Citations

Abstract Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men – women) = −0.295 (90% highest posterior density interval = −0.556 to −0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.

Abstract Cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) is activated in cells with defective DNA damage repair and signaling (DDR) factors, but a direct role for DDR factors in regulating cGAS activation in response to micronuclear DNA is still poorly understood. Here, we provide novel evidence that Nijmegen breakage syndrome 1 (NBS1) protein, a well-studied DNA double-strand break (DSB) sensor—in coordination with Ataxia Telangiectasia Mutated (ATM), a protein kinase, and Carboxy-terminal binding protein 1 interacting protein (CtIP), a DNA end resection factor—functions as an upstream regulator that prevents cGAS from binding micronuclear DNA. When NBS1 binds to micronuclear DNA via its fork-head–associated domain, it recruits CtIP and ATM via its N- and C-terminal domains, respectively. Subsequently, ATM stabilizes NBS1’s interaction with micronuclear DNA, and CtIP converts DSB ends into single-strand DNA ends; these two key events prevent cGAS from binding micronuclear DNA. Additionally, by using a cGAS tripartite system, we show that cells lacking NBS1 not only recruit cGAS to a major fraction of micronuclear DNA but also activate cGAS in response to these micronuclear DNA. Collectively, our results underscore how NBS1 and its binding partners prevent cGAS from binding micronuclear DNA, in addition to their classical functions in DDR signaling.

Composite classic Hodgkin lymphoma and follicular lymphoma (CHLFL) is a rare and poorly characterized entity. Herein, we report the clinicopathologic features of 22 cases of CHLFL from 3 institutions and we assess 27 additional cases reported in the literature. In our cohort (n=22), patients with CHLFL had a median age of 61 years and an equal male to female incidence. Most cases (95%) arose de novo with the remaining patients having a history of non-Hodgkin lymphoma. CHLFL always involved lymph nodes (100%) and most cases (95%) revealed 2 distinct areas separately diagnostic for CHL and FL. The CHL component represented a variable proportion of the overall neoplasm (5% to 90%) and was either mixed cellularity (82%) or nodular sclerosis (18%) type. The Hodgkin/Reed-Sternberg cells expressed CD30 (100%), PAX5 (100%), CD15 (62%), BCL6 (47%), BCL2 (29%), and EBER (25%), in a polymorphous inflammatory background typical of CHL. The FL component was low-grade in 55%, grade 3A in 36%, and grade 3B in 9% of cases. All 3 cases investigated by cytogenetic methods for a clonal relationship between the CHL and FL components were clonally related. These clinicopathologic features of our cohort are similar to those of cases reported in the literature. The 5-year overall survival in combined patients with CHLFL (n=49) was 48%, comparable to CHL but worse than FL in the elderly. In summary, CHLFL is a rare entity that most often occurs in older adults, involves lymph nodes, and most commonly presents de novo. In the small number of cases assessed, the CHL and FL components are usually clonally related suggesting that the CHL and FL components may share a common progenitor B-cell, likely a mutated germinal center B-cell.

ABSTRACT Background Critically ill patients with severe acute kidney injury (AKI) requiring kidney replacement therapy (KRT) have a grim prognosis. Recently, multiple studies focused on the impact of KRT initiation time [i.e., accelerated versus watchful waiting KRT initiation (WWS-KRT)] on patient outcomes. We aim to review the results of all related clinical trials. Methods In this systematic review, we searched all relevant randomized clinical trials from January 2000 to April 2021. We assessed the impacts of accelerated versus WWS-KRT on KRT dependence, KRT-free days, mortality and adverse events, including hypotension, infection, arrhythmia and bleeding. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. Results A total of 4932 critically ill patients with AKI from 10 randomized clinical trials were included in this analysis. The overall 28-day mortality rate was 38.5%. The 28-day KRT-dependence rate was 13.0%. The overall incident of KRT in the accelerated group was 97.4% and 62.8% in the WWS-KRT group. KRT in the accelerated group started 36.7 h earlier than the WWS-KRT group. The two groups had similar risks of 28-day [pooled log odds ratio (OR) 1.001, P = 0.982] and 90-day (OR 0.999, P = 0.991) mortality rates. The accelerated group had a significantly higher risk of 90-day KRT dependence (OR 1.589, P = 0.007), hypotension (OR 1.687, P < 0.001) and infection (OR 1.38, P = 0.04) compared with the WWS-KRT group. Conclusions This meta-analysis revealed that accelerated KRT leads to a higher probability of 90-day KRT dependence and dialysis-related complications without any impact on mortality rate when compared with WWS-KRT. Therefore, we suggest the WWS-KRT strategy for critically ill patients.

AbstractBackgroundMultiple myeloma (MM) measurable residual disease (MRD) evaluated by flow cytometry is a surrogate for progression‐free and overall survival in clinical trials. However, analysis and reporting between centers lack uniformity. We designed and evaluated a consensus protocol for MM MRD analysis to reduce inter‐laboratory variation in MM MRD reporting.MethodsSeventeen participants from 13 countries performed blinded analysis of the same eight de‐identified flow cytometry files from patients with/without MRD using their own method (Stage 1). A consensus gating protocol was then designed following survey and discussions, and the data re‐analyzed for MRD and other bone marrow cells (Stage 2). Inter‐laboratory variation using the consensus strategy was reassessed for another 10 cases and compared with earlier results (Stage 3).ResultsIn Stage 1, participants agreed on MRD+/MRD− status 89% and 68% of the time respectively. Inter‐observer variation was high for total numbers of analyzed cells, total and normal plasma cells (PCs), limit of detection, lower limit of quantification, and enumeration of cell populations that determine sample adequacy. The identification of abnormal PCs remained relatively consistent. By consensus method, average agreement on MRD− status improved to 74%. Better consistency enumerating all parameters among operators resulted in near‐unanimous agreement on sample adequacy.ConclusionUniform flow cytometry data analysis substantially reduced inter‐laboratory variation in reporting multiple components of the MM MRD assay. Adoption of a harmonized approach would meet an important need for conformity in reporting MM MRD for clinical trials, and wider acceptance of MM MRD as a surrogate clinical endpoint.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is highly contagious and causes coronavirus disease 2019 (COVID-19). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is the most accurate and reliable molecular assay to detect active SARS-CoV-2 infection. However, a rapid increase in test subjects has created a global bottleneck in testing capacity. Given that efficient nucleic acid extraction greatly affects reliable and accurate testing results, we compared three extraction platforms: MagNA Pure 96 DNA and Viral NA Small Volume kit on MagNA Pure 96 (Roche, Basel, Switzerland), careGENETM Viral/Pathogen HiFi Nucleic Acid Isolation kit (WELLS BIO Inc., Seoul, Korea) on KingFisher Flex (Thermo Fisher Scientific, Rocklin, CA, USA), and SGRespiTM Pure kit (Seegene Inc., Seoul, Korea) on Maelstrom 9600 (Taiwan Advanced Nanotech Inc., Taoyuan, Taiwan). RNA was extracted from 245 residual respiratory specimens from the different types of samples (i.e., NPS, sputum, and saliva) using three different kits. The 95% limits of detection of median tissue culture infectious dose per milliliter (TCID50/mL) for the MagNA Pure 96, KingFisher Flex, and Maelstrom 9600 were 0.37–3.15 × 101, 0.41–3.62 × 101, and 0.33–1.98 × 101, respectively. The KingFisher Flex platform exhibited 99.2% sensitivity and 100% specificity, whereas Maelstrom 9600 exhibited 98.3–100% sensitivity and 100% specificity. Bland–Altman analysis revealed a 95.2% concordance between MagNA Pure 96 and KingFisher Flex and 95.4% concordance between MagNA Pure 96 and Maelstrom 9600, indicating that all three platforms provided statistically reliable results. This suggests that two modifying platforms, KingFisher Flex and Maelstrom 9600, are accurate and scalable extraction platforms for large-scale SARS-CoV-2 clinical detection and could help the management of COVID-19 patients.

AbstractBackgroundIsolated REM Sleep Behavior Disorder (iRBD) patients are known to be at high risk for developing an overt synucleinopathy – particularly Dementia with Lewy Bodies (DLB) and Parkinson’s Disease (PD). Reduced nigrostriatal uptake on 123I‐FP‐CIT SPECT reflects dopamine deficiency, which is common in the overt synucleinopathies. We sought to assess how 123I‐FP‐CIT SPECT imaging in iRBD changes longitudinally and whether an abnormal 123I‐FP‐CIT SPECT scan precedes and predicts future transition to an overt synucleinopathy.MethodParticipants with polysomnography‐confirmed iRBD from the Mayo Clinic Alzheimer’s Disease Research Center database +/‐ North American Prodromal Synucleinopathy (NAPS) Consortium who had two or more longitudinal 123I‐FP‐CIT SPECT scans and been followed prospectively for at least 24 months were included in this analysis. Striatonigral dopamine transporter uptake was evaluated semi‐quantitatively with 123I‐FP‐CIT SPECT using DaTQUANT software (GE Healthcare) to calculate z‐scores of putamen uptake.ResultThirty‐five iRBD participants (86% male) were evaluated prospectively (mean 62.5 ± 19.4 months) and underwent two or more 123I‐FP‐CIT SPECT scans at a minimum of 12 months intervals. Thirteen participants (37%) developed an overt synucleinopathy (11 DLB and 2 PD; phenoconverters) and 22 participants (63%) remained as iRBD (stable iRBD). Phenoconverters were older (mean 70.8 ± 7.0 vs 63.4 ± 6.0 years old) and had more negative DaTQUANT putamen z‐scores (mean ‐1.68 ± 1.42 vs ‐0.33 ± 1.52) than stable iRBD participants at baseline. Among phenoconverters, nine participants (69%) had one or more 123I‐FP‐CIT SPECT scans with DaTQUANT putamen z‐score of <‐2.0 prior to phenoconversion, and mean time from initial DaTQUANT putamen z‐score of <‐2.0 to phenoconversion was 36.8 ± 28.7 months. In stable RBD participants, eight participants (36%) showed a decline in DaTQUANT putamen z‐score of >1 between the most recent and the baseline scan, and four participants (18%) presented DaTQUANT putamen z‐score of <‐2.0 at the most recent scan.ConclusionThese findings suggest that a decline in putamen uptake on 123I‐FP‐CIT SPECT in iRBD serves as a predictor and a surrogate biomarker for progression of iRBD to an overt synucleinopathy.

Abstract Introduction: Treatment resistance remains a challenge that most patients (pts) with MM will encounter in their disease course. With each subsequent line of therapy (LOT), pt outcomes and health-related quality of life (HRQoL) worsen. Pts with MM who are refractory to immunomodulatory drugs, proteasome inhibitors (PIs), and anti-CD38 antibodies (triple-class refractory; TCR) have a poor prognosis and the holistic burden is not well understood. To capture these features, the ongoing prospective Connect ® MM Disease Registry was used to report treatment patterns and outcomes in pts with TCR MM. Methods: Data from September 28, 2009 to February 4, 2021 were used. Eligible pts were ≥18 years of age at first documented diagnosis of MM, which became TCR during their disease course. MM was defined as refractory to therapies based on the International Myeloma Working Group Criteria. Index date was defined as first record of TCR during the disease course. Data analyzed included pt characteristics, treatment patterns pre- and post-index, overall survival (OS), healthcare resource utilization (HCRU), and HRQoL. General HRQoL was captured by EQ-5D-3L utility index (range −0.11-1, higher score indicated better HRQoL), EQ-5D visual analog scale (VAS) score (range 0-100, "worst imaginable" to "best imaginable" health status), and FACT-G total score (range 0-108). Disease-specific HRQoL was measured by FACT-MM total score (range 0-164), FACT-MM Trial Outcome Index (TOI) (range 0-112), and the Brief Pain Inventory (BPI) average pain item (range 0-10, "no pain" to "worst pain you can imagine"). Higher scores indicated better HRQoL for all FACT-related index scores. Cohort-level clinically meaningful change in HRQoL during post-index year 1 was defined as 0.08 for the EQ-5D utility index, 7 for the EQ-5D VAS, and 6-8 points for the FACT-G total score. Validated thresholds were unavailable for other index scores. All statistical analyses were descriptive. Results: This analysis included 240 pts identified from the Registry. Mean age at index date was 68.1 (standard deviation [SD] 10.4) years. Mean time from initial MM diagnosis was 64.1 (SD 26.9) months. 63.3% of pts had prior stem cell transplantation. Mean number of prior LOTs was 4 (SD 1.7). 64.6% of pts had received a subsequent MM LOT since index date. Median follow-up time post-index date was 4.6 months. Treatment pattern analysis of post-index treated pts (Table A) revealed that retreatment with an immunomodulatory drug, PI, or anti-CD38 agent post-index date was common, led by carfilzomib (47.1%) and pomalidomide (40.0%). However, no therapeutic combination was preferred in this pt population. Regarding their index therapy (first post-index LOT), 70.3% and 22.6% were on triplet and quadruplet combination therapy; 3.2% initiated belantamab mafodotin, selinexor, melflufen, and/or idecabtagene vicleucel; mean duration of treatment was 5.6 (SD 6.1) months. For all pts, median OS was 8.9 months; median OS for those who received &lt; 4 prior LOTs (43.8%) versus those who received 4 or more prior LOTs (56.2%) was 10.0 and 8.0 months, respectively. Regarding HCRU during the post-index follow-up, all-cause and MM-related hospitalizations were observed in 49.6% and 23.8% of all eligible pts, respectively. Among these pts, annualized mean number of all-cause/MM-related hospitalization and length of hospital stay were estimated as 8.5 (SD 18.2)/11.0 (SD 25.2) and 64.0 days (SD 80.0)/ 69.2 days (SD 83.7), respectively. Analysis of HRQoL showed a numerical decline in HRQoL relative to index during the 1-year post-index period across all studied HRQoL instruments. There was a clinically meaningful decline in HRQoL from baseline following the index date based on the EQ-5D utility index, EQ-5D VAS, and FACT-G total score (Table B). Conclusion: Pts with TCR MM experienced poor survival, substantial hospitalizations, and a clinically meaningful decline in HRQoL. 35.4% of pts did not receive any new LOTs since the disease became TCR. Among those who did receive subsequent LOTs, re-treatment with an immunomodulatory drug, PI, or anti-CD38 antibody therapy occurred, showing a lack of novel treatment options. This study suggests novel tolerable and efficacious therapeutic agents are needed to address the burden of illness in pts with MM. Figure 1 Figure 1. Disclosures Tang: Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hari: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ramasamy: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Joshi: Bristol Myers Squibb: Current Employment. Liu: Bristol Myers Squibb: Current Employment. Che: Bristol Myers Squibb: Current Employment. Hernandez: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Abonour: Jensen: Honoraria, Research Funding; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Hardin: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Rifkin: Sanofi: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Coherus: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Ailawadhi: BeiGene, Ltd.: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Ascentage: Research Funding; Medimmune: Research Funding; Cellectar: Research Funding; Xencor: Research Funding; GSK: Consultancy, Research Funding; Takeda: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy. Lee: Legend Biotech: Consultancy; Sanofi: Consultancy; Oncopetides: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Karyopharm: Consultancy; Regeneron: Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding. Terebelo: Pharmacylics: Speakers Bureau; Celgene-BMS: Consultancy; Takeda: Speakers Bureau; Janssen: Speakers Bureau. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services . Narang: Bristol Myers Squibb: Consultancy; TG Pharma: Consultancy. Toomey: Bristol Myers Squibb: Consultancy. Gasparetto: Oncopeptide: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Gsk: Consultancy, Honoraria, Speakers Bureau. Wagner: Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Athenex Inc: Consultancy; Eli Lilly, Johnson & Johnson: Other: Spouse, previously held individual stocks;. Jagannath: Janssen Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Legend Biotech: Consultancy; Sanofi: Consultancy; Takeda: Consultancy.

Abstract Introduction: The interleukin-3 receptor alpha chain (CD123) is a cell-surface target aberrantly expressed on various myeloid neoplasms including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelofibrosis (MF). Tagraxofusp (TAG, SL-401), a first-in-class CD123-targeted therapy, is the only treatment approved by the FDA and EMA for patients (pts) with BPDCN. It has also been investigated in phase 1/2 clinical trials for AML (including pts with minimal residual disease [MRD]), CMML, and MF. We report the aggregated safety data of TAG monotherapy from trials in BPDCN, AML, CMML, and MF. Methods: An integrated safety analysis was performed for pts who received TAG monotherapy in three phase 1/2, multicenter clinical studies: Study 0114 (NCT02113982; BPDCN/AML), Study 0214 (NCT02270463; AML with/without MRD), and Study 0314 (NCT02268253; CMML/MF; Table 1). Pts received the recommended phase 2 dose of 12 mcg/kg/day (d) IV on d1-3 (MF and CMML) or d1-5 (BPDCN and AML) and were analyzed for incidence and timing of treatment-related adverse events (TRAEs), AEs of interest, and discontinuations. Safety data for TAG monotherapy, reported as individual case study reports (ICSRs) postapproval (US) and from an early access program (EAP; EU) are also presented. Results: In total, 201 pts receiving TAG (12 mcg/kg/d) in a clinical trial setting were included: BPDCN, n=86; AML, n=36; AML with/without MRD, n=10; CMML, n=33; MF, n=36. As of Jul 2021, 11 (6%) pts discontinued TAG due to any-grade (Gr) TRAE. Most common TRAEs (any-Gr) are shown in Table 2 and included hypoalbuminemia (41%), increased alanine aminotransferase (ALT; 40%), increased aspartate aminotransferase (AST; 39%), and thrombocytopenia (26%). The most common Gr ≥3 TRAEs were thrombocytopenia (n=41; 20%), increased AST (n=40; 20%), and increased ALT (n=35; 17%). Tumor lysis syndrome occurred in 5% of pts and 1.5% had infusion-related reactions. Any-Gr and Gr ≥3 hematologic TRAEs are presented in Table 3. Most common was thrombocytopenia. All TRAEs were transient in nature; prolonged bone marrow suppression was not observed. Overall, 23% (47/201) of pts experienced ≥1 treatment-related serious AE. Onset of most TRAEs, irrespective of Gr, commonly occurred in cycle 1 and resolved by cycle 2. Although the number of pts in cycles ≥2 was lower than in cycle 1, the incidence rates of common TRAEs also substantially decreased in subsequent cycles. Capillary leak syndrome (CLS) occurred in 17% of the overall 201 pts. The majority of all CLS events were nonsevere, Gr ≤2 (n=22; 63%); also reported were Gr 3, n=10 (29%); Gr 4, n=3 (9%), and 2 pts experienced a Gr 5 event. Onset of CLS was usually within the first week of cycle 1 (median time to onset [range], d: 5.5 [1-51]) and resolved quickly (median time to resolution [range], d: 5.0 [2-69]); no pts experienced the first onset after cycle 2. Of the 15 pts who resumed treatment after an initial CLS event, only 1 pt experienced a recurrence. The most common AEs reported as ICSRs postapproval and from an EAP (December 2018 to June 2021) were CLS, blood albumin decreased, thrombocytopenia, pyrexia, and hepatic enzyme increased. No new safety signals that would alter the safety profile were observed. Conclusions: This integrated analysis represents the largest collection of safety data (N=201) following treatment with TAG monotherapy. TAG has an established and manageable safety profile, with the vast majority of AEs reported as transient and decreasing in frequency/severity with increasing cycles. CLS was reported in 17% of pts; onset was usually within cycle 1, resolved quickly (median time to resolution: 5.0 d) by early intervention measures including holding treatment, and no pts experienced first onset after cycle 2. Risk-minimization guidelines for CLS were developed and implemented during clinical trials and incorporated into prescribing information. No myelosuppression or cumulative toxicity was observed over multiple treatment cycles. The safety profile observed postapproval and in the EAP was consistent with the clinical trial data reported, reflecting successful adoption of risk-management strategies in real-world practice. These data confirm the favorable benefit-risk profile of TAG monotherapy has been maintained in the 3 years following US approval. Figure 1 Figure 1. Disclosures Pemmaraju: ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Blueprint Medicines: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb Co.: Consultancy; Pacylex Pharmaceuticals: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Aptitude Health: Consultancy; Celgene Corporation: Consultancy; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; Daiichi Sankyo, Inc.: Other, Research Funding; Samus: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Affymetrix: Consultancy, Research Funding; DAVA Oncology: Consultancy; Plexxicon: Other, Research Funding; Roche Diagnostics: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ImmunoGen, Inc: Consultancy. Kantarjian: NOVA Research: Honoraria; Aptitude Health: Honoraria; Immunogen: Research Funding; BMS: Research Funding; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Jazz: Research Funding; Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wang: Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Takeda: Consultancy, Honoraria, Other: Advisory board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Lane: N-of-One: Consultancy, Honoraria; Stemline Therapeutics: Research Funding; Qiagen: Consultancy, Honoraria; AbbVie: Research Funding. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Rizzieri: Celltron/Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: presentation to FDA for biosimilar review ; AROG: Other; Amgen: Other: personal fee; Bayer: Consultancy, Honoraria; Kite: Other: personal fee; Mustang: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Other: personal fee; Gilead: Other: personal fee; Jazz: Other: personal fee; Pharmacyclics: Other. Vasu: Seattle Genetics: Other: travel support; Boehringer Ingelheim: Other: Travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Gupta: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Constellation Pharma: Consultancy, Honoraria; Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Lee: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: 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. Schiller: Sangamo: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; FujiFilm: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Onconova: Research Funding; Celator: Research Funding; Actuate: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Trovagene: Research Funding; Deciphera: Research Funding; Gamida Cell Ltd.: Research Funding; Forma: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding; Takeda: Research Funding; Geron: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Constellation Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Tolero: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Samus: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Elevate: Research Funding; Delta-Fly: Research Funding; Genentech-Roche: Research Funding; Ariad: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Foran: trillium: Research Funding; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; OncLive: Honoraria; servier: Honoraria; gamida: Honoraria; takeda: Research Funding; boehringer ingelheim: Research Funding; abbvie: Research Funding; certara: Honoraria; bms: Honoraria; pfizer: Honoraria; sanofi aventis: Honoraria; revolution medicine: Honoraria; taiho: Honoraria; syros: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Walter: Macrogenics: Consultancy, Research Funding; Jazz: Research Funding; Pfizer: Consultancy, Research Funding; Selvita: Research Funding; Amphivena: Consultancy, Other: ownership interests; Agios: Consultancy; Astellas: Consultancy; BMS: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Sieminski: Stemline Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Mughal: Oxford University Press, Informa: Other: financial benefit and/or patents ; Stemline: Current Employment, Current holder of stock options in a privately-held company. Konopleva: Calithera: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; KisoJi: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Cellectis: Other: grant support; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding.