Citations

AbstractBackgroundLiver biopsy is the gold standard to stage fibrosis in liver disease. Several scoring systems have been studied to predict advanced fibrosis in liver disease. Those scores have not been validated in pediatric liver transplant patients.AimEvaluate the performance of three fibrosis scores (FSc) in assessing the presence of advanced fibrosis (AF) in children after orthotopic liver transplantation (OLT).MethodsPatients < 20 years of age who underwent liver biopsy post‐OLT with laboratory values within 1 month of the biopsy were included. Fibrosis was determined by an experienced pathologist (F0‐4). We defined AF as F3‐4. The following FSc were calculated: AST/ALT ratio, APRI, and FIB‐4 index. Receiver operating characteristic curve analysis was done to assess the FSc performance in predicting AF.ResultsA total of 232 biopsies were analyzed, of those 42 (18.1%) showed AF (F3‐4). FIB‐4 was significantly higher in patients with AF compared to those without AF [median value of 1.1 [0.7, 3.0] and 0.6 [0.2, 1.4], respectively (p = .02)]; however, FIB‐4 had satisfactory accuracy to diagnose AF with significant overlap and AUC of 0.68 (CI 0.56–0.81). Cutoff points of 0.2 and 3.03 were used to rule in and rule out AF, respectively. AST/ALT and APRI were not significantly different between patients with and without AF.ConclusionEven though FIB‐4 had satisfactory accuracy in detecting AF in pediatric transplant patients, noninvasive hepatic FSc developed in adults still performed poorly. Our results highlight the need to develop a reliable pediatric FSc.

Abstract With the application of modern investigative technologies, cholestatic liver diseases of genetic etiology are increasingly identified as the root cause of previously designated “idiopathic” adult and pediatric liver diseases. Here, we review advances in the field enhanced by a deeper understanding of the phenotypes associated with specific gene defects that lead to cholestatic liver diseases. There are evolving areas for clinicians in the current era specifically regarding the role for biopsy and opportunities for a “sequencing first” approach. Risk stratification based on the severity of the genetic defect holds promise to guide the decision to pursue primary liver transplantation versus medical therapy or nontransplant surgery, as well as early screening for HCC. In the present era, the expanding toolbox of recently approved therapies for hepatologists has real potential to help many of our patients with genetic causes of cholestasis. In addition, there are promising agents under study in the pipeline. Relevant to the current era, there are still gaps in knowledge of causation and pathogenesis and lack of fully accepted biomarkers of disease progression and pruritus. We discuss strategies to overcome the challenges of genotype–phenotype correlation and draw attention to the extrahepatic manifestations of these diseases. Finally, with attention to identifying causes and treatments of genetic cholestatic disorders, we anticipate a vibrant future of this dynamic field which builds upon current and future therapies, real‐world evaluations of individual and combined therapeutics, and the potential incorporation of effective gene editing and gene additive technologies.

Abstract Transcriptome sequencing has identified multiple subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL) of prognostic significance, but a minority of cases lack a known genetic driver. Here, we used integrated whole-genome (WGS) and -transcriptome sequencing (RNA-seq), enhancer mapping, and chromatin topology analysis to identify previously unrecognized genomic drivers in B-ALL. Newly diagnosed (n = 3221) and relapsed (n = 177) B-ALL cases with tumor RNA-seq were studied. WGS was performed to detect mutations, structural variants, and copy number alterations. Integrated analysis of histone 3 lysine 27 acetylation and chromatin looping was performed using HiChIP. We identified a subset of 17 newly diagnosed and 5 relapsed B-ALL cases with a distinct gene expression profile and 2 universal and unique genomic alterations resulting from aberrant recombination-activating gene activation: a focal deletion downstream of PAN3 at 13q12.2 resulting in CDX2 deregulation by the PAN3 enhancer and a focal deletion of exons 18-21 of UBTF at 17q21.31 resulting in a chimeric fusion, UBTF::ATXN7L3. A subset of cases also had rearrangement and increased expression of the PAX5 gene, which is otherwise uncommon in B-ALL. Patients were more commonly female and young adult with median age 35 (range,12-70 years). The immunophenotype was characterized by CD10 negativity and immunoglobulin M positivity. Among 16 patients with known clinical response, 9 (56.3%) had high-risk features including relapse (n = 4) or minimal residual disease &gt;1% at the end of remission induction (n = 5). CDX2-deregulated, UBTF::ATXN7L3 rearranged (CDX2/UBTF) B-ALL is a high-risk subtype of leukemia in young adults for which novel therapeutic approaches are required.

PURPOSE Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome–negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population. PATIENTS AND METHODS Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome–negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis. RESULTS Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively. CONCLUSION Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome–negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.

663 Background: GI malignancies continue to be a major cause of cancer related deaths, despite advances in therapy options. In pancreatic cancer, the presence of homologous recombination mutations (HRM) has been shown to confer increased sensitivity to platinum chemotherapy. However, the role of HRM mutations in other GI cancers remains to be determined. The focus of this study is to evaluate the prognostic nature of core and noncore HRM in nonpancreatic GI cancers. Additionally, we aim to understand the predictive nature of these mutations related to platinum exposure. Methods: This was a retrospective review of patients at Moffitt Cancer Center with a primary stage IV nonpancreatic GI cancer treated with platinum therapy. All patients had next generation sequencing and were in the Clinical Genomics Action Committee database between 1/1/2013 and 11/1/2020. All patients had either a core HRM (BRCA1, BRCA2, PALB2) or noncore HRM (such as ATM, ATR, BARD1, BRIP1, FANCA, NBN, and RAD51). Patients were grouped into core HRM vs. noncore HRM. Response was stratified between responders (complete response and partial response) vs. non responders (stable disease and progressive disease), based on RECIST criteria. Progression free survival and overall survival were estimated using Kaplan-Meier method, and the log-rank test was used to assess the difference in progression free survival (PFS) and overall survival (OS) by HRM status and type of platinum therapy used. Results: There were 72 patients included in the study: the majority of patients were male (65.3%) and Caucasian (87.5%). Twenty-one (29.2%) patients had a core HRM and 51 (70.8%) had a noncore HRM. There was no significant difference in response rate between patients with core HRM and patients with noncore HRM for evaluable patients (n = 66): 20.0% of patients with core HRM vs. 21.7% of patients with noncore HRM demonstrated a response to platinum therapy (p = 0.41). An improved OS was noted for patients with core HRM vs. those with noncore HRM at 68.9 vs. 24.3 months (p = 0.019). An improved PFS was also seen in patients with core HRM at 10.4 months vs. 6.3 months with noncore HRM (p = 0.027). There was no difference in PFS based on type of platinum therapy used (oxaliplatin vs. carboplatin vs. cisplatin), while an improved OS was noted for patients treated with oxaliplatin vs. carboplatin vs. cisplatin at 43.1 vs. 28.2 vs. 16.0 months (p = 0.011). Conclusions: Our study demonstrated that in stage IV nonpancreatic GI malignancies treated with platinum therapy, patients with core HRM had a greater OS and PFS compared to those with noncore HRM, suggesting a potential prognostic and predictive role of these mutations. Further studies are needed to confirm our findings.

174 Background: Colorectal cancer (CRC), while one of the most common cancer diagnoses, can behave heterogeneously based on molecular characteristics. A subset of patients (pts) with CRC are characterized with mismatch repair deficiency (MMR-d), these pts exhibit encouraging responses to immunotherapy. The predictive nature of various factors, such as BRAF status, age, and MMR-D protein loss type, have been investigated in pts with MMR-d CRC. However, the prognostic role of these factors has not been well established. The purpose of this study was to identify characteristics that influence survival in MMR-d mCRC. Methods: This study evaluated pts with MMR-d mCRC in the Flatiron database. Overall survival (OS) was determined from date of diagnosis of stage IV disease to date of death and stratified based on age greater than or less than 50 years, BRAF mutation status, RAS mutation status, and type of MMR gene loss. For statistical analysis, the Chi-Square test was implemented to determine the prognostic significance of clinical and molecular features. Univariate and multivariate analyses were determined through the Cox regression model. Results: There were 1,101 pts in the study. The majority of pts were older than 50 (79.7%), Caucasian (75%), and had ECOG 0-1 (83.4%). Among the 803 pts with known BRAF status, 44.3% (n=356) had BRAF V600E mutation and 55.7% (n=447) were BRAF wildtype. Pts with BRAF V600E mutation had OS of 18.9 months vs. 33.2 months for pts with wild type BRAF (HR 1.52, 95% CI: 1.25-1.86, p<0.001). Pts older than 50 had a lower median OS vs. those who were ≤50 at 21.4 months vs. 38.7 months (HR 1.66, 95% CI: 1.33-2.07, p<0.001). When comparing MSH2/MSH6 mutations to MLH1/PMS2, a trend towards improved OS was seen with median survival of 35.2 months vs. 22.7 months, respectively (HR 0.79, 95% CI: 0.61-1.02, p=0.067). On multivariate analysis, BRAF mutation and older age continued to be associated with differences in survival, while KRAS mutation and specific MMR gene loss did not. Conclusions: BRAF V600E mutation and age greater than 50 are associated with decreased survival for pts with MMR-D mCRC. KRAS mutations and specific MMR alterations are not associated with differences in survival.