Citations

Abstract MYC oncoproteins regulate transcription of genes directing cell proliferation, metabolism, and tumorigenesis. A variety of alterations drive MYC expression in acute myeloid leukemia (AML), and enforced MYC expression in hematopoietic progenitors is sufficient to induce AML. Here we report that AML and myeloid progenitor cell growth and survival rely on MYC-directed suppression of Transcription Factor EB (TFEB), a master regulator of the autophagy–lysosome pathway. Notably, although originally identified as an oncogene, TFEB functions as a tumor suppressor in AML, where it provokes AML cell differentiation and death. These responses reflect TFEB control of myeloid epigenetic programs by inducing expression of isocitrate dehydrogenase-1 (IDH1) and IDH2, resulting in global hydroxylation of 5-methycytosine. Finally, activating the TFEB–IDH1/IDH2–TET2 axis is revealed as a targetable vulnerability in AML. Thus, epigenetic control by an MYC–TFEB circuit dictates myeloid cell fate and is essential for maintenance of AML. Significance: Alterations in epigenetic control are a hallmark of AML. This study establishes that a MYC–TFEB circuit controls AML differentiation and epigenetic programs by inducing IDH1/IDH2 and hydroxylation of 5-methylcytosine, that TFEB functions as a tumor suppressor in AML, and that this circuit is a targetable vulnerability in AML. See related commentary by Wu and Eisenman, p. 116.

AbstractThis case report underlines the importance of molecular characterization of genomic duplications and other structural variants in the prenatal setting to guide clinical interpretation, genetic counseling, and perinatal medical care.

Abstract Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Abstract ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in H3 K27M-mutant glioma. Given that the thalamus has the highest extra-striatal expression of DRD2, we performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 on active clinical trials as of 5/22/19 enrollment (n=19 recurrent and 10 post-radiation, non-recurrent; 5–70 years old). As of 12/18/2019, PFS6 and OS12 are 26.3% and 36.8%, respectively, in the recurrent group. For non-recurrent patients, with median follow up of 21.9 months (8.6–26.6) from diagnosis, median PFS or OS have not been reached. This surpasses historical OS of 13.5 months. Best response by RANO includes 1 CR, 3 PR, 4 SD, 8 PD for recurrent patients and 2 PR, 4 SD, 1 PD for non-recurrent patients (4 on-trial patients experienced regressions that are yet unconfirmed responses). Median duration of response for recurrent patients is 14.0 months (2.0–33.1). Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. In summary, single agent ONC201 administered at recurrence, or adjuvantly following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients who currently have no effective treatments following radiation. Investigations are ongoing to assess whether micro-environmental DRD2 expression explains the early exceptional responses in thalamic H3 K27M-mutant glioma.

Abstract INTRODUCTION Because treatment and clinical management decisions for children with NF1-OPG remain challenging, we sought to establish evidence-based guidelines. We prospectively enrolled children with newly-diagnosed NF1-OPGs, and gathered standardized clinical neuro-oncology and ophthalmology assessments. METHODS Only children with NF1 and newly diagnosed OPGs, confirmed by central review, were eligible. Indications for obtaining the initial MRI, as well as factors associated with the decision to treat with chemotherapy or observe without treatment, were obtained. Quantitative visual acuity (VA), other ophthalmic features, and imaging were captured at standard time points. Goal enrollment is 250 subjects. RESULTS One-hundred thirty-three children (52% female) from 20 institutions met inclusion criteria, and were included in this preliminary analysis. Eighty-six percent of subjects were able to perform quantitative VA testing at enrollment. The most common reasons for the diagnostic MRI included screening related to NF1 diagnosis (36.8%), ophthalmologic concerns (29.3%), and non-ophthalmologic concerns (24.8%), such as headache. To date, twenty subjects have initiated treatment with chemotherapy, twelve (9%) at the time of the initial OPG diagnosis. Median age at OPG diagnosis was 3.1 years. Age and sex distribution were similar in subjects immediately entering the observation and treatment arms (median age 3.0 versus 3.5 years, respectively). CONCLUSION Most children with NF1-OPGs are observed at time of their initial OPG diagnosis, rather than treated. Importantly, a large proportion of children are able to complete quantitative VA testing at enrollment. Once enrollment is complete, these data will help to establish evidence-based guidelines for clinical management of NF1-OPGs.

Background: Previous cross-sectional studies analyzing quality of life (QOL) outcomes in patients with sporadic vestibular schwannoma (VS) have shown surprisingly little difference among treatment modalities. To date, there is limited prospective QOL outcome data available comparing baseline to posttreatment scores. Study Design: Prospective longitudinal study using the disease-specific Penn Acoustic Neuroma Quality of Life (PANQOL) scale. Setting: Large academic skull base center. Patients: Patients diagnosed with unilateral VS who completed a baseline survey before treatment and at least one posttreatment survey. Main Outcome Measures: Change in PANQOL scores from baseline to most recent survey. Results: A total of 244 patients were studied, including 78 (32%) who elected observation, 118 (48%) microsurgery, and 48 (20%) stereotactic radiosurgery. Patients who underwent microsurgery were younger (p < 0.001) and had larger tumors (p < 0.001) than those who underwent observation or radiosurgery; there was no significant difference in duration of follow-up among management groups (mean 2.1 yrs; p = 0.28). When comparing the total PANQOL score at baseline to the most recent survey, the net change was only –1.1, –0.1, and 0.3 points on a 100-point scale for observation, microsurgery, and radiosurgery, respectively (p = 0.89). After multivariable adjustment for baseline features, there were no statistically significant changes when comparing baseline to most recent scores within each management group for facial function, general health, balance, hearing loss, energy, and pain domains or total score. However, the microsurgical group experienced a 10.8-point improvement (p = 0.002) in anxiety following treatment, compared with 1.5 (p = 0.73) and 5.3 (p = 0.31) for observation and radiosurgery, respectively. Conclusions: In this prospective longitudinal study investigating differences in QOL outcomes among VS treatment groups using the disease-specific PANQOL instrument, treatment did not modify QOL in most domains. Microsurgery may confer an advantage with regard to patient anxiety, presumably relating to the psychological benefit of “cure” from having the tumor removed.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

Background: The rapid reduction in tumor burden by the oral B-cell lymphoma-2 inhibitor venetoclax (Ven) poses a risk of tumor lysis syndrome (TLS) for patients (pts) with chronic lymphocytic leukemia (CLL). The approved 5-week Ven dose ramp-up, along with prophylaxis and monitoring, effectively mitigate this risk of TLS but also introduce some logistical challenges to starting the drug. Moreover, the long ramp-up period may lead to clinical deterioration while pts are receiving lower doses, particularly for those with rapid disease progression after B-cell receptor pathway inhibitor (BCRi) therapy. Accelerated Ven dose ramp-up has been explored in a limited number of prior studies, including the prospective M14-032 trial (Jones et al. Lancet Oncol 2018) and a single-center retrospective study (Koenig et al. ASH 2019); these studies had conflicting results with regard to the risk of TLS. We conducted a multicenter study to systematically characterize the safety profile and feasibility of an accelerated Ven ramp-up schedule in pts with previously treated CLL. Methods: This is a retrospective chart review from 4 large academic US medical centers of 36 pts with relapsed/refractory CLL and a documented ramp-up period of &lt;5 weeks (duration at treating physician's discretion). The study period was defined from 1 month before to 1 month after ramp-up. TLS risk before Ven initiation was assessed per the label. Safety endpoints included the proportion of pts who experienced Grade ≥3 adverse events (AEs), TLS per Howard criteria (laboratory, clinical, or any reported TLS), and/or metabolic abnormalities observed during ramp-up. Feasibility of accelerated ramp-up was measured by assessing the proportion of pts who reached the target 400-mg dose or an alternative stable dose, defined as continuous/stable Ven dosing for ≥1 month after ramp-up. Descriptive statistics were calculated. Results: The median age at Ven initiation was 67.5 years (range 53-84) and 58.3% of pts had deletion 17p or TP53 mutation (Table 1). Pts were heavily pretreated (median of 3 lines of prior therapy [range 1-7]) and 88.9% had prior BCRi therapy; 27 pts (75.0%) had BCRi as immediate prior line of therapy before Ven. Before Ven initiation, 7 pts (19.4%) were at high risk of TLS, 13 (36.1%) at medium risk of TLS, and 15 (41.7%) at low risk of TLS; 1 unknown. Last line of therapy was discontinued in 30 pts (83.3%). Twenty-one pts (58.3%) received Ven monotherapy, 11 (30.6%) received Ven plus rituximab, 1 (2.8%) received Ven plus obinutuzumab, and 3 (8.3%) received Ven plus other (including ibrutinib, duvelisib, or idelalisib). Thirty-three pts (91.7%) underwent accelerated ramp-up as an inpatient, with a median hospital stay of 11 days (range 3-28). A stable dose of Ven was reached by 34 pts (94.4%), with median time of 15 days (range 3-66) to stable dose. Twenty-eight of these 34 pts (82.4%) reached the full 400 mg as their stable dose, with median time of 19.5 days (range 11-66). Overall, 15 pts (41.7%) experienced Grade ≥3 AEs and 4 (11.1%) discontinued Ven during ramp-up (2 pts due to clinical TLS, and 1 patient each due to persistent cytopenias and enrollment in hospice care). Seven pts (19.4%) had TLS (5 [13.9%] laboratory, 2 [5.6%] clinical), and 9 pts (25.0%) developed a metabolic abnormality only that did not meet Howard criteria for TLS (Table 2). Both pts with clinical TLS received Ven ramp-up while hospitalized; 1 high risk and 1 medium risk at baseline. Life-threatening (Grade 4) acute kidney injury and hypovolemic shock were reported for both. Of those pts with TLS, 4 (57.1%) required supportive medications. All AEs of TLS (including clinical events) resolved. Conclusion: In this multicenter study exploring accelerated Ven ramp-up, 82% of pts reached a stable dose of Ven 400 mg. TLS was observed in 19% of pts, including 2 pts with clinical TLS, which in both cases was reversible. Our data suggest that although the risk of TLS with an accelerated ramp-up appears to be greater than with 5-week Ven ramp-up per label, an accelerated Ven ramp-up schedule appears feasible at experienced academic centers with close inpatient monitoring. This dosing regimen may be beneficial for relapsed CLL pts with aggressive disease, particularly those progressing immediately after BCRi therapy. While promising, the approach cannot be routinely recommended until results are validated in a prospective clinical trial. Disclosures Davids: BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; AbbVie: Consultancy; Eli Lilly: Consultancy; MEI Pharma: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Sunesis: Consultancy; Gilead Sciences: Consultancy; Zentalis: Consultancy; Syros Pharmaceuticals: Consultancy; Research to Practice: Honoraria; Merck: Consultancy; Surface Oncology: Research Funding. Shadman:TG therapeutics: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mustang Bio: Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Sunesis: Research Funding; Gilead: Research Funding; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Ended employment in the past 24 months. Parikh:GlaxoSmithKline: Honoraria; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding. Ujjani:MorphoSys: Consultancy; Genentech: Consultancy, Honoraria; Atara: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Chen:AbbVie: Other: Institutional research grants, Research Funding. Johnson:AbbVie: Other: Institutional research grants, Research Funding. Jiang:AbbVie: Current Employment, Other: may hold stock or options. Llamas:AbbVie: Current Employment, Other: may hold stock or options. Feng:AbbVie: Current Employment, Other: may hold stock or options. Khan:ICON plc: Current Employment, Other: a company contracted by AbbVie for this study. Lamanna:MingSight: Other: Institutional research grants, Research Funding; Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Columbia University Medical Center: Current Employment; Juno: Other: Institutional research grants, Research Funding; Octapharma: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Loxo: Research Funding. OffLabel Disclosure: "Venetoclax is a BCL-2 inhibitor indicated: for treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. CLL/SLL: Dosing with venetoclax begins with a 5-week ramp-up."