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Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic value for broadscale molecular MRD after ven/aza treatment is less clear. We aimed to determine the utility of retrospective assessment using multi-gene molecular MRD by droplet digital polymerase chain reaction (ddPCR). We found this approach correlates with outcomes in a cohort of patients receiving frontline ven/aza for AML. The predictive value of ddPCR MRD persisted when NPM1 mutations were removed from analysis, as well as after adjustment for the impact of stem cell transplant on outcomes. Late achievement of MRD negativity, including after SCT, was still associated with superior outcomes compared to persistently detectable MRD. We further explored the impact of ven/aza on the burden of different classes of mutations, and identified the persistence of splicing factor mutations, commonly associated with MDS, as a consistent finding after ven/aza treatment. These data add to our understanding of the effects of ven/aza on AML disease biology and provide details on molecular depth of remission that can guide prospective trials in the future.

Acute myeloid leukemia (AML) is a rare subtype of acute leukemia in the pediatric and adolescent population but causes disproportionate morbidity and mortality in this age group. Standard chemotherapeutic regimens for AML have changed very little in the past 3-4 decades, but the addition of targeted agents in recent years has led to improved survival in select subsets of patients as well as a better biological understanding of the disease. Currently, one key paradigm of bench-to-bedside practice in the context of adult AML is the focus on leukemia stem cell (LSC)-targeted therapies. Here, we review current and emerging immunotherapies and other targeted agents that are in clinical use for pediatric AML through the lens of what is known (and not known) about their LSC-targeting capability. Based on a growing understanding of pediatric LSC biology, we also briefly discuss potential future agents on the horizon.

Background Aims: Vector copy number (VCN), an average quantification of transgene copies unique to a chimeric antigen receptor (CAR) T-cell product, is a characteristic that must be reported prior to patient administration, as high VCN increases the risk of insertional mutagenesis. Historically, VCN assessment in CAR T-cell products has been performed via quantitative polymerase chain reaction (qPCR). qPCR is reliable along a broad range of concentrations, but quantification requires use of a standard curve and precision is limited. Digital PCR (dPCR) methods were developed for absolute quantification of target sequences by counting nucleic acid molecules encapsulated in discrete, volumetrically defined partitions. Advantages of dPCR compared with qPCR include simplicity, reproducibility, sensitivity and lack of dependency on a standard curve for definitive quantification. In the present study, the authors describe a dPCR assay developed for analysis of the novel bicistronic CD19 × CD22 CAR T-cell construct., Methods: The authors compared the performance of the dPCR assay with qPCR on both the QX200 droplet dPCR (ddPCR) system (Bio-Rad Laboratories, Inc, Hercules, CA, USA) and the QIAcuity nanoplate-based dPCR (ndPCR) system (QIAGEN Sciences, Inc, Germantown, MD, USA). The primer-probe assay was validated with qPCR, ndPCR and ddPCR using patient samples from pre-clinical CAR T-cell manufacturing production runs as well as Jurkat cell subclones, which stably express this bicistronic CAR construct., Results: ddPCR confirmed the specificity of this assay to detect only the bicistronic CAR product. Additionally, the authors' assay gave accurate, precise and reproducible CAR T-cell VCN measurements across qPCR, ndPCR and ddPCR modalities., Conclusions: The authors demonstrate that dPCR strategies can be utilized for absolute quantification of CAR transgenes and VCN measurements, with improved test-retest reliability, and that specific assays can be developed for detection of unique constructs., Competing Interests: Declaration of competing interest TJF is an employee of Sana Biotechnology, Inc., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

1_r4a4zuxuKaltura., Competing Interests: Nothing to report., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Allogeneic hematopoietic stem cell transplantation (SCT) after a patient with acute myeloid leukemia (AML) achieves a remission from intensive chemotherapy (IC) is given with curative intent. Recently, venetoclax-based regimens have become the standard of care for patients with newly diagnosed AML who are unfit for IC. If these patients achieve remission, they may also be considered for potentially curative consolidation with SCT. There are limited data comparing outcomes after SCT with these different induction strategies. The purpose of the current study was to evaluate depth of remission before SCT and outcomes after SCT in adults with nonrelapsed/refractory AML receiving pre-SCT therapy with either venetoclax/azacitidine (ven/aza) or IC. This was a retrospective, single-institution analysis of 169 patients receiving SCT in first remission after IC or ven/aza. Patient demographics and AML risk features were collected, as well as pre-SCT measurable residual disease (MRD) assessed by flow cytometry and molecular methods. Relapse, transplantation-related mortality, incidence of acute and chronic graft-versus-host-disease (GVHD), and death from any cause were also recorded. Descriptive and survival statistics were applied to these data to compare IC and ven/aza groups. Cox proportional hazard models were used for univariate and multivariate analyses. We demonstrate that despite differences in baseline factors between these groups, outcomes were similar. Relapse-free and overall survival, as well as cumulative incidences of transplantation-related mortality, relapse, and acute and chronic GVHD were comparable between groups. Exploring survival in younger (<65 years) versus older (≥65 years) patients by treatment group did not alter these results. Finally, although pre-SCT MRD by flow cytometry was significantly predictive of post-SCT relapse and survival in the IC + SCT patients, it was not significantly predictive of relapse and survival in the ven/aza + SCT patients. Although these findings require prospective validation in a larger cohort of patients, they suggest that ven/aza followed by SCT is a reasonable management strategy for transplantation candidates at any age., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: : The burden of alcohol-associated liver disease (ALD) in the United States (US) has continued to worsen in the background of rising rates of alcohol use disorder. Patients with ALD present to care at a late stage, often with the sequela of liver decompensation, such as gastrointestinal bleeding and infection. ALD is now the leading indication for liver transplantation. We aimed to measure the quality of care delivered to hospitalized patients with alcoholic hepatitis (AH) across 3 domains: 1) alcohol-use disorder (AUD) care, 2) inpatient cirrhosis care, and 3) alcohol-associated liver disease (ALD) care-and observe associations between quality of care and outcomes., Methods: : We included hospital encounters between January 1, 2016 and January 1, 2019 to a large, diverse integrated health system for AH with active alcohol use within the prior 60 days. The diagnosis of AH was determined based on previously published clinical and laboratory criteria. Quality indicator (QI) pass rates were calculated as the proportion of patients eligible for each indicator who received the QI within the timeframe specified. We then evaluated the association between the receipt of all QIs and 6-month mortality, as well as AUD-specific QIs and 30-day readmission., Results: : Of the 179 patients, the median age was 47 years-old, 59.2% were male and 49.2% were non-Hispanic White. The median Model for End-Stage Liver Disease-Sodium score was 25, while the median discriminant function was 33. Patients were followed for an average of 21 months. Overall, 14% of patients died during the index hospitalization while 17.3% died following discharge and 24.8% were re-admitted within 30-days. QI pass-rates were variable across the different domains. Few patients received AUD care-pass rates for receipt of pharmacotherapy and behavioral therapy at 6 months were only 19.1% and 35.1%, respectively. There was a significant association between receiving behavioral therapy and 6-month mortality-3% vs 18%, p  = 0.05., Conclusion: : The quality of care received during hospital encounters for AH is variable, and AUD-specific therapy is low. Future quality of care initiatives are warranted to link patients to AUD treatment to ensure optimal care and maximize patients survival in this at-risk population., Competing Interests: The authors report no conflicts of interest., (© 2021 The Authors.)

We sought to identify specific gaps in preventive care provided to outpatients with cirrhosis and to determine factors associated with high quality of care (QOC), to guide quality improvement efforts. Outpatients with cirrhosis who received care at a large, academic tertiary health care system in the United States were included. Twelve quality indicators (QIs), including preventive care processes for ascites, esophageal varices, hepatic encephalopathy, hepatocellular carcinoma (HCC), and general cirrhosis care, were measured. QI pass rates were calculated as the proportion of patients eligible for a QI who received that QI during the study period. We performed logistic regression to determine predictors of high QOC (≥ 75% of eligible QIs) and receipt of HCC surveillance. Of the 439 patients, the median age was 63 years, 59% were male, and 19% were Hispanic. The median Model for End-Stage Liver Disease-Sodium score was 11, 64% were compensated, and 32% had hepatitis C virus. QI pass rates varied by individual QIs, but were overall low. For example, 24% received appropriate HCC surveillance, 32% received an index endoscopy for varices screening, and 21% received secondary prophylaxis for spontaneous bacterial peritonitis. In multivariable analyses, Asian race (odds ratio [OR]: 3.7, 95% confidence interval [CI]: 1.3-10.2) was associated with higher QOC, and both Asian race (OR: 3.3, 95% CI: 1.2-9.0) and decompensated status (OR: 2.1, 95% CI: 1.1-4.2) were associated with receipt of HCC surveillance. A greater number of specialty care visits was not associated with higher QOC. Conclusion: Receipt of outpatient preventive cirrhosis QIs was variable and overall low in a diverse cohort of patients with cirrhosis. Variation in care by race/ethnicity and illness trajectory should prompt further inquiry into identifying modifiable factors to standardize care delivery and to improve QOC., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Society guidelines recommend surveillance with abdominal ultrasound with or without serum alpha-fetoprotein every 6 months for adults at increased risk of developing HCC. However, adherence is often suboptimal. We assessed the feasibility of a coordinated telephone outreach program for unscreened patients with cirrhosis within the Veteran's Affairs (VA) health care system. Using a patient care dashboard of advanced chronic liver disease in the VA Greater Los Angeles Healthcare System, we identified veterans with a diagnosis of cirrhosis, a platelet count ≤ 150,000/uL, and no documented HCC surveillance in the previous 8 months. Eligible veterans received a telephone call from a patient navigator to describe the risks and benefits of HCC surveillance. Orders for an abdominal ultrasound and alpha-fetoprotein were placed for veterans who agreed to surveillance. Veterans who were not reached by telephone received an informational letter by mail to encourage participation. Of the 129 veterans who met the eligibility criteria, most were male (96.9%). The most common etiology for cirrhosis was hepatitis C (64.3%), and most of the patients had compensated cirrhosis (68.2%). The patient navigators reached 32.5% of patients by phone. Patients in each group were similar across clinical and demographic characteristics. Patients who were called were more likely to undergo surveillance (adjusted odds ratio = 2.56, 95% confidence interval: 1.03-6.33). Most of the patients (72.1%) completed abdominal imaging when reached by phone. Conclusion: Targeted outreach increased uptake of HCC surveillance among patients with cirrhosis in a large, integrated, VA health care system., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

Venetoclax is approved for older untreated acute myeloid leukemia (AML) patients. Venetoclax was available prior to approval off-label. We assessed our single-institution off-label experience with venetoclax/azacitidine, comparing outcomes with a clinical trial cohort that administered this regimen at the same institution. Thirty-three untreated AML patients unfit or unwilling to receive induction chemotherapy and prescribed venetoclax/azacitidine off-trial were retrospectively analyzed and compared with 33 patients who received the same therapy on trial. Outcomes were compared, and comparisons were made to a theoretical scenario in which off-trial patients received induction. Digital droplet polymerase chain reaction evaluated measurable residual disease (MRD). Off-trial venetoclax was attainable in nearly all patients for whom this was desired. The complete remission (CR)/CR with incomplete blood count recovery rate was 63.3% for off-trial patients who received treatment and 84.9% for trial patients (P = .081). The median overall survival for off-trial patients who received treatment was 381 days (95% confidence interval [CI], 174, not reached) vs 880 days (95% CI, 384, not reached) for trial patients (P = .041). Prior exposure to hypomethylating agents was associated with worse outcomes. Response rates with venetoclax/azacitidine were not inferior to a theoretical scenario in which patients received induction, and early death rates were less than expected with induction. MRD negativity was achievable. Newly diagnosed AML patients treated in a "real-world" scenario with off-trial venetoclax/azacitidine had inferior outcomes compared with patients treated in the setting of a clinical trial. Additionally, this therapy may be as effective, and less toxic, when compared with induction chemotherapy., (© 2019 by The American Society of Hematology.)

From an organismal perspective, cancer cell populations can be considered analogous to parasites that compete with the host for essential systemic resources such as glucose. Here, we employed leukemia models and human leukemia samples to document a form of adaptive homeostasis, where malignant cells alter systemic physiology through impairment of both host insulin sensitivity and insulin secretion to provide tumors with increased glucose. Mechanistically, tumor cells induce high-level production of IGFBP1 from adipose tissue to mediate insulin sensitivity. Further, leukemia-induced gut dysbiosis, serotonin loss, and incretin inactivation combine to suppress insulin secretion. Importantly, attenuated disease progression and prolonged survival are achieved through disruption of the leukemia-induced adaptive homeostasis. Our studies provide a paradigm for systemic management of leukemic disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background & Aims: As more treatment options for inflammatory bowel diseases become available, it is important to identify patients most likely to respond to different therapies. We created and validated a scoring system to identify patients with Crohn's disease (CD) who respond to vedolizumab., Methods: We collected data from the GEMINI 2 phase 3 trial of patients with active CD treated with vedolizumab for 26 weeks (n = 814) and performed logistic regression analysis to identify factors associated with clinical, steroid-free, and durable remission (derivation set). We used these data to develop a clinical decision support tool, which we validated using data from 366 participants in a separate clinical practice observational cohort of patients with active CD treated with vedolizumab for 26 weeks (the VICTORY cohort). We evaluated the ability of this tool to identify patients in clinical remission or corticosteroid-free remission, or those with mucosal healing (MH), clinical remission with MH, or corticosteroid-free remission with MH after vedolizumab therapy using receiver operating characteristic area under the curve (AUC) analyses. The primary outcome was to develop and validate a list of factors associated with achieving remission by vedolizumab in patients with active CD., Results: In the derivation analysis, we identified absence of previous treatment with a tumor necrosis factor antagonist (+3 points), absence of prior bowel surgery (+2 points), absence of prior fistulizing disease (+2 points), baseline level of albumin (+0.4 points per g/L), and baseline concentration of C-reactive protein (reduction of 0.5 points for values between 3.0 and 10.0 mg/L and 3.0 points for values >10.0 mg/L) as factors associated with remission. In the validation set, our model identified patients in clinical remission with an AUC of 0.67, patients in corticosteroid-free remission with an AUC of 0.66, patients with MH with an AUC of 0.72, patients in clinical remission with MH with an AUC of 0.73, and patients in corticosteroid-free clinical remission with MH with an AUC of 0.75. A cutoff value of 13 points identified patients in clinical remission after vedolizumab therapy with 92% sensitivity, patients in corticosteroid-free remission with 94% sensitivity, patients with MH with 98% sensitivity, patients with clinical remission and MH with 100% sensitivity, and patients with corticosteroid-free clinical remission with MH with 100% sensitivity., Conclusions: We developed and validated a scoring system to identify patients with CD most likely to respond to 26 weeks of vedolizumab therapy. Further studies are needed to optimize its accuracy in select populations and determine its cost-effectiveness., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The mixed-lineage leukemia 1 (MLL1) gene (now renamed Lysine [K]-specific MethylTransferase 2A or KMT2A ) on chromosome 11q23 is disrupted in a unique group of acute leukemias. More than 80 different partner genes in these fusions have been described, although the majority of leukemias result from MLL1 fusions with one of about six common partner genes. Approximately 10% of all leukemias harbor MLL1 translocations. Of these, two patient populations comprise the majority of cases: patients younger than 1 year of age at diagnosis (primarily acute lymphoblastic leukemias) and young- to-middle-aged adults (primarily acute myeloid leukemias). A much rarer subgroup of patients with MLL1 rearrangements develop leukemia that is attributable to prior treatment with certain chemotherapeutic agents-so-called therapy-related leukemias. In general, outcomes for all of these patients remain poor when compared to patients with non- MLL1 rearranged leukemias. In this review, we will discuss the normal biological roles of MLL1 and its fusion partners, how these roles are hypothesized to be dysregulated in the context of MLL1 rearrangements, and the clinical manifestations of this group of leukemias. We will go on to discuss the progress in clinical management and promising new avenues of research, which may lead to more effective targeted therapies for affected patients.