Hepatic Transaminitis Research Articles

Predictors of mortality in scrub typhus: A hospital-based study.

Scrub typhus is a potentially life-threatening febrile illness associated with serious complications viz. pneumonia, acute respiratory distress syndrome, hepatic failure, acute kidney injury, encephalitis, and shock often culminating in mortality. We aimed to identify the predictors of mortality in scrub typhus. This prospective observational study was conducted in a tertiary referral hospital of the north Indian state of Uttarakhand on in-patients of scrub typhus hospitalized over 1 year. Of the 109 cases studied (54.1% males), 44% were aged <40 years. Fever (95.4%), loss of appetite (55.9%), myalgia (47.7%), pallor (40.3%), hepatomegaly (27.5%), eschar (17.4%), and splenomegaly (13.7%) were the main clinical features. Hepatic transaminitis (69.7%), renal insufficiency (44.0%), respiratory failure (37.6%), shock (33.9%), central nervous system (CNS) involvement (21.1%), and severe anemia (7.3%) were the major complications at presentations. Intensive care and mechanical ventilation were utilized in 33.9% and 15.5% of cases, respectively. Multivariate logistic regression suggested renal insufficiency, CNS involvement, shock, severe anemia, and mechanical ventilation independently associated with death. Respiratory failure, renal insufficiency and neurological involvement, mechanical ventilation, shock, and severe anemia at presentation predict mortality in scrub typhus.

Daily compared with alternate-day levamisole in pediatric nephrotic syndrome: an open-label randomized controlled study.

Levamisole is less expensive and has a better toxicity profile compared to other steroid sparing agents used in nephrotic syndrome. It has a plasma half-life of 2.0 to 5.6hours, but is conventionally administered on alternate days. We aimed to assess whether daily levamisole is safe and more effective than standard alternate-day therapy in maintaining remission in children with frequently relapsing or steroid-dependent nephrotic syndrome (FR/SDNS). An open-label randomized controlled trial was conducted in children with FR/SDNS. Group A received daily while Group B received alternate-day levamisole (2-3mg/kg/dose) for 12months. Prednisolone was tapered off by 3months. Patients were monitored for relapses, further steroid requirement, and adverse effects. A total of 190 children with FR/SDNS (94 in Group A and 96 in Group B) were analyzed. Sustained remission for 12months was observed in 36% of Group A and 27% of Group B patients (p = 0.18). Numbers completing 12months in the study were 67% in Group A and 56% in Group B (p = 0.13). Time to first relapse, persistent FR/SDNS, and withdrawal due to poor compliance were statistically similar in both groups, while relapse rate and cumulative steroid dosage were significantly lower in Group A compared to Group B (p = 0.03 and p = 0.02, respectively). The incidence of adverse effects was comparable in both groups, with reversible leucopenia and hepatic transaminitis being the commonest. Daily levamisole therapy was not superior to alternate-day therapy in maintaining sustained remission over 12months. Nevertheless, relapse rate and cumulative steroid dosage were significantly lower without increased adverse effects.

Clinical features and management of individuals admitted to hospital with monkeypox and associated complications across the UK: a retrospective cohort study

The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. 156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30-44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3 (IQR 349-828). Rectal or perianal pain (including proctitis) was the most common indication for hospital admission (44 [28%] of 156). Severe pain was reported in 89 (57%) of 156, and secondary bacterial infection in 82 (58%) of 142 individuals with available data. Median admission duration was 5 days (IQR 2-9). Ten individuals required surgery and two cases of encephalitis were reported. 38 (24%) of the 156 individuals received tecovirimat with early cessation in four cases (two owing to hepatic transaminitis, one to rapid treatment response, and one to patient choice). No deaths occurred during the study period. Although life-threatening mpox appears rare in hospitalised populations during the current outbreak, severe mpox and associated complications can occur in immunocompetent individuals. Analgesia and management of superimposed bacterial infection are priorities for patients admitted to hospital. None.

CTIM-12. A PHASE 1 TRIAL OF IMMUNORADIOTHERAPY WITH THE IDO ENZYME INHIBITOR (BMS-986205) AND NIVOLUMAB IN PATIENTS WITH NEWLY DIAGNOSED MGMT PROMOTER UNMETHYLATED IDHwt GLIOBLASTOMA

Abstract BACKGROUND IDHwt glioblastoma with unmethylated MGMT gene promoter carries a poor prognosis. Preclinical studies have shown that combination of radiotherapy and dual immunotherapy with nivolumab and IDO inhibition significantly prolongs survival of mice with an orthotopic glioblastoma [Ladomersky, et al. CCR 2018;24(11):2559-2573]. In a clinical trial in patients with newly diagnosed glioblastoma with unmethylated MGMT we substituted temozolomide for dual immunotherapy combination. METHODS Phase 1 trial [NCT04047706] using a 3 + 3 dose-escalation design. All received standard radiotherapy (30 x 2 Gy) with addition of once daily oral BMS-986205 and intravenous nivolumab (240mg every 2 weeks) begining on day 1 of radiotherapy and continuing until disease progression or intolerance. BMS-986205 dosing was increased from 50 mg to 100 mg. DLT period encompasses 6 weeks of radiotherapy and the 4 subsequent weeks. Immunocorrelatives being conducted before and after treatment include mass spectrometry for tryptophan and kynurenine levels, immunohistochemistry of resected tumor, and RNA-sequencing and flow cytometric analysis of PBMCs. RESULTS Twelve patients were treated on 2 dose levels of BMS-986205 (50, 100 mg). Treatment-emergent toxicity was as expected for this population. Three (25%) treatment-related SAEs were reported. Dose limiting toxicity of grade 3 transaminase elevation was observed in 2 patients at the 100 mg dose level, while at lower doses of BMS-986205 no substantial alterations of liver enzymes was observed. No other relevant treatment related toxicity occured. Ongoing immunocorrelative profiling and preliminary outcome data (all patients minimal follow-up &amp;gt;12 months) will be available at the time of the meeting. CONCLUSIONS Dose limiting toxicity of BMS-986205 in combination with nivolumab and radiotherapy is hepatic (reversible) transaminitis. The recommended dose for further investigation is 50 mg. Accrual is ongoing for the MGMT promoter methylated cohort using the same regimen without withholding temozolomide. A randomized phase 2/3 trial is approved within the NRG network.

Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells

AbstractChimeric antigen receptor (CAR) T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional CRS, a comprehensive characterization of CAR T-cell–associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Among 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase, and occasionally hemophagocytosis. Development of carHLH was associated with preinfusion natural killer(NK) cell lymphopenia and higher bone marrow T-cell:NK cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK cell lymphopenia amplified preinfusion differences in those with carHLH without evidence for defects in NK cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.

Increased Risk of Toxicity with Novel PI3K Delta Inhibitor Combinations Compared with Standard Use in Non-Hodgkin Lymphoma Patients

Introduction: PI3Kδ inhibition has demonstrated significant efficacy in the treatment of lymphoid malignancies, leading to the approval of idelalisib as a single agent for follicular lymphoma and SLL and in combination with rituximab in CLL. However, therapy is not curative and agents in this class are associated with treatment limiting toxicities (e.g. pneumonitis, colitis, transaminitis). Clinical trials are investigating novel combinations in efforts to increase response depth while limiting treatment durations to avoid toxicities. Given the unique side effects associated with PI3Kδ inhibition, data is needed to guide use in routine clinical practice and to direct future development of this therapeutic class.Methods: We report on the cumulative experience of therapy with PI3Kδ inhibitors (idelalisib, duvelisib or INCB040093) administered with or without rituximab or obinutuzumab as well as investigational combinations (+JAK1inhibitor, +SYK inhibitor, or + bendamustine rituximab). Demographic and clinical data were collected on all non-Hodgkin lymphoma patients treated with a PI3Kδ inhibitor at a single institution. Data on all treatment related adverse events (AEs) were graded according to the CTCAE V4.03 criteria. Cause specific cox-proportional hazards models were used to model the risk of grade 3 or 4 AEs associated with treatment regimen, treatment history, and age, in the presence of the competing risk of death.Results: Seventy-nine patients were treated with a PI3Kδ inhibitor (median age 68 years, 87% relapsed/refractory , 78% on clinical trial) for a median of 3.5 months (range 0.2 to 30). Thirty-four patients were treated with a single agent PI3Kδ inibitor +/- an anti-CD20 antibody (standard group) and 45 patients were treated with a novel PI3Kδ combination (novel group). There were no significant differences in demographics or previous treatment between these two groups.All patients experienced AEs and 68.4% of patients had at least one grade 3/4 (severe) AE, many of which were immune-mediated and infectious events. Two patients died from treatment related toxicity (cause-specific mortality 7%). The incidence rate of severe AEs was significantly higher in the novel combinations group (5.2 vs. 2.1 per person-year; p<0.05). Fifty-four percent of patients discontinued because of an AE. Figure one illustrates a higher cumulative probability of discontinuing from an AE in the novel group, which had a significantly higher risk of discontinuation from AE compared to the standard group (HR 2.8, 95%CI 1.41, 5.76; p<0.01). There was no increase in colitis/diarrhea or hepatic transaminitis in novel combinations compared to standard use. However, we did see a significantly increased risk of pneumonitis in the novel group (HR 4.07, 95% CI 1.23, 13.42; p<0.02) compared to standard use, largely due to use of the idelalisib + SYK inhibitor doublet. The novel group was also at a higher, though non-significant, risk of severe infectious AEs (HR1.81, 95%CI 0.62, 5.93; p>0.05) mostly due to sinopulmonary infections. Previously untreated patients had over two times the risk of a severe AE compared to previously treated patients (HR 2.62, 95%CI 1.19,5.18; p<0.01). There was no evidence of a difference in risk of severe AEs between younger and older patients (HR 1.07, 95%CI 0.62, 1.86, p>0.05).Conclusions: Several ongoing studies are investigating novel PI3Kδ-based combinations given initial results demonstrated with idelalisib. Our data suggests that the known immune-mediated and infectious toxicities are more common with novel targeted combinations studied to date. Combinations of B-cell signaling inhibitors appear particularly toxic and should be avoided. Phase I investigations should use a traditional conservative dose escalation schema with prolonged monitoring for delayed side effects. Antimicrobial prophylaxis may be needed in future combinatorial investigations. Further, clinical use and future development should focus on relapsed patients given the increased risk of immune-mediated events in untreated patients. [Display omitted] DisclosuresCasulo:Gilead: Honoraria, Other: travel support; Infinity: Consultancy; Celgene: Research Funding. Reagan:Seattle Genetics: Research Funding. Friedberg:Bayer HealthCare Pharmaceuticals.: Other: Data and Safety Monitoring Board: Bayer HealthCare Pharmaceuticals.. Barr:Seattle Genetics: Consultancy; Gilead: Consultancy; Infinity: Consultancy; Celgene: Consultancy; Novartis: Consultancy; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

Beyond Cytokine Storm: Optimizing Treatment Strategies to Target the Complex Interplay between CAR Mediated Inflammatory Response, Disseminated Intravascular Coagulation and Macrophage Activation Syndrome

Background: Cytokine release syndrome (CRS) is a well described, non-specific toxicity of CAR therapy caused by high-level immune activation. Generally, CRS starts within a week of CAR-T cell infusion, is typically self-limited, and mitigation strategies utilizing tocilizumab (anti-IL6 receptor antibody) and/or corticosteroids are rapidly effective. Despite initial improvement, delayed manifestations including disseminated intravascular coagulation (DIC) and macrophage activation syndrome (MAS) may occur in some for whom CAR mediated inflammatory responses continue to evolve. To improve upon the safety profile of CAR therapy, we report on our experience with DIC and MAS.Design: We report on the toxicity profile of the first 30 children and young adults with relapsed/refractory CD22+ ALL treated on our phase I dose escalation anti-CD22 CAR therapy. All had routine monitoring of cytokines, fibrinogen, D-Dimer, PT/INR, PTT and CBC. Following observations of clinically significant DIC, we prospectively evaluated markers of activated coagulation, including: thrombomodulin, E-selectin, s-VCAM, v-ICAM, P-selectin, prothrombin fragment 1 + 2, tissue factor, and PAI-1. Markers for MAS, including ferritin, triglycerides and soluble IL2R were monitored, as well as immunohistochemical staining for hemophagocytosis on the bone marrow aspirate/biopsy.Results: From December 2014 to July 2017, 30 patients with ALL were treated at 3 dose levels. CRS was seen in 24/30 (80%), which was grade 1-2 in all, except for one grade 4. Eight of 24 (33%) with CRS developed DIC, which was grade 2 (no bleeding) in 3 patients and grade 3 (with bleeding) in 5 patients. Bleeding complications were primarily mucosal and included diffuse alveolar hemorrhage, epistaxis, hematuria, subconjunctival hemorrhage and petechiae/purpura that appeared disproportionate to the platelet count and typically occurred after resolution of acute CRS. Correspondingly, morphologic evaluation revealed hypogranular/agranular platelets seen in 16 of 20 patients (confirmed by electron microscopy in one), of whom 7 had DIC, suggesting an acquired platelet function defect; such patients received higher transfusion support. In those with DIC, PT/INR/PTT and D-Dimer rose with onset of CRS. Fibrinogen, initially elevated with the onset of CRS, fell precipitously with resolution of fever. At the time of clinically evident DIC, in 8 of 12 evaluable subjects, P-selectin values rose at least 50%, on average 17.6 days after CAR-T infusion and in 11 of 12 evaluable subjects, endothelial markers rose and peaked 2 weeks after CAR-T infusion (mean 15.2 days). Treatment of DIC was primarily supportive; methylprednisolone, starting at 0.5-1 mg/kg was initiated in patients with active bleeding, and continued q6-8 hours until stabilization. Resolution of DIC typically coincided with decrease in ferritin, suggesting an inflammatory mediated coagulopathy. Accordingly, patients with DIC also had statistically significantly higher ferritin (median 361,585 v 14,349, p<0.0001) IFN-g, IL-1b, IL-6, IL-8, IL-10 and MIP-1a (p<0.01 for all) than in those without DIC, mimicking elevations seen in MAS. Further supporting the link to MAS, 3 of 4 patients with DIC had soluble IL2R levels > 5-fold x the upper limit of normal at 2 weeks post CAR therapy. Additionally, one patient with DIC had active hemophagocytosis at the 1 month evaluation (Figure), which in the constellation of hepatic transaminitis, cytopenias and hyperferritinemia led to a diagnosis of MAS. Treatment with single agent anakinra, an IL-1 receptor antagonist, initiated as a steroid-sparing agent, was well tolerated and led to full resolution of hemophagocytosis; importantly, it did not impede ongoing CAR response, with clearance of all minimal residual disease from the one month to the two-month restaging time point.Conclusion: An intricate relationship exists between the initial inflammatory CRS, and later complications of DIC and MAS potentially induced by CAR T related inflammation. Although steroids and supportive care measures may stabilize DIC, cytokine profiles, which include elevated IL-1b, can assist when choosing targeted, steroid-sparing therapies such as anakinra. Future directions will include exploring the link between inflammation, DIC, and MAS and optimizing targeted anti-inflammatory strategies earlier in the treatment course to prevent serious complications. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Copanlisib for the treatment of adults with relapsed follicular lymphoma

ABSTRACT Introduction Follicular lymphoma (FL) is the second most common histotype of lymphoma and is considered an incurable disease. The need for new treatment options has led to the development of innovative targeted agents, including inhibitors of the phosphatidylinositol-3-kinase (PI3K) pathway. Areas covered Copanlisib, an intravenous pan–class I PI3K inhibitor, has been approved by the US Food and Drug Administration (FDA) for the treatment of relapsed FL in patients who have received at least two prior systemic therapies. In this article, we critically review the mechanism of action, clinical efficacy, safety, dosage, administration, and role of copanlisib in the treatment of relapsed FL. Expert opinion Treatment with copanlisib results in clinically relevant and durable responses in heavily pretreated patients with relapsed or refractory FL. In addition, copanlisib has a manageable safety profile in this population, with low rates of severe hepatic transaminitis, diarrhea, colitis, and noninfectious pneumonitis. Further investigations of copanlisib within combination regimens will potentially allow to move copanlisib to an earlier line of therapy for FL. However, results of the CHRONOS-4 clinical trial evaluating copanlisib with standard chemoimmunotherapy (rituximab with bendamustine or CHOP) are not yet available.

Incidence of oxandrolone induced hepatic transaminitis in patients with burn injury

The benefits of oxandrolone in burn patients has led to its accepted use in the burn care community, however details regarding the most common adverse effect, transaminitis, remains unclear. The purpose of this study was to determine the incidence of transaminitis in patients with burn injury and identify risk factors associated with the development of transaminitis. This single-center, retrospective risk factor analysis compared burn patients on oxandrolone with and without the development of transaminitis, defined as any aspartate aminotransferase or alanine aminotransferase value >100mg/dL. Patient demographics, past medical history, lab values, and burn characteristics were recorded. Overall 28 out of 66 (42%) patients developed transaminitis. The transaminitis group had a significantly higher proportion of other concomitant medications with a transaminitis risk (p=0.045). No significant difference in liver dysfunction or length of stay was observed between the two groups. Oxandrolone induced transaminitis is occurring in patients significantly more frequently than previously reported warranting further research to guide monitoring requirements, use of concomitant medications, and to determine if rechallenging after resolution should be considered.

Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia

Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted in 6 (12%) and grade 3/4 infections in 11 (22%) patients. No patient developed sinusoidal obstruction syndrome (SOS) during InO therapy; however, 11 of 21 (52%) patients who underwent hematopoietic stem cell transplantation (HSCT) following InO developed SOS. Downregulation of surface CD22 was detected as a possible escape mechanism in three patients who developed a subsequent relapse after InO. We conclude that InO is a well-tolerated, effective therapy for children with relapsed ALL and prospective studies are warranted. Identification of risk factors for developing post-HSCT SOS and strategies to mitigate this risk are ongoing.

Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer

Treatment options for patients with disease progression after treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) are limited. Tucatinib is an oral, potent, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor (TKI) being developed as a novel treatment for ERBB2/HER2-positive breast cancer. To determine the maximum tolerated dosage of tucatinib in combination with T-DM1 in the treatment of patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases. In this phase 1b open-label, multicenter, clinical trial, 57 participants enrolled between January 22, 2014, and June 22, 2015, were 18 years of age or older with ERBB2/HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Data were analyzed between January and March 2018. Tucatinib 300 mg or 350 mg administered orally twice per day for 21 days and T-DM1 3.6 mg/kg administered intravenously once every 21 days. Safety assessments, pharmacokinetics, and response were assessed using RECIST 1.1 every 2 cycles for 6 cycles, followed by every 3 cycles. Fifty-seven T-DM1-naive patients (median [IQR] 51 [44.0-63.0] years of age) who had undergone a median of 2 earlier HER2 therapies (range, 1-3) were treated. The tucatinib maximum tolerated dosage was determined to be 300 mg administered twice per day with dose-limiting toxic reactions seen at 350 mg twice per day. Pharmacokinetic analysis showed that there was no drug-drug interaction with T-DM1. Adverse events seen among the 50 patients treated at the maximum tolerated dosage regardless of causality included nausea (36 patients; 72%), diarrhea (30 patients; 60%), fatigue (28 patients; 56%), epistaxis (22 patients; 44%), headache (22 patients; 44%), vomiting (21 patients; 42%), constipation (21 patients; 42%), and decreased appetite (20 patients; 40%); the majority of adverse events were grade 1 or 2. Tucatinib-related toxic reactions that were grade 3 and above included thrombocytopenia (7 patients; 14%) and hepatic transaminitis (6 patients; 12%). In this study, tucatinib in combination with T-DM1 appeared to have acceptable toxicity and to show preliminary antitumor activity among heavily pretreated patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases. ClinicalTrials.gov Identifier: NCT01983501.

Safety of Outpatient Parenteral Antimicrobial Therapy in Children.

Outpatient parenteral antimicrobial therapy (OPAT) provides numerous benefits but may pose unique risks in children. We aimed to determine rates of OPAT antimicrobial- and intravenous access-related complications and their associations with specific antimicrobials and type of intravenous access in pediatric patients. Observational cohort study of patients receiving OPAT from August 2008 to May 2015 cared for by the Infectious Diseases service at a tertiary children's hospital. Primary outcome was antimicrobial discontinuation (AD) because of OPAT-associated complications. Secondary outcomes were unplanned outpatient healthcare visits and readmissions from OPAT-associated complications. Seven hundred and seven intravenous antimicrobials were prescribed in 540 cases. Nondevice-associated musculoskeletal infection was the most common diagnosis (39%). Ceftriaxone (30%), cefazolin (27%) and vancomycin (22%) were the most commonly used antimicrobials. Complications led to AD, ≥1 unplanned outpatient healthcare visit and ≥1 readmission in 23%, 30% and 17% of cases, respectively. Compared with use of ceftriaxone, use of oxacillin was associated with a significantly higher risk of AD because of any antimicrobial-related complication [hazard ratio (HR), 3.3; 95% confidence interval (CI): 1.2-9.7) and because of hepatic transaminitis (HR, 32.8; 95% CI: 4.02-268.2). Subjects treated with intravenous clindamycin (HR, 2.6; 95% CI: 1.1-5.8) and with a peripherally inserted central catheter (HR, 2.6; 95% CI: 1.04-6.3) were more likely to have unplanned outpatient visits. Use of oxacillin during OPAT was associated with higher rate of AD. Patients treated with clindamycin and those with a peripherally inserted central catheter had higher rates of unplanned outpatient visits. Providers should strongly consider alternative treatment options when possible.

Investigating Ethnic Differences in Toxicities of Childhood ALL Therapy

IntroductionAcute lymphoblastic leukemia (ALL) is the most common childhood cancer with an excellent survival rate due to advancements in therapy. However, significant chemotherapy treatment-related toxicities (TRTs) are associated with the intensity of such treatments, which can affect quality of life, preclude the ability to provide optimal therapy, and impact survival. Further, outcomes are worse among certain minority populations, including Hispanic patients. At this single institution with a predominately Hispanic population, we sought to review several TRTs and determine whether Hispanic ethnicity may be a risk factor for increased severe, short-term TRTs and to explore the effects of TRTs on event-free survival (EFS).MethodsThis study is a retrospective chart-review of patients diagnosed with ALL at Children’s Hospital Los Angeles from January 2008 to December 2010. Infants, patients with Down’s syndrome and those who transferred to another institution during therapy were excluded from this study. Demographic and TRT information were collected from the electronic medical record, from the start of treatment until 30 days after the end of primary therapy, relapse, transplant, or death. TRTs were graded per the Common Terminology Criteria for Adverse Events version 4.0; only toxicities severe enough to negatively effect patients’ quality of life, chemotherapy continuation, and survival were included. The specific TRTs were fractures, osteonecrosis, and peripheral neuropathy of ≥ grade 2, fungal and culture-positive bacterial infections, thrombosis, pancreatitis, and hyperbilirubinemia ≥ grade 3, and hepatic transaminitis ≥ grade 4. The X2 test was used to compare the proportions of Hispanic and non-Hispanic patients with and without the selected TRTs. Univariable and multivariable Cox regression models were used to examine the association of patient demographics with EFS and time to TRT. All analyses were performed using a 2-sided test and completed using the statistical software Stata.ResultsOf the 172 patients diagnosed with ALL between 2008 and 2010, 138 patients are included in this study, 124 with B-cell ALL and 14 with T-cell ALL. Among the 138 patients, 57.2% were male, 24.6% were obese, 76.1% were Hispanic, and 58% were classified as high-risk by the NCI Rome criteria. The median age at diagnosis was 7.9 years (range 1.1 to 20). All patients were treated according to ongoing Children’s Oncology Group therapeutic studies. During the course of therapy, 23 patients relapsed, 3 developed secondary malignancy, and 2 patients died from infection. There were 156 TRTs observed in 85 patients, with 61.6% of patients experiencing one or more of the selected TRTs. The most common TRTs were infectious and gastrointestinal/hepatobiliary events. While Hispanic patients had 2.2 times higher frequency of pancreatitis than non-Hispanic patients and 1.8 times more hyperbilirubinemia, there were no statistically significant differences in the incidence of any TRTs by ethnicity. NCI high risk and older age were the only significant predictors of any TRT (p<0.001). Obesity was significantly associated with the development of pancreatitis and hyperbilirubinemia (p=0.01). Ethnicity, NCI risk, and ages were all predictive of EFS in the univariable analysis, with Hispanic ethnicity associated with 3.4-fold increase in risk of relapse and death when compared to non-Hispanics (p = 0.047). In the multivariable setting, NCI risk was the only significant predictor of EFS, although there was a trend in increased risk of relapse and death among Hispanic patients.DiscussionIn this relatively small cohort of patients, we did not identify ethnicity as a risk factor for increased TRTs during therapy for ALL, although certain TRTs such as pancreatitis and hyperbilirubinemia may be more common among Hispanic patients. As expected, Hispanic ethnicity, NCI risk, and age at diagnosis were risk factors for increased relapse and death. These results may suggest that additional factors, such as genetics, disease biology, or medication compliance, may play a more significant role in worse outcomes for Hispanic patients, rather than difference in tolerance of the treatment itself. Analyses of a larger cohort of patients are ongoing to confirm these results and to comprehensively analyze the determinants of pancreatitis and hepatic toxicity, and their interaction with obesity in Hispanic patients with ALL. [Display omitted] DisclosuresBhojwani:Amgen: Other: Blinatumumab global pediatric advisory board 2015.

Clinical Adverse Effects of Endothelin Receptor Antagonists: Insights From the Meta-Analysis of 4894 Patients From 24 Randomized Double-Blind Placebo-Controlled Clinical Trials.

BackgroundEvidence of the clinical safety of endothelin receptor antagonists (ERAs) is limited and derived mainly from individual trials; therefore, we conducted a meta‐analysis.Methods and ResultsAfter systematic searches of the Medline, Embase, and Cochrane Library databases and the ClinicalTrials.gov website, randomized controlled trials with patients receiving ERAs (bosentan, macitentan, or ambrisentan) in at least 1 treatment group were included. All reported adverse events of ERAs were evaluated. Summary relative risks and 95% CIs were calculated using random‐ or fixed‐effects models according to between‐study heterogeneity. In total, 24 randomized trials including 4894 patients met the inclusion criteria. Meta‐analysis showed that the incidence of abnormal liver function (7.91% versus 2.84%; risk ratio [RR] 2.38, 95% CI 1.36–4.18), peripheral edema (14.36% versus 9.68%; RR 1.44, 95% CI 1.20–1.74), and anemia (6.23% versus 2.44%; RR 2.69, 95% CI 1.78–4.07) was significantly higher in the ERA group compared with placebo. In comparisons of individual ERAs with placebo, bosentan (RR 3.78, 95% CI 2.42–5.91) but not macitentan (RR 1.17, 95% CI 0.42–3.31) significantly increased the risk of abnormal liver function, whereas ambrisentan (RR 0.06, 95% CI 0.01–0.45) significantly decreased that risk. Bosentan (RR 1.47, 95% CI 1.06–2.03) and ambrisentan (RR 2.02, 95% CI 1.40–2.91) but not macitentan (RR 1.08, 95% CI 0.81–1.46) significantly increased the risk of peripheral edema. Bosentan (RR 3.09, 95% CI 1.52–6.30) and macitentan (RR 2.63, 95% CI 1.54–4.47) but not ambrisentan (RR 1.30, 95% CI 0.20–8.48) significantly increased the risk of anemia. ERAs were not found to increase other reported adverse events compared with placebo.ConclusionsThe present meta‐analysis showed that the main adverse effects of treatment with ERAs were hepatic transaminitis (bosentan), peripheral edema (bosentan and ambrisentan), and anemia (bosentan and macitentan).

P46 The management of abnormal lfts in an hiv positive pregnant woman

Background Acutely deranged liver function tests (LFTs) in HIV positive pregnant women present challenges in balancing pregnancy-related conditions, antiretroviral (ARVs) toxicities and prevention of mother to child transmission (MTCT). A 34 year old HIV positive lady with a history of poor engagement in care, psychosis, cognitive impairment and recent nevirapine resistance was admitted at 26 weeks gestation under mental health legislation due to cognitive impairment and self-neglect. Method She was commenced on darunavir/ritonavir 600 mg bd, truvada and raltegravir but three weeks later, at 29 weeks gestation, she developed rapidly progressive hepatic transaminitis. Abdominal ultrasound scan was normal and tests for viral hepatitis negative. Pre-eclampsia was excluded, leaving three working diagnoses: drug-induced hepatitis, obstetric cholestasis or acute fatty liver of pregnancy. ARVs were stopped but transaminases continued to rise (ALT 614 and AST 716 U/L). Clotting screen and platelet count remained normal but the patient began to complain of epigastric pain. HIV viral load had risen to 241 copies/ml. In view of deteriorating maternal health and the increasing risk of MTCT (HIV viral load expected to rise), the baby was delivered at 31 weeks’ gestation by semi-elective caesarean after a course of antenatal steroids. The baby received antiviral prophylaxis in the form of abacavir, lamivudine and zidovudine; HIV RNA was undetectable at three months (MTCT extremely unlikely). Nine days after delivery the patient’s LFTs normalised. Conclusion Darunavir-induced hepatitis typically presents with increased AST and ALT. In this case, LFTs only started to improve following delivery of the baby, suggesting a pregnancy related cause.

Hepatic Artery Infusion: Still an Option?

Time and science have been kind to patients with colorectal cancer metastatic to the liver. The combination of a decrease in surgical mortality, increased operative tools, increase in the number of active chemotherapeutic drugs— both general and targeted—accompanied by an acceptance of multimodality therapies have improved patient outcomes. A few tools have maintained a quiet hum in the treatment cacophony. The focus of the paper by Ammori et al. is one of those tools: the continuous hepatic artery infusion (CHAI) pump. Emerging in the 1980s as an effective method of delivering floxuridine to the liver via the hepatic artery, its success was consistent but simultaneously limited to a few centers and physicians (medical oncologists and surgeons) who had adequate and specific skill in using this treatment modality. There were many challenges to the use of continuous infusion hepatic artery delivery of floxuridine. They included the complexities of managing the idiopathic liver transaminitis with appropriate dose reductions, surgically placing the pump and working through the vagaries of the hepatic arterial anatomy, dealing with the mechanical challenges of accessing the chambers for filling, and removing the drug and replacing with heparinized saline, and a continued surveillance for late biliary sclerosis. Clearly, using the technology in the ‘‘adjuvant setting,’’ i.e., following hepatic resection for colorectal metastases, was most problematic. The saving grace in this setting was that the patient did not require an additional surgery for the pump placement; however, concerns of functional liver reserve and recovery created an enhanced anxiety. Despite all the challenges, the committed group of oncologists (medical and surgical) consistently demonstrated in pilot and phase 2 studies, a series of outcomes that exceeded those generated with only the systemic chemotherapy available during the same time period. When the limited choice for chemotherapy morphed from 5-fluoruracil and leucovorin—excellent agents with known toxicity and carefully studied therapeutic regimens— to oxaliplatin, irinotecan, capecitabine, and subsequently the targeted agents led initially by bevacizumab and cetuximab, that’s when things changed. An enthusiasm for the new agents with potential for sequential use and improved response rates emerged. The CHAI with the reasonably toxic floxuridine fell from favor and nearly all medical oncologists began to transition their clinical practice to the new systemic agents. A few strongholds of CHAI remained active but the incorporation of pump based chemotherapy rapidly lost ground. The clinical trials that had been developed during the height of interest in pump therapy suffered poor accrual and failed to definitively answer the question of superiority or even equivalence (noninferiority). During this same timeframe came the battle cry for more aggressive surgical approaches following successful ‘‘neoadjuvant’’ conversion chemotherapy. The selection of neoadjuvant treatments were focused on efficacy measured as response and safety as measured by the morbidity and mortality of the subsequent operations. Those practitioners with experience in CHAI accepted and worked around the hepatocyte damage as measured in the hepatic transaminitis and the measurable and presumed intraand extrahepatic biliary injury that resulted from the chemotherapy-infused blood bathing the biliary structures. Thoughtful attempts to reduce the injury with dexamethasone were admirable but not adequate to consistently reduce hepatic injury. The ‘‘soft’’ hepatic damage of oxaliplatin (sinusoidal injury), fluoropyrimidine and irinotecan (steatosis), and bevacizumab pales compared with a liver arterially infused 2 weeks on and 2 weeks off with floxuridine. It is almost ironic to consider the current restrictions on timing of hepatic surgery after systemic chemotherapy compared with the post-CHAI liver. So where does this leave us when faced with colorectal cancer metastatic to the liver? Metastatic disease that is resectable at presentation may or may not be treated with Society of Surgical Oncology 2013

A decade review of chickenpox among pediatric immunocompromised patients at the King Chulalongkorn Memorial Hospital, Thailand.

Background: Varicella zoster virus (VZV) infection among immunocompromised patients leads to high morbidity and mortality. Objective: Describe the natural history and treatment outcomes of chickenpox among immunocompromised children hospitalized in a tertiary care center in the era of acyclovir treatment. Methods: We conducted a retrospective chart review of immunocompromised children hospitalized with chickenpox at King Chulalongkorn Memorial Hospital between January 1, 2000 and December 31, 2009. Demographic data, clinical manifestations, treatment, and complications were extracted from the patients’ charts. Rate of complications were compared among underlying disease by using chi-square test. Results: There were 61 admissions. Median interquartile range, (IQR) age was 79 (31 to 123) months. There were 31 (51%) children with hematologic malignancies, 20 (33%) on immununosuppressive drugs, six (10%) neonates, and four (6%) HIV positive. Index cases were from household members (23%), community (15%), and hospital (6%) whereas 56% had no information. Cases peaked during February to March. Median (IQR) duration of fever and active skin lesions were four (3 to 6) and five (4 to 7) days, respectively. All, except one, received acyclovir (50% intravenous, 48% switched from intravenous to oral, 2% oral). Median (IQR) duration of acyclovir treatment and hospitalization were 10 (7 to 14) and nine (7 to 10) days, respectively. Complications included bacterial skin infections (10%), hepatic transaminitis (8%), pneumonia (5%), and disseminated varicella (1%). Rates of complications were 18% among children with malignancies, 3% on immunosuppressive drugs, and none in neonates or HIV positives (p = 0.047). Two children (3%) died due to disseminated varicella and severe pneumonia. Conclusion: Mortality rate of chickenpox among immunocompromised patients on acyclovir treatment is 3%. Children with hematologic malignancies have the highest rate of complications. Keywords: Chicken pox, complications, immunocompromised host, mortality, varicella zoster virus

Phase I/II study of MK-0646, the humanized monoclonal IGF-1R antibody in combination with gemcitabine or gemcitabine plus erlotinib (E) for advanced pancreatic cancer.

4039 Background: MK-0646 binds to IGF-1R and blocks its interaction with IGF-I/ II ligands, enhances gemcitabine (G)-induced apoptosis and inhibits the MEK/Erk and the PI3-kinase/Akt signaling which are important in cellular proliferation, survival and drug resistance in pancreatic cancer. Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/Akt pathways mediate resistance to anti- EGFR agents such as E. Methods: Patients with stage IV, previously untreated pancreatic cancer, ECOG performance status (PS) 0-1, adequate hematologic and organ function were enrolled. MK-0646 was escalated in two dose levels using 3+3 statistical design. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Blood was collected at study entry for IGF-1 and IGFBP-3 levels. Arm A: G 1,000 mg/m2 over 100 min, weekly × 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly × 4; Arm B: G 1,000 mg/m2 over 100 min, weekly × 3, MK-0646: 5 or 10 mg/kg over 60 min, weekly × 4 + E 100 mg daily. Phase II study uses adaptive randomized design with Arm A, Arm B and Arm C (G + E). Cycles repeated q 4 weeks. Study endpoints: maximal tolerated dose, progression-free survival, response rate, toxicity and overall survival. Results: 28 pts enrolled, 22 males, 2 prior Whipple, 27 PS 1, 1 PS 0. Median of 2 cycles administered (range 1, 12+). Hematologic toxicity: grade 3 or 4 neutropenia (n = 14) or thrombocytopenia (n = 5). Other grade 3 toxicities: hyperglycemia (n = 5), fatigue (n = 5), ALT (n = 4). Dose-limiting toxicity reached in Arm B at dose level 2 (MK-0646 at 10 mg/kg + E + G): febrile neutropenia (n = 1), hepatic transaminitis (n = 1). Radiologic responses: 6 PR (including 1 hepatic CR), 10 PD, 8 SD, 3 too early,1 not treated. 5 sustained PRs (range = 20+, 44+ weeks). Median TTP 8 weeks (range 4, 44+weeks). Ranges for: IGF-1 levels, 28-280 ng/mL; IGFBP-3 levels, 900-4,000 ng/mL. The range of IGF-1:IGFBP-3 ratios for patients with PR and SD was 0.027-0.036 versus .034-.058 for patients with PD. Conclusions: MK-0646 is tolerable in a dose of 10 mg/kg with G 1,000 mg/m2 and at 5 mg/kg with G 1,000 mg/m2 and E 100 mg. Sustained PRs occurred. A randomized phase II study is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck

Abstract 2760: Phase I study of MK-0646, the humanized monoclonal antibody against IGF-1R in combination with gemcitabine or gemcitabine + erlotinib (E) for advanced, previously untreated pancreatic cancer

Abstract BACKGROUND: MK-0646 binds to IGF-1R and blocks its interaction with the IGF-I/ II ligands, enhances gemcitabine (G)-induced apoptosis and inhibits the MEK/ Erk and the PI3-kinase/ Akt signaling pathways which are important in cellular proliferation, survival and drug resistance in pancreatic cancer. Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/ Akt pathways mediate resistance to anti-EGFR agents such as E. The combination of IGF-1R and EGFR antagonists has demonstrated synergy in preclinical pancreatic cancer models. METHODS: Patients with stage IV, previously untreated pancreatic cancer, ECOG performance status (PS) 0-1, adequate hematologic and organ function were enrolled. MK-0646 was escalated in two dose levels using 3+3 statistical design. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Blood was collected at study entry for IGF-1 and IGFBP-3 levels. Arm A: G 1000 mg/m2 over 100 min, weekly x 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly x 4; Arm B: G 1000 mg/m2 over 100 min, weekly x 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly x 4 + E 100 mg daily. Cycles were repeated q 4 weeks. Radiologic responses were measured with RECIST (study radiologist PB). Study endpoints: maximal tolerated dose, progression-free survival, response rate, toxicity and overall survival. RESULTS: 22 pts enrolled, 15 males, 2 prior Whipple, 20 PS 1, 2 PS 0. Median of 2 cycles (range 1-8) administered as of 9/09. Hematologic toxicity was common: grade 3 or 4 neutropenia (n=9) or thrombocytopenia (n=6). Other grade 3 toxicities: hyperglycemia (n=2), fatigue (n=2), ALT (n=3). Dose limiting toxicity reached in Arm B at dose level 2 (MK-0646 at 10 mg/kg + E + G): febrile neutropenia (n=1), hepatic transaminitis (n=1). Radiologic responses: 5 PR (including 1 hepatic CR), 7 PD, 8 SD, 1 not evaluated, 1 not treated. TTP range (based on 12 pts) was 4 to &amp;gt;36 weeks. Ranges for: IGF-1 levels, 28-280 ng/mL; IGFBP-3 levels, 900-4000 ng/mL. The range of IGF-1 to IGFBP-3 ratios for patients with PR and SD was .027-.036 versus a range of .034-.058 for patients with PD. CONCLUSION: MK-0646 is tolerable in a dose of 10 mg/kg with G 1000 mg/m2 and at 5 mg/kg with G 1000 mg/m2 and E 100 mg. Promising anti-tumor activity was noted. A randomized phase II study will be conducted with the control arm of G+E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2760.

Abstract B121: Phase I study of MK-0646, a humanized monoclonal antibody against IGF-1R in combination with gemcitabine or gemcitabine + erlotinib (E) for advanced previously untreated pancreatic cancer

Abstract Background: MK-0646 binds to IGF-1R and blocks its interaction with the IGF-I/ II ligands, enhances gemcitabine (G)-induced apoptosis and inhibits the MEK/ Erk and the PI3-kinase/Akt signaling. Collectively, these pathways are important in cellular proliferation, survival and drug resistance in pancreatic cancer. Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/ Akt pathways mediate resistance to anti-EGFR agents such as E. IGF-1R + EGFR antagonists result in synergistic anti-tumor activity in preclinical pancreatic cancer models. Methods: Patients with stage IV, previously untreated pancreatic cancer, ECOG performance status (PS) 0–1, adequate hematologic and organ function were enrolled. MK-0646 was escalated in two dose levels using 3+3 statistical design. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Arm A: G 1000 mg/m2 over 100 min, weekly × 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly × 4; Arm B: same schedule of G and MK-0646 as Arm A + E 100 mg daily. Cycles were repeated every 4 weeks. Radiologic responses measured with RECIST (study radiologist PB). Study endpoints: maximal tolerated dose, progression-free survival (PFS), response rate, toxicity and overall survival. Results: 22 pts enrolled, 15 males, 2 priorWhipple, 20 PS 1, 2 PS 0. Median of 2 cycles (range 1–8) administered as of 9/09. Hematologic toxicity was common: grade 3 or 4 neutropenia (n=9) or thrombocytopenia (n=6). Other grade 3 toxicities: hyperglycemia (n=2), fatigue (n=2), ALT (n=3). Two dose limiting toxicities observed in Arm B at dose level 2 (MK-0646 at 10 mg/kg + E + G): febrile neutropenia (n=1), hepatic transaminitis (n=1). Best radiologic responses: 6 PR (including 1 hepatic CR), 7 PD, 3 SD, 4 too early, 1 not evaluated, 1 not treated. PFS range in weeks for evaluable patients (n=12) was (4, 36+). Conclusion: MK-0646 is tolerable in a dose of 10 mg/kg with G 1000 mg/m2 and at 5 mg/kg with G 1000 mg/m2 and E 100 mg. Promising anti-tumor activity was noted. A randomized phase II study will be conducted with the control arm of G+E. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B121.