Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Leukemia stem cells (LSCs) drive the initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often persist after conventional chemotherapy resulting in relapse 1-5. In this report, we show that treatment of older AML patients with the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax in combination with azacitidine results in deep and durable remissions and is superior to conventional treatments. We hypothesized that these promising clinical results were due to targeting LSCs. Analysis of LSCs from patients undergoing treatment with venetoclax + azacitidine showed disruption of the TCA cycle manifested by decreased alpha-ketoglutarate and increased succinate levels, suggesting inhibition of electron transport chain complex II. In vitro modeling confirmed inhibition of complex II via reduced glutathionylation of succinate dehydrogenase. These metabolic perturbations suppress oxidative phosphorylation (OXPHOS), which efficiently and selectively targets LSCs. Our findings show for the first time that a therapeutic intervention can eradicate LSCs in AML patients by disrupting the metabolic machinery driving energy #

Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, upfront resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax + azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profi le, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these fi ndings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. SIGNIFICANCE: Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.

Given the limited treatment options for relapsed lymphoma post-allogeneic hematopoietic cell transplantation (post-allo-HCT) and the success of programmed death 1 (PD-1) blockade in classical Hodgkin lymphoma (cHL) patients, anti-PD-1 monoclonal antibodies (mAbs) are increasingly being used off-label after allo-HCT. To characterize the safety and efficacy of PD-1 blockade in this setting, we conducted a multicenter retrospective analysis of 31 lymphoma patients receiving anti-PD-1 mAbs for relapse post-allo-HCT. Twenty-nine (94%) patients had cHL and 27 had ≥1 salvage therapy post-allo-HCT and prior to anti-PD-1 treatment. Median follow-up was 428 days (range, 133-833) after the first dose of anti-PD-1. Overall response rate was 77% (15 complete responses and 8 partial responses) in 30 evaluable patients. At last follow-up, 11 of 31 patients progressed and 21 of 31 (68%) remain alive, with 8 (26%) deaths related to new-onset graft-versus-host disease (GVHD) after anti-PD-1. Seventeen (55%) patients developed treatment-emergent GVHD after initiation of anti-PD-1 (6 acute, 4 overlap, and 7 chronic), with onset after a median of 1, 2, and 2 doses, respectively. GVHD severity was grade III-IV acute or severe chronic in 9 patients. Only 2 of these 17 patients achieved complete response to GVHD treatment, and 14 of 17 required ≥2 systemic therapies. In conclusion, PD-1 blockade in relapsed cHL allo-HCT patients appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment-refractory GVHD. PD-1 blockade post-allo-HCT should be studied further but cannot be recommended for routine use outside of a clinical trial.

BACKGROUND: Sinonasal malignancies are a rare and heterogeneous group of tumors for which there is a paucity of robust data with which to guide management decisions. The authors used the National Cancer Data Base to better understand the presenting characteristics of these tumors and to compare outcomes by treatment modality. METHODS: The National Cancer Data Base was queried for sinonasal malignancies diagnosed between 2004 and 2012. Overall survival was assessed using multivariate analyses and propensity score matching. RESULTS: A total of 11,160 patients were identified for the initial analysis. The majority were male, aged 40 to 69 years, with tumors of the nasal cavity or maxillary sinus. Squamous cell histology was most common. The majority of patients presented with advanced tumor stage but without locoregional lymph node or distant metastases. Treatment modalities were compared for squamous cell carcinomas. In multivariate analysis, compared with surgery alone, patients who received adjuvant radiotherapy (hazard ratio [HR], 0.658 [P<.001]), adjuvant chemoradiotherapy (HR, 0.696 [P=.002]), or neoadjuvant therapy (HR, 0.656 [P = .007]) had improved overall survival. Patients who received radiotherapy alone (HR, 1.294 [P=.001]) or chemotherapy alone (HR, 1.834 [P<.001]) had worse outcomes. These findings were validated in propensity score matching. It is important to note that neoadjuvant chemoradiotherapy was associated with achieving a negative surgical margin (odds ratio, 2.641 [P=.045]). CONCLUSIONS: Surgery is the mainstay of therapy for patients with sinonasal malignancies, but multimodality therapy is associated with improved overall survival.

With the rapid development of modern genotyping technology, it is becoming commonplace to genotype densely spaced genetic markers such as single nucleotide polymorphisms (SNPs) along the genome. This development has inspired a strong interest in using multiple markers located in the target region for the detection of association. We introduce a principal components (PCs) regression method for candidate gene association studies where multiple SNPs from the candidate region tend to be correlated. In this approach, the total variance in the original genotype scores is decomposed into parts that correspond to uncorrelated PCs. The PCs with the largest variances are then used as regressors in a multiple regression. Simulation studies suggest that this approach can have higher power than some popular methods. An application to CHI3L2 gene expression data confirms a significant association between CHI3L2 gene expression level and SNPs from this gene that has been previously reported by others.

Background: Little is known about the relative harms of edible and inhalable cannabis products. Objective: To describe and compare adult emergency department (ED) visits related to edible and inhaled cannabis exposure. Design: Chart review of ED visits between 1 January 2012 and 31 December 2016. Setting: A large urban academic hospital in Colorado. Participants: Adults with ED visits with a cannabis-related International Classification of Diseases, Ninth or 10th Revision, Clinical Modification (ICD-9-CM or ICD-10-CM), code. Measurements: Patient demographic characteristics, route of exposure, dose, symptoms, length of stay, disposition, discharge diagnoses, and attribution of visit to cannabis. Results: There were 9973 visits with an ICD-9-CM or ICD-10-CM code for cannabis use. Of these, 2567 (25.7%) visits were at least partially attributable to cannabis, and 238 of those (9.3%) were related to edible cannabis. Visits attributable to inhaled cannabis were more likely to be for cannabinoid hyperemesis syndrome (18.0% vs. 8.4%), and visits attributable to edible cannabis were more likely to be due to acute psychiatric symptoms (18.0% vs. 10.9%), intoxication (48% vs. 28%), and cardiovascular symptoms (8.0% vs. 3.1%). Edible products accounted for 10.7% of cannabis-attributable visits between 2014 and 2016 but represented only 0.32% of total cannabis sales in Colorado (in kilograms of tetrahydrocannabinol) during that period. Limitation: Retrospective study design, single academic center, self-reported exposure data, and limited availability of dose data. Conclusion: Visits attributable to inhaled cannabis are more frequent than those attributable to edible cannabis, although the latter is associated with more acute psychiatric visits and more ED visits than expected. Primary Funding Source: Colorado Department of Public Health and Environment.

Key Points Responses and survival with venetoclax for “real-world” AML patients were promising but inferior to those treated in a clinical trial. Compared with induction, response rates are as high as would be predicted and venetoclax patients had a lower than expected early death rate.

Venetoclax (ven) + azacitidine (aza) is the standard of care for newly-diagnosed acute myeloid leukemia (AML) patients who are not candidates for intensive chemotherapy (IC). Some patients who are IC candidates instead receive ven/aza. We retrospectively analyzed newly-diagnosed AML patients who received ven/aza (N=143) or IC (N=149), to compare outcomes and seek variables that could predict response to one or the other therapy, and ascertain whether treatment recommendations can be refined. The response rate for ven/aza was 76.9% and 70.5% for IC. The median overall survival (OS) for IC was 884 days compared to 483 for ven/aza (p=0.0020). A propensity-matched cohort was utilized to compare outcomes in the setting of equivalent baseline variables, and when matched for age, biological risk, and transplantation, the median OS was 705 days for IC and not reached for ven/aza (p=0.0667). Variables that favored response to ven/aza over IC included older age, secondary AML and RUNX1 mutations. AML M5 favored response to IC over ven/aza. In the propensity-matched cohort analyzing OS, older age, adverse risk and RUNX1 mutations favored ven/aza over IC, while intermediate risk favored IC over ven/aza. In conclusion, IC patients have improved OS compared to ven/aza. However, in a propensity-matched cohort of patients with equivalent baseline factors, there was a trend toward a favorable OS for ven/aza. Specific variables, such as reported here for the first time RUNX1 mutations, can be identified that favor ven/aza or IC, helping to guide treatment decisions for patients who may be eligible candidates for either therapy.