strong efficacy signal in pts with PTCL with impressive durable responses. Two expansion cohorts at DL4 have been added (20 additional PTCL, 10 B-cell lymphoma pts) to obtain additional data on tolerability and efficacy and biomarkers of response in these pts. Clinical trial information: NCT03017820 .

Abstract #1404927: Glycogenic Hepatopathy is a Rare Reversible Condition with Optimal Glycemic Control in Type 1 Diabetes Mellitus

Glycogenic hepatopathy (GH) is a rare complication of type 1 DM due to over-insulin use to achieve glycemic control due to excessive calorie intake. GH developed due to the accumulation of glycogen in hepatocytes predominantly seen in the pediatric population with poorly controlled DM type 1 and rarely seen in DM 2 and characterized by transient transaminitis and hepatomegaly. Liver biopsy is the gold standard and non-invasive tests are having a limited role. 18-year-old Hispanic male with poorly controlled type 1 DM, dyslipidemia, and post-ablative hypothyroidism. The patient was non-compliant with medical treatment leading to multiple hospitalizations for diabetes ketoacidosis (DKA) and also hypoglycemic events. The patient was clinically asymptomatic (denied any nausea/vomiting or abdominal pain) and was never been diagnosed with liver dysfunction in the past. Physical examination was significant for the enlarged liver but no splenomegaly, otherwise unremarkable. Initial routine labs revealed elevated aminotransferases ALT 1329 IU/L and AST 1987 IU/L otherwise CBC and CMP, TSH were unremarkable. HbA1c was 13.7. A liver ultrasound revealed diffuse fatty infiltration and hepatomegaly (20.5 cm). No signs of biliary stones or obstruction. Serology for viral Hepatitis A’’, ‘B’ and ‘C’ were negative. Autoimmune hepatitis workup (ANA, ASMA, AMA) and celiac serology were negative. The patient underwent a liver biopsy and showed diffuse hepatocyte swelling with frequent glycogenated nuclei consistent with glycogenic hepatopathy with minimal inflammation and no evidence of steatosis. Minimal sub-sinusoidal fibrosis (Fibrosis stage 0/6). The patient was counseled for strict glycemic control with a low-carb diet (portion control) and proper use of insulin with close office follow-up and regular monitoring of blood sugar at home. Within 6 months, HbA1C improved from 13.7% to 9.8% and ALT improved from 1329 to 51 IU/L and AST decreased from 1987 to 57 IU/L. During a nine-month follow-up visit, AST and ALT remained low at 44 and 31 IU/L respectively. Patient followed the The patient underwent a repeat liver biopsy which revealed minimal accumulation of glycogen deposits and minimal hepatocyte inflammation and no evidence of fibrosis. GH and NAFLD are indistinguishable clinically and NAFLD is more prevalent in DM although GH is a revertible disease within 2-14 weeks with better glycemic control. The pathophysiology of GH is incompletely understood. It is believed to be the consequence of recurrent fluctuations of glucose level with hyperglycemia and hypoglycemia and hyperinsulinism. Supra-physiological doses of insulin to manage blood sugar are believed to be the cause of this condition. Awareness of Glycogenic hepatopathy is essential, and the proper management of elevated liver enzymes is to be addressed in uncontrolled type 1 DM patients. Recurrence of GH has been reported with repeated episodes of DKA. Further research is needed to investigate this phenomenon.

Letermovir as Cytomegalovirus Prophylaxis in a Pediatric Cohort: A Retrospective Analysis

Letermovir is an attractive cytomegalovirus (CMV) prophylactic agent, but published data in children are scarce. This retrospective chart review aimed to describe our experience using letermovir as CMV prophylaxis in pediatric hematopoietic cell transplantation (HCT) recipients. Pediatric patients (age <20 years) undergoing allogeneic HCT and receiving letermovir prophylaxis in the Mayo Clinic Pediatric Bone Marrow Transplant Program were eligible for inclusion in this retrospective chart review. Medical records were reviewed to evaluate letermovir dosing, CMV levels, laboratory values, and reports of adverse effects. Between October 2020 and April 2022, 9 patients age 4 to 19 years undergoing allogeneic HCT in the Pediatric Bone Marrow Transplant Program received letermovir prophylaxis, either 240 mg or 480 mg daily at a mean and median dose of 10 mg/kg/day. Letermovir was crushed and administered via nasogastric tube in 4 of 9 patients. Two patients received letermovir for secondary CMV prophylaxis after initial treatment with ganciclovir/valganciclovir, and the remaining 7 received letermovir for primary prophylaxis. One patient, a 20-kg 6-year-old female receiving 240 mg (12 mg/kg), experienced low-level CMV viremia while on letermovir. No other patients experienced CMV reactivation while on letermovir prophylaxis. In 2 patients, transient mild transaminitis was noted within the first weeks of letermovir therapy, which resolved without intervention, and its relationship to letermovir could not be clearly established. Letermovir administration was feasible and well tolerated as CMV prophylaxis in our small cohort of pediatric patients undergoing HCT. Larger, prospective studies are warranted to confirm the safety and efficacy of letermovir in children. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Toxicity and Dosimetric Parameters of Ablative Radiation Therapy in the Management of Patients with Child-Pugh B/C Liver Function and Unresectable Hepatocellular Carcinoma (HCC)

To date there is no clear standard non-surgical therapeutic option for HCC patients. Ablative radiation therapy (SBRT/HIGRT) is an emerging non-invasive treatment for patients with HCC. However, there is concern about the risk for radiation-induced liver toxicity following radiation in patients with decompensated liver function (Child-Pugh B/C).We retrospectively identified all patients with unresectable, non-metastatic HCC treated with SBRT/HIGRT and underlying Child-Pugh B or C liver function prior to radiation therapy at our University and Veterans Affairs (VA) radiation oncology departments from 2014 to 2019. Primary endpoints included treatment-related toxicity, as well as, evaluation of dosimetric parameters for OAR.38 patients (39 treatment courses) were included. Most patients (97%) had Child-Pugh B7-B9 (62% CP B7, 21% CP B8, 15% CP B9) or ALBI grade 2-3 (69% ALBI grade 2, 31% ALBI grade 3) liver disease prior to radiation therapy. A single patient had Child-Pugh C10 liver function. The most commonly utilized regimens include 50 Gy in either 5 or 10 fractions. The median delivered dose was 50 Gy (range 30-50) in an average of 7.5 fractions (range 5-10). Most patients had a single lesion (63%) with a median lesion size of 3.2 cm (range 1.10-7.40 cm). The mean liver dose was 9.40 Gy (range 3.38-23.94) with a liver D800cc of 4.14 Gy (range 0.35-17.31). All patients completed their intended treatment course with a median follow up of 43 months. Four (10.3%) treatment courses resulted in non-classical radiation-induced liver disease (RILD) (defined as an increase of 2 or more points in Child-Pugh score), compared to 8.3% for patients with Child-Pugh A liver function treated during a similar time period. Otherwise, one patient (2.6%) experienced acute grade 3+ (non-RILD) hepatobiliary toxicity (transient transaminitis). Two-year freedom from local progression was 73% (95% CI 37-90%), median overall survival 12 months (95% CI 5-25 months), and median progression free-survival was not reached.Ablative radiation therapy as definitive management for patients with unresectable, non-metastatic HCC appears to be reasonably well tolerated in patients with decompensated liver function at baseline (Child-Pugh B7-B9), with low rates of RILD and encouraging local control. With careful selection, these patients appear to be reasonable candidates for consideration of SBRT/HIGRT. Our analysis did not include enough patients with Child-Pugh C10+ disease to draw meaningful conclusions.

Retraction Note: Safety and efficacy of favipiravir versus hydroxychloroquine in management of COVID-19: A randomised controlled trial

Favipiravir is considered a potential treatment for COVID-19 due its efficacy against different viral infections. We aimed to explore the safety and efficacy of favipiravir in treatment of COVID-19 mild and moderate cases. It was randomized-controlled open-label interventional phase 3 clinical trial [NCT04349241]. 100 patients were recruited from 18th April till 18th May. 50 patients received favipiravir 3200 mg at day 1 followed by 600 mg twice (day 2–day 10). 50 patients received hydroxychloroquine 800 mg at day 1 followed by 200 mg twice (day 2–10) and oral oseltamivir 75 mg/12 h/day for 10 days. Patients were enrolled from Ain Shams University Hospital and Assiut University Hospital. Both arms were comparable as regards demographic characteristics and comorbidities. The average onset of SARS-CoV-2 PCR negativity was 8.1 and 8.3 days in HCQ-arm and favipiravir-arm respectively. 55.1% of those on HCQ-arm turned PCR negative at/or before 7th day from diagnosis compared to 48% in favipiravir-arm (p = 0.7). 4 patients in FVP arm developed transient transaminitis on the other hand heartburn and nausea were reported in about 20 patients in HCQ-arm. Only one patient in HCQ-arm died after developing acute myocarditis resulted in acute heart failure. Favipiravir is a safe effective alternative for hydroxychloroquine in mild or moderate COVID-19 infected patients.

Results Of a Phase I Study Of Clofarabine and 2 Gy Total Body Irradiation (TBI) As a Non-Myeloablative Preparative Regimen For Hematopoietic Stem Cell Transplantation (HSCT) In High Risk Children With Hematologic Malignancies: A Multi-Center TACL Study

BackgroundReduced intensity conditioning (RIC) regimens for HSCT in hematologic malignancies are successful in reducing transplant related mortality (TRM) and making HSCT available for a select group of high risk patients. Despite HSCT and its associated graft-versus-leukemia (GVL) effect, the risk of relapse remains high with RIC regimens. Clofarabine is a second generation purine analogue with significant anti-leukemic activity in pediatric patients. We postulated that a non-myeloablative (NMA) preparative regimen with clofarabine and 2 Gy TBI may lead to sustained engraftment with low TRM in high-risk children with hematologic malignancies undergoing related and unrelated HSCT. Patient and MethodsThe primary aim of the Phase I study was to establish the maximum feasible dose (MFD) of clofarabine in conjunction with 2 Gy TBI that leads to durable engraftment with acceptable toxicity in a high-risk pediatric population. Patients between 1-21 years of age with leukemia and undergoing HSCT with significant co-morbidities or any condition that will make them at high risk of TRM with a myeloablative regimen were eligible. Patients had to be in CR or CRp (no morphologic disease, ANC >0.75 x 109/L but without platelet recovery) status prior to HSCT with a PS score of >50 with no active infection, a creatinine clearance of >70 ml/min/1.73m2 and liver enzymes <5X ULN. Patients were stratified according to donor source- related donor (RD) or unrelated donor (UD; 10/10 or 9/10 HLA match) arms. Peripheral blood stem cells (PBSC) were the preferred graft source (BM was allowed for RD only). Cyclosporine and mycophenolate mofetil were used as GVHD prophylaxis. A phase I modified 3+3 design was used with engraftment, severe toxicity and TRM as study end-points. Starting dose of clofarabine was 40 mg/m2 x 5 days with escalation to 52 mg/m2 in case of non-engraftment and acceptable toxicity in the first cohort or de-escalation to 30 mg/m2for dose limiting toxicity (DLT) or TRM. Patients completed the dose evaluation at 100 days post-HSCT, but were followed for 1 year post- transplant and were censored at relapse or death. ResultsSeventeen pediatric patients with a median age of 9 years (range 1-18) enrolled on the study between 7/2010 and 5/2013 and 16 have completed 100-day post-HSCT evaluations. Ten patients had ALL (CR2 =5; CR3 =4 and CR4=1) while 7 had AML (PIF=1; CR1= 1; CR2=3 and secondary AML=3); 9 received UD and 8 received RD grafts. All patients were heavily pre-treated and the indication for the NMA approach was: prior HSCT (n=6), prior liver transplant (n=2), trisomy 21 (n=2) or significant comorbidities (n=7).There was no observed TRM or DLT in the first cohort (clofarabine 40 mg/m2/dose x 5 days) in both the UD and RD strata. The dose was escalated to 52 mg/m2/dose in the next cohorts. All patients tolerated the maximum dose well and no DLT was reported. Significant non-hematologic toxicities (CTC ≥ grade 3) observed were- transient transaminitis (ALT increase in 30% and AST increase in 17%); anorexia (35%) and skin reactions in 16%.PBSC was the stem cell source for all patients, except 3 who had received BM from a RD. Median cell dose was 6.8 x 106 CD34+/kg (range: 2.2-11.5 x 106/kg). All patients achieved neutrophil and platelet engraftment at a median of 19 days (range: 9-25) and 11 days (range: 3-29), respectively. CD3 chimerism analysis at day+30 post-transplant showed donor engraftment in all patients; 15 were full donor (>95%) and 2 showed mixed chimerism (53% and 81% donor).Ten (58%) patients developed acute GVHD, 8 (47%) had ≤ Grade II and 2 (11%) had Grade III acute GVHD. Seven (41%) patients relapsed (4/8 RD and 3/9 in UD arms) at a median time of +106 days (range: 88-190) post-HSCT and all of them died due to disease. Ten patients (58%) are alive and disease free; six have completed 1 year evaluations and 4 are still in follow-up. ConclusionThe MFD of clofarabine in combination with 2 Gy TBI was determined to be 52 mg/m2. This regimen is well tolerated and leads to brisk and sustained donor engraftment in a pediatric population that is at high risk of TRM. Disclosures:Thompson:Sanofi Aventis: Speakers Bureau.

MO004PRIMARY BILIARY CHOLANGITIS PRESENTING WITH RENAL FANCONI SYNDROME: A FORGOTTEN PHENOTYPE

Abstract Background and Aims Primary biliary cholangitits (PBC) is an autoimmune liver disease, leading to liver fibrosis and cirrhosis. It is a rare disease affecting 1 in 3-4000 people and is more common in females. Symptoms may go unnoticed and include itch and fatigue. Most patients have anti-mitochondrial antibodies (AMA) as well as raised gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) levels. First line treatment for PBC is ursodeoxycholic acid and is usually continued lifelong. It improves liver biochemistry, histological progression of liver disease and liver transplant-free survival. Renal complications of PBC include distal renal tubular acidosis (RTA), tubule-interstitial nephritis (TIN) and renal Fanconi syndrome. Method We reviewed a case of PBC presenting with renal Fanconi syndrome. Results A 48-year-old female was referred to the renal clinic due to progressive decline in renal function since she was diagnosed with type 2 diabetes in 2007. She was also known to have AMA (&amp;gt;1:640) and previously had transient transaminitis. She was clinically well with no major symptoms but reported that she had had a few episodes of urinary tract infection in the previous year. Her diabetes was managed with lifestyle modifications in the past until a few months ago when Metformin was introduced. However, her HbA1c level had never been greater than 55 mmol/mol. Urine dipstick in the clinic showed pH of 6, blood+, glucose+++, protein+++ and ketone trace. The severity of glycosuria was inconsistent with her glycaemic control. There was a disparity between her urine albumin/creatinine ration (ACR) of 18.8g/mol and protein/creatinine ratio (PCR) of 124mg/mmol. Myeloma screen was negative and further urine analysis showed generalised aminoaciduria. She also had hypouricaemia, intermittent hypophosphataemia and non-anion gap metabolic acidosis. These results are in keeping with renal Fanconi syndrome. Her eGFR was 48 ml/min/1.72m2 in 2007 and was 21 ml/min/1.72m at the time of review. A renal biopsy was undertaken, and the appearances were suggestive of mild tubulo-interstitial nephritis; the glomeruli were unremarkable; there was mild chronic tubulo-interstitial damage. She was started on oral steroid, sodium bicarbonate and ursodeoxycholic acid. The course of steroid had a slight transitory beneficial effect on the renal function. Conclusion Distal RTA is the usual renal feature of PBC, occurring in 1/3 of cases with advanced disease. In contrast, proximal RTA associating with renal Fanconi syndrome occurs rarely. Like our case, the cases that have been previously reported show that Fanconi syndrome occurred during the early phase of PBC in the absence of marked hepatic abnormalities, and were associated with CKD. Fanconi syndrome and TIN are renal features of mitochondrial cytopathies and are perhaps a forgotten association of PBC. Antimitochondrial antibodies may play a role in the onset of tubulo-interstitial nephritis and Fanconi syndrome.

RETRACTED ARTICLE: Safety and efficacy of favipiravir versus hydroxychloroquine in management of COVID-19: A randomised controlled trial

Favipiravir is considered a potential treatment for COVID-19 due its efficacy against different viral infections. We aimed to explore the safety and efficacy of favipiravir in treatment of COVID-19 mild and moderate cases. It was randomized-controlled open-label interventional phase 3 clinical trial [NCT04349241]. 100 patients were recruited from 18th April till 18th May. 50 patients received favipiravir 3200 mg at day 1 followed by 600 mg twice (day 2–day 10). 50 patients received hydroxychloroquine 800 mg at day 1 followed by 200 mg twice (day 2–10) and oral oseltamivir 75 mg/12 h/day for 10 days. Patients were enrolled from Ain Shams University Hospital and Assiut University Hospital. Both arms were comparable as regards demographic characteristics and comorbidities. The average onset of SARS-CoV-2 PCR negativity was 8.1 and 8.3 days in HCQ-arm and favipiravir-arm respectively. 55.1% of those on HCQ-arm turned PCR negative at/or before 7th day from diagnosis compared to 48% in favipiravir-arm (p = 0.7). 4 patients in FVP arm developed transient transaminitis on the other hand heartburn and nausea were reported in about 20 patients in HCQ-arm. Only one patient in HCQ-arm died after developing acute myocarditis resulted in acute heart failure. Favipiravir is a safe effective alternative for hydroxychloroquine in mild or moderate COVID-19 infected patients.

Olanzapine for the Treatment of Breakthrough Vomiting in Children Receiving Moderate and High Emetogenic Chemotherapy

The efficacy of olanzapine (mean dose 0.09 mg/kg/dose) was evaluated in 31 children 2-18 years of age, for chemotherapy induced breakthrough vomiting. Among 42 chemotherapy blocks with emesis, complete and partial responses were observed in 34 (80.9%) and 6 (14.3%) blocks, respectively, while 1/31(2.4%) patient had refractory vomiting. Mild sedation and transient transaminitis were the observed side effects.

Clinical Outcomes Following Tocilizumab Administration in Mechanically Ventilated Coronavirus Disease 2019 Patients.

A retrospective cohort analysis of 21-day outcomes for consecutive mechanically ventilated patients treated with tocilizumab from March 24, 2020, to May 4, 2020. Nine ICUs at six hospitals within a hospital system in Houston, Texas, United States. The first 62 coronavirus disease 2019 patients on invasive mechanical ventilation who were treated with tocilizumab, which was considered for all patients with severe disease. Tocilizumab was administered either at a weight-based dose of 4-8 mg/kg or at a flat dose of 400 mg, with repeat administration in some patients at the physician's discretion. The primary outcomes were mortality and clinical improvement, defined as extubation. By day 21 post-tocilizumab, clinical improvement occurred in 36 patients (58%) and 13 patients (21%) died. In both univariable and multivariable analyses, age less than 60 years was associated with clinical improvement. Transient transaminitis was the most common adverse reaction, occurring in 25 patients (40%). Based on clinical outcomes and mortality rates seen in previous reports of mechanically ventilated patients, tocilizumab, as part of the management strategy for severe coronavirus disease 2019, represents a promising option. These findings support the need for evaluation of tocilizumab in a randomized controlled trial.

MON-LB126 A Benign and Favorable Diagnosis: Glycogen Hepatopathy Causing Transient Transaminitis During Diabetic Ketoacidosis in Type 1 Diabetes Mellitus

Background: Transient transaminitis is a rarely discussed complication of uncontrolled diabetes mellitus (DM). Known as glycogenic hepatopathy (GH), it is belived to be caused by build-up of glycogen in hepatocytes. Recognized as benign and reversible, GH is associated with hepatomegaly (>90% cases) and primarily seen in patients with type 1 DM during periods of inadequate hyperglycemic control. Differential diagnoses include glycogen storage diseases, nonalcoholic fatty liver disease, hepatosclerosis, autoimmune hepatitis, hemochromatosis, Wilson disease, and acute viral hepatitis.1 Case Report: A 26-year-old African American female with type 1 DM and sickle cell presented on multiple occasions to the emergency department with abdominal pain associated with nausea, vomiting and diarrhea. Initial labs consistently included glucose levels >600 mg/dL (70-105 mg/dL), elevated anion gap ranging 20-40s mEq/L (5-15 mEq), and severe metabolic acidosis reflective of diabetic ketoacidosis (DKA). Labs were also significant for repeated mild transaminitis despite adequate fluid hydration.After several admissions, we observed a distinct pattern of mild transaminitis that directly fluctuated with her levels of blood glucose. With some minor lag, the patient’s liver enzymes normalized when her glucose levels normalized and DKA resolved.Further work-up ruled out more common etiologies of liver injury. Multiple abdominal ultrasounds and CT scans showed a normal sized liver without obvious structural abnormalities. Labs were significant for negative hepatitis B and hepatitis C; several negative anti-smooth muscle, anti-nuclear antibody, centromere antibody, and liver kidney microsomal type 1 antibody; normal levels of ceruloplasmin and alpha 1 anti-trypsin; low iron levels 23 ug/dL (60-180 ug/dL); borderline low IgG 627 mg/dL (700-1600 mg/dL).We hypothesized that the patient likely had GH by exclusion of other liver pathologies and given the context of transient transaminitis during DKA. Conclusion: GH is a benign and favorable diagnosis in diabetic patients with elevated transaminases.1 Given the small number of cases of GH reported, there is a need to record and analyze more patients with likely GH in order to better understand the condition. Appropriate clinician awareness of GH can also eliminate the need for time consuming and costly workup.

SUN-495 Rapid Resolution of Hyperthyroidism Induced Hepatic Dysfunction with Methimazole

Background:Hepatic dysfunction in the setting of hyperthyroidism is difficult to diagnose and poses a challenge in therapy, since the classic medications used are potentially hepatotoxic.Clinical case:A 51-year-old female patient presented with fatigue, palpitations and tremors. BP 146/65 mmHg, HR 111 bpm and Temp 97.8 F. She was severely thyrotoxic with 3 + DTRs, tremors, enlarged thyroid gland with bruit on auscultation, clear lungs and no lower extremities edema. Blood tests showed TSH <0.003 IU/ml (0.450-5.330 IU/ml), Free T4 5.33 ng/dL (0.45-1.80 ng/dL), Free T3 > 30.0 pg/mL (2.3-4.2 pg/mL). Liver enzymes showed elevation in transaminases with ALT 319 IU/L (7-40 IU/L), AST 330 IU/L (7-40 IU/L) normal total Bilirubin 0.7 mg/dL (0.1-1.5 mg/dL) and Alkaline phosphatase 65 IU/L (40-200 IU/L). Transaminases were also elevated 3 weeks prior to presentation and this was extensively worked up with no identifiable etiology to explain the liver dysfunction. She was started on beta blocker therapy and admitted to the ICU. She had no clinical or echocardiographic evidence of cardiac dysfunction and remained hemodynamically stable. She was started on Methimazole 45 mg daily. The patient improved clinically and a pronounced decline in transaminase levels was documented in the first 72 hours. She was discharged home on day 3 of admission. On follow up visit her transaminases were found to have completely normalized within 14 days.Discussion:The diagnosis of elevated transaminases in hyperthyroidism is a challenge. This is due to the possibility of multiple etiologies including decreased cardiac output and/or liver congestion, concomitant primary liver disease or more specifically autoimmune hepatic disease such as primary biliary cirrhosis. (1-2). Incidentally Methimazole has been associated with transient asymptomatic transaminitis typically during the first three months of therapy (3). Our case indicates, that methimazole can be used in patients with a presumed diagnosis of hyperthyroidism induced hepatotoxicity after all possible etiologies are ruled out. Hyperthyroidism as the cause of liver dysfunction can only be entertained after all those etiologies are ruled out and upon resolution of transaminase elevation in conjunction with improvement in the hyperthyroid state itself, as was demonstrated in this case.Conclusion:Methimazole can be safely used in patients with severe hyperthyroidism and elevated liver enzymes when all other etiologies of liver dysfunction have been ruled out.

Hemodynamic Effects of Adding Simvastatin to Carvedilol for Primary Prophylaxis of Variceal Bleeding: A Randomized Controlled Trial.

Beta-blockers are the mainstay agents for portal pressure reduction and to modestly reduce hepatic venous pressure gradient (HVPG). We studied whether addition of simvastatin to carvedilol in cirrhotic patients for primary prophylaxis improves the hemodynamic response. Cirrhotic patients with esophageal varices and with baseline HVPG > 12 mm Hg were prospectively randomized for primary prophylaxis to receive either carvedilol (group A, n = 110) or carvedilol plus simvastatin (group B, n = 110). Primary objective was to compare hemodynamic response (HVPG reduction of ≥20% or <12 mm Hg) at 3 months, and secondary objectives were to compare first bleed episodes, death, and adverse events. The groups were comparable at baseline. The proportion of patients achieving HVPG response at 3 months was comparable between groups (group A-36/62 [58.1%], group B-36/59 [61%], P = 0.85). The degree of mean HVPG reduction (17.3% and 17.8%, respectively, P = 0.98) and hemodynamic response (odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.43-1.83, P = 0.74) was also not different between the groups. Patients who achieved target heart rate with no hypotensive episodes in either group showed better hemodynamic response (77.8% vs 59.2%, P = 0.04). Failure to achieve target heart rate (OR: 0.48; 95% CI: 0.22-1.06) and Child C cirrhosis (OR: 4.49; 95% CI: 1.20-16.8) predicted nonresponse. Three (3.7%) patients on simvastatin developed transient transaminitis and elevated creatine phosphokinase and improved with drug withdrawal. Two patients in each group bled (P = 0.99). Three patients and 1 patient, respectively, in group A and B died (P = 0.32), with sepsis being the cause of death. Addition of simvastatin to carvedilol for 3 months for primary prophylaxis of variceal bleeding does not improve hemodynamic response over carvedilol monotherapy. Simvastatin usage should be closely monitored for adverse effects in Child C cirrhotic patients.

275P - Primary central nervous system lymphoma treated with high-dose methotrexate and rituximab: Preliminary results in Vietnam

BackgroundCurrent treatment for primary central nervous system lymphoma involves high-dose methotrexate based regimen. In low&middle-income countries like Vietnam, a shortage of drugs and monitoring is common. The present study reports the first experience and preliminary results of 25 patients PCNSL treated with HD-MTX and RTX. MethodsFollowing Institutional Review Board approval by Vietnam National Institute for Cancer Control, a prospective study evaluating the treatment of histologically confirmed PCNSL with combined biweekly HD-MTX (8g/m2/dose) and weekly RTX (375 mg/m2/dose) for 8 cycles. Responders received consolidation treatment with 2 additional cycles, followed by maintenance with monthly HD-MTX for up to 12 months. Patients received aggressive hydration infusion to maintain a urine output of ≥ 100 ml/h and a urinary pH of > 7, until serum MTX levels had decreased to ≤ 0.1 µM/l. Serum MTX levels were monitored daily. Leucovorin rescue was initiated 24 h after completion of MTX infusion and administered at 50 mg IV every 6 h for the first 4 doses and then 30 mg IV until serum MTX levels were ≤0.1 µM/l. Leucovorin dosing was increased in cases of slow MTX clearance. The primary end point was radiographic response, and drug-related toxicity and secondary were survival. ResultsFrom 01/2017 to 12/2018, 25 patients were analysed (13 males and 12 females, median age 58.6). Following a mean of 10,72 cycles, the response rate and CR rate was 88% and 36%. The median PFS was 13 months and the OS has not yet been attained. MTX clearance was achieved by 72h in 198/268 cycles, and by 96h in 92%; 30.9% cycles needed escalation of leucovorin rescue dose. Toxicity: transient transaminitis (72%), mucotitis (59%) and diarhea (61.9%), febrile neutropenia (8%). Pneumonia was observed in 2 patients. 4 patients had renal dysfunction and 2 patient had dialysis. ConclusionsRTX combined HDMTX for PCNSL is possible in lower-middle income countries like Vietnam but should be done in experienced centers capable of close monitoring serum MTX levels to prevent toxicity. The addition of RTX to HD-MTX in the treatment of PCNSL may increase response rates and prolong PFS. The final results currently in progress will more definitively estimate the survival. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Trametinib for aggressive gliomas in adults with neurofibromatosis type 1.

e13562 Background: Neurofibromatosis type 1 (NF1) is caused by mutations of the tumor suppressor gene NF1 resulting in decreased levels of neurofibromin and dysregulation of the RAS pathway, including MEK/ERK upregulation. NF1 is characterized by multiple benign and malignant tumors. Central nervous system tumors have an overall standardized incidence ratio of 37.5 in population studies with high rates of aggressive gliomas in adults with NF1. The response to standard glioma therapies is mixed. MEK1/2 inhibitors have shown activity in NF1 driven plexiform neurofibromas and low grade gliomas, however, data is lacking about the optimal dose or sequencing of MEK1/2 inhibitors for adults with NF1 associated aggressive gliomas. We present recent experiences with the MEK1/2 inhibitor trametinib in adults with NF1 and aggressive gliomas. Methods: A retrospective chart review was conducted on all adult patients with NF1 and astrocytoma treated with trametinib at the Johns Hopkins Brain Cancer Program between 2016-2018. Results: Three patients met selection criteria. Two received trametinib as initial therapy (2 mg daily). All developed an acneiform rash; one had transient transaminitis requiring temporary discontinuation and subsequent dose reductions. Clinical benefit was achieved associated with two partial radiographic responses. Conclusions: Astrocytomas in adults with NF1 often have a more aggressive course than suggested by histology. The cases presented here demonstrate clinical benefit from single agent MEK inhibition as well as possible synergistic effects with conventional therapies for gliomas in this patient population. These observations highlight the need for further research in this area. [Table: see text]

Safety and Efficacy of Blinatumomab in Patients with Central Nervous System (CNS) Disease: A Single Institution Experience

Safety and Efficacy of Blinatumomab in Patients with Central Nervous System (CNS) Disease: A Single Institution Experience

Blinatumomab Administered Concurrently with Oral Tyrosine Kinase Inhibitor Therapy Is a Well-Tolerated Consolidation Strategy and Eradicates Measurable Residual Disease in Adults with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Introduction: Incorporation of ABL-targeted oral tyrosine kinase inhibitors (TKIs) to conventional chemotherapy regimens has improved outcomes for adult patients (pts) with (w/) Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, the addition of chemotherapy to TKIs may increase rates of infectious complications, organ toxicity, hospitalization, and mortality. As a result, we and others have investigated novel chemotherapy-sparing approaches for pts w/ Ph+ ALL. The CD3/CD19-targeted bispecific T-cell engager blinatumomab (BLIN) has demonstrated single-agent activity in pts w/ B-ALL w/ minimal residual disease (MRD) or relapsed/refractory (R/R) ALL, including R/R Ph+ ALL (Martinelli et al., J Clin Oncol, 2017). In an effort to deepen responses, we have used BLIN concomitantly w/ commercially available TKIs as consolidation and re-induction therapy. Reported experience w/ BLIN+TKI is limited. Herein we describe the observed safety and efficacy of BLIN+TKI in pts w/ Ph+ ALL w/ varying disease burden at our institution.Methods: We reviewed electronic medical records of pts ≥ 18 years (yrs) old w/ previously treated Ph+ ALL receiving BLIN w/ concomitant, FDA-approved TKIs at Memorial Sloan Kettering Cancer Center (MSKCC) who began BLIN+TKI between March 2017 and April 2018. The primary objectives were to characterize the safety/toxicity profile and rates of MRD negativity by flow cytometry (FACS) and/or quantitative real-time PCR for BCR-ABL1 transcripts following consolidation (n=9) or re-induction (n=2) w/ BLIN+TKI.Results: Eleven pts (6F, 5M) were identified (Table 1). Median age at start of BLIN+TKI was 61.2 yrs (range, 27.7-76.9). Three pts had undergone prior allogeneic hematopoietic cell transplantation (alloHCT). No pt had baseline hepatic dysfunction, central nervous system (CNS) or extramedullary (EM) disease prior to BLIN+TKI. All pts had documented CD19 expression on blasts prior to treatment. Ponatinib (PON) was the most commonly used TKI (n=7) followed by dasatinib (DAS, n=3), and nilotinib (NIL, n=1); one pt taking BLIN+PON briefly received BLIN+DAS during cycle 1. All pts were admitted for initiation of BLIN+TKI. BLIN was started at 9 mcg/day IVCI w/ escalation to 28 mcg/day IVCI on day 8 (per recommended dosing for pts w/ R/R ALL) in 10 pts and at 28 mcg/day IVCI in one pt (per flat dosing schedule described by Gökbuget et al., Blood, 2018).All 7 pts w/ MRD by FACS (n=5) and/or BCR-ABL1 PCR (n=7) prior to BLIN+TKI exhibited MRD negativity by FACS following 1 cycle of BLIN+TKI; 6 of these 7 pts achieved complete molecular response (CMR) by PCR following 1 cycle (n=5) or 2 cycles (n=1) of BLIN+TKI. All 6 remain in ongoing CMR at 1.8-15.1 months after initial achievement of CMR. Neither of the 2 pts w/ morphologic disease responded to BLIN+TKI and ultimately succumbed to their disease. The 2 pts who began BLIN+TKI in CMR have both maintained continuous CMR. Three pts have proceeded to 1st (n=2) or 2nd (n=1) alloHCT post-BLIN+TKI, without documented, relevant toxicities attributable to prior blinatumomab exposure. Median event-free and overall survival were not reached in this small group of pts, w/ median follow-up of 7.7 months among survivors (range, 3.2-16.0 months).Three pts developed grade 1 cytokine release syndrome (CRS). Notably, 2 of these pts had morphologic ALL at time of BLIN+TKI; none of these events warranted interruption of therapy or corticosteroids. No pts developed neurologic toxicity. Five pts exhibited transient transaminitis during BLIN+TKI; none reached recommended parameters to discontinue BLIN. Of these 5 pts, 4 were on concurrent PON. One pt required dose attenuation of PON; hepatic enzymes otherwise normalized w/o intervention.Conclusions: Our small series suggests that BLIN+TKI may be a safe and effective consolidation strategy for pts w/ MRD+ Ph+ ALL to achieve or sustain CMR, creating a platform for alloHCT or other post-remission therapy. Observed rates of CRS were higher and neurologic toxicity appeared lower (none documented) than in other studies of BLIN in pts w/ MRD (Gökbuget et al., Blood, 2018). Higher risk of transaminitis was noted in pts receiving BLIN+PON and warrants further observation, particularly as 28 mcg/day IVCI flat dosing is increasingly used for pts w/ MRD. Earlier incorporation of BLIN+TKI into treatment paradigms for Ph+ ALL may limit toxicity while deepening response and maintaining CMR. [Display omitted] DisclosuresKing:Genentech: Other: Advisory Board . Tallman:Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; Cellerant: Research Funding; ADC Therapeutics: Research Funding; AbbVie: Research Funding; AROG: Research Funding; BioSight: Other: Advisory board. Park:Pfizer: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Adaptive Biotechnologies: Consultancy; Shire: Consultancy. Geyer:Dava Oncology: Honoraria.

Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab

ContextMetastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterized by MMR deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade with pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC. Case reportA 58-year-old female with known Lynch syndrome presented with severe Cushing's syndrome and was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after 12 weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure. ConclusionTreatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supraphysiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage.