Highlights d Patients with severe COVID-19 accumulate HLA-DR Low monocytes and immature neutrophils in blood/lungs d Calprotectin level positively correlates with neutrophil count and disease severity d Loss of non-classical monocytes could identify high risk of severe COVID-19

In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).

Key Points• Enasidenib, a selective inhibitor of mutant-IDH2 enzymes, was safe and welltolerated in patients with IDH2-mutated myeloid malignancies.• Enasidenib induced hematologic responses in patients with relapsed/refractory AML in this dose-escalation and expansion study. ABSTRACTRecurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, leading to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human, phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients (N=239) and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML (n=176), from the phase 1 dose-escalation and expansion phases of the study. In the doseescalation phase, an MTD was not reached at doses ranging from 50-650 mg daily.Enasidenib 100 mg daily was selected for the expansion phase based on pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3-4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDHinhibitor-associated differentiation syndrome (IDH-DS; 7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission was 19.7 months. Continuous daily enasidenib treatment was generally well-tolerated and induced hematologic responses in patients who had failed prior AML therapy. Inducing differentiation of myeloblasts, not cytotoxicity, appears to drive the clinical efficacy of enasidenib.

Key Points An increase in the classical monocyte subset to >94% of total monocytes discriminates CMML from other monocytoses with high specificity. This characteristic increase in classical monocytes disappears in CMML patients who respond to hypomethylating agents.

The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.

B y early March 2020, the spread of the coronavirus disease 2019 (COVID-19) outbreak had reached the Paris area, France. Since then, all medical resources have been reorganized to handle the pandemic. As a tertiary cancer center, Gustave Roussy has followed two objectives: define processes to safely sustain cancer care in a secured environment and reorganize internally to adapt its capacities to hospitalize patients with cancer and COVID-19 illness. Patients with cancer have been considered at increased risk of COVID-19, on the rationale of the increased systemic immunosuppressive state caused by the underlying malignancy and anticancer treatments. The first report from a retrospective cohort in China suggested that patients with cancer were observed to have a higher risk of severe events (for example, a composite endpoint of intensive care unit (ICU) admission, invasive ventilation or death) compared with patients without cancer (seven (39%) of 18 patients versus 124 (8%) of 1,572 patients; P = 0.0003) and that patients with cancer deteriorated more rapidly than those without cancer 1. While general determinants of COVID-19 severity have emerged from large cohorts from China and Italy 2,3 , limited data are available on the specificity of patients with cancer to help the oncology community to identify patients at risk of severe COVID-19. Furthermore, the impact of COVID-19 infection on ongoing cancer care is unexplored. This study investigated the determinants of clinical worsening and death, as well as the impact on cancer care, for the first patients sequentially managed for COVID-19 and cancer in an academic tertiary cancer center. Results Patient population. From 24 March 2020 until 29 April 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected in 196 (12%) of 1,633 tests performed internally at the Gustave Roussy Cancer Centre. Overall, 209 patients were identified (including a few identified by PCR with reverse transcription (RT-PCR) performed at another facility and some diagnosed by computed tomography scan alone) and the final study population included 178 adult patients. The following were reasons for exclusion: pediatric population (six patients); non-cancer patients (19 patients); and COVID-19 ultimately ruled out (six patients). Baseline demographics, comorbidities and underlying cancer characteristics for

Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.

The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient’s plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.