Abstract: Extremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher risk for adverse pulmonary and neurodevelopmental outcomes. In the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) Hydrocortisone Trial, hydrocortisone neither reduced rates of BPD or death nor increased rates of neurodevelopmental impairment (NDI) or death. Objective To determine whether estimated risk for grades 2 to 3 BPD or death is associated with the effect of hydrocortisone on the composite outcomes of (1) grades 2 to 3 BPD or death and (2) moderate or severe NDI or death. Design, Setting, and Participants This secondary post hoc analysis used data from the NICHD NRN Hydrocortisone Trial, which was a double-masked, placebo-controlled, randomized clinical trial conducted in 19 US academic centers. The NICHD HRN Hydrocortisone Trial enrolled infants born at a gestational age of less than 30 weeks who received mechanical ventilation for at least 7 days, including at the time of enrollment, and who were aged 14 to 28 postnatal days. Infants were enrolled between August 22, 2011, and February 4, 2018, with follow-up between 22 and 26 months of corrected age completed on March 29, 2020. Data were analyzed from September 13, 2021, to March 25, 2023. Intervention Infants were randomized to 10 days of hydrocortisone or placebo treatment. Main Outcomes and Measures Infants’ baseline risk of grades 2 to 3 BPD or death was estimated using the NICHD Neonatal BPD Outcome Estimator. Differences in absolute and relative treatment effects by baseline risk were evaluated using interaction terms in models fitted to the efficacy outcome of grades 2 to 3 BPD or death and the safety outcome of moderate or severe NDI or death by follow-up. Results Among the 799 infants included in the analysis (421 boys [52.7%]), the mean (SD) gestational age was 24.9 (1.5) weeks, and the mean (SD) birth weight was 715 (167) g. The mean estimated baseline risk for grades 2 to 3 BPD or death was 54% (range, 18%-84%) in the study population. The interaction between treatment group and baseline risk was not statistically significant on a relative or absolute scale for grades 2 to 3 BPD or death; the size of the effect ranged from a relative risk of 1.13 (95% CI, 0.82-1.55) in quartile 1 to 0.94 (95% CI, 0.81-1.09) in quartile 4. Similarly, the interaction between treatment group and baseline risk was not significant on a relative or absolute scale for moderate or severe NDI or death; the size of the effect ranged from a relative risk of 1.04 (95% CI, 0.80-1.36) in quartile 1 to 0.99 (95% CI, 0.80-1.22) in quartile 4. Conclusions and Relevance In this secondary analysis of a randomized clinical trial, the effect of hydrocortisone vs placebo was not appreciably modified by baseline risk for grades 2 to 3 BPD or death. Trial Registration ClinicalTrials.gov Identifier: NCT01353313

Abstract: Anti–vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. Objective To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Design, Setting, and Participants Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53) without CI-DME. Interventions Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Main Outcomes and Measures Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Results Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57] ; P   & amp;lt; .001). The mean (SD) change in visual acuity from baseline to 4 years was −2.7 (6.5) letters with aflibercept and −2.4 (5.8) letters with sham (adjusted mean difference, −0.5 letters [97.5% CI, −2.3 to 1.3]; P  = .52). Antiplatelet Trialists’ Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Conclusions and Relevance Among patients with NPDR but without CI-DME, at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME. Trial Registration ClinicalTrials.gov Identifier: NCT02634333

Abstract: The DRCR Retina Network Protocol AC showed no significant difference in visual acuity outcomes over 2 years between treatment with aflibercept monotherapy and bevacizumab first with switching to aflibercept for suboptimal response in treating diabetic macular edema (DME). Understanding the estimated cost and cost-effectiveness of these approaches is important. Objective To evaluate the cost and cost-effectiveness of aflibercept monotherapy vs bevacizumab-first strategies for DME treatment. Design, Setting, and Participants This economic evaluation was a preplanned secondary analysis of a US randomized clinical trial of participants aged 18 years or older with center-involved DME and best-corrected visual acuity of 20/50 to 20/320 enrolled from December 15, 2017, through November 25, 2019. Interventions Aflibercept monotherapy or bevacizumab first, switching to aflibercept in eyes with protocol-defined suboptimal response. Main Outcomes and Measures Between February and July 2022, the incremental cost-effectiveness ratio (ICER) in cost per quality-adjusted life-year (QALY) over 2 years was assessed. Efficacy and resource utilization data from the randomized clinical trial were used with health utility mapping from the literature and Medicare unit costs. Results This study included 228 participants (median age, 62 [range, 34-91 years; 116 [51%] female and 112 [49%] male; 44 [19%] Black or African American, 60 [26%] Hispanic or Latino, and 117 [51%] White) with 1 study eye. The aflibercept monotherapy group included 116 participants, and the bevacizumab-first group included 112, of whom 62.5% were eventually switched to aflibercept. Over 2 years, the cost of aflibercept monotherapy was $26 504 (95% CI, $24 796-$28 212) vs $13 929 (95% CI, $11 984-$15 874) for the bevacizumab-first group, a difference of $12 575 (95% CI, $9987-$15 163). The aflibercept monotherapy group gained 0.015 (95% CI, −0.011 to 0.041) QALYs using the better-seeing eye and had an ICER of $837 077 per QALY gained compared with the bevacizumab-first group. Aflibercept could be cost-effective with an ICER of $100 000 per QALY if the price per dose were $305 or less or the price of bevacizumab was $1307 per dose or more. Conclusions and Relevance Variability in individual needs will influence clinician and patient decisions about how to treat specific eyes with DME. While the bevacizumab-first group costs still averaged approximately $14 000 over 2 years, this approach, as used in this study, may confer substantial cost savings on a societal level without sacrificing visual acuity gains over 2 years compared with aflibercept monotherapy.

Abstract: Presence of predominantly peripheral diabetic retinopathy (DR) lesions on ultra-widefield fluorescein angiography (UWF-FA) was associated with greater risk of DR worsening or treatment over 4 years. Whether baseline retinal nonperfusion assessment is additionally predictive of DR disease worsening is unclear. Objective To assess whether the extent and location of retinal nonperfusion identified on UWF-FA are associated with worsening in Diabetic Retinopathy Severity Scale (DRSS) score or DR treatment over time. Design, Setting, and Participants This cohort study was a prospective, multicenter, longitudinal observational study with data for 508 eyes with nonproliferative DR and gradable nonperfusion on UWF-FA at baseline. All images were graded at a centralized reading center; 200° ultra-widefield (UWF) color images were graded for DR at baseline and annually for 4 years. Baseline 200° UWF-FA images were graded for nonperfused area, nonperfusion index (NPI), and presence of predominantly peripheral lesions on UWF-FA (FA PPL). Interventions Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures Association of baseline UWF-FA nonperfusion extent with disease worsening, defined as either 2 or more steps of DRSS worsening within Early Treatment Diabetic Retinopathy Study fields on UWF-color images or receipt of DR treatment. Results After adjusting for baseline DRSS, the risk of disease worsening over 4 years was higher in eyes with greater overall NPI (hazard ratio [HR] for 0.1-unit increase, 1.11; 95% CI, 1.02-1.21; P  = .02) and NPI within the posterior pole (HR for 0.1-unit increase, 1.35; 95% CI, 1.17-1.56; P   & amp;lt; .001) and midperiphery (HR for 0.1-unit increase, 1.08; 95% CI, 1.00-1.16; P  = .04). In a multivariable analysis adjusting for baseline DRSS score and baseline systemic risk factors, greater NPI (HR, 1.11; 95% CI, 1.02-1.22; P  = .02) and presence of FA PPL (HR, 1.89; 95% CI, 1.35-2.65; P   & amp;lt; .001) remained associated with disease worsening. Conclusions and Relevance This 4-year longitudinal study has demonstrated that both greater baseline retinal nonperfusion and FA PPL on UWF-FA are associated with higher risk of disease worsening, even after adjusting for baseline DRSS score and known systemic risk. These associations between disease worsening and retinal nonperfusion and FA PPL support the increased use of UWF-FA to complement color fundus photography in future efforts for DR prognosis, clinical care, and research.

Abstract: Ultra-widefield (UWF) imaging improves the ability to identify peripheral diabetic retinopathy (DR) lesions compared with standard imaging. Whether detection of predominantly peripheral lesions (PPLs) better predicts rates of disease worsening over time is unknown. Objective To determine whether PPLs identified on UWF imaging are associated with increased disease worsening beyond the risk associated with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) score. Design, Setting, and Participants This cohort study was a prospective, multicenter, longitudinal observational study conducted at 37 US and Canadian sites with 388 participants enrolled between February and December 2015. At baseline and annually through 4 years, 200° UWF-color images were obtained and graded for DRSS at a reading center. Baseline UWF-color and UWF-fluorescein angiography (FA) images were evaluated for the presence of PPL. Data were analyzed from May 2020 to June 2022. Interventions Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures Predominantly peripheral lesions were defined as DR lesions with a greater extent outside vs inside the 7 standard ETDRS fields. Primary outcome was disease worsening defined as worsening 2 steps or more on the DRSS or receipt of DR treatment. Analyses were adjusted for baseline DRSS score and correlation between 2 study eyes of the same participant. Results Data for 544 study eyes with nonproliferative DR (NPDR) were analyzed (182 [50%] female participants; median age, 62 years; 68% White). The 4-year disease worsening rates were 45% for eyes with baseline mild NPDR, 40% for moderate NPDR, 26% for moderately severe NPDR, and 43% for severe NPDR. Disease worsening was not associated with color PPL at baseline (present vs absent: 38% vs 43%; HR, 0.78; 95% CI, 0.57-1.08; P  = .13) but was associated with FA PPL at baseline (present vs absent: 50% vs 31%; HR, 1.72; 95% CI, 1.25-2.36; P   & amp;lt; .001). Conclusions and Relevance Although no association was identified with color PPL, presence of FA PPL was associated with greater risk of disease worsening over 4 years, independent of baseline DRSS score. These results suggest that use of UWF-FA to evaluate retinas peripheral to standard ETDRS fields may improve the ability to predict disease worsening in NPDR eyes. These findings support use of UWF-FA for future DR staging systems and clinical care to more accurately determine prognosis in NPDR eyes.

Abstract: Background: Acute myeloid leukemia (AML) outcomes in the elderly, particularly intensive chemotherapy (IC)-ineligible patients (pts), are poor. Venetoclax (VEN), a BCL2 inhibitor, in combination with low-intensity regimens has shown excellent efficacy in AML and is approved for IC-ineligible pts as frontline therapy. Outcomes and expectations of AML after failure of frontline VEN-based regimens are unknown. Methods: We conducted a retrospective study to determine pt outcomes after failure of frontline therapy with VEN and hypomethylating agents (HMA). Newly diagnosed (ND) AML pts enrolled on 2 clinical trials of VEN+HMA (NCT02203773, NCT03404193) with refractory AML or relapse after initial response to VEN+HMA were included. In 1 trial, ND IC-ineligible AML pts (≥65 years [yr]) received VEN 400-1200 mg daily with decitabine (DEC) for 5 days or azacitidine (AZA) for 7 days. The other trial enrolled ND IC-ineligible AML pts ( & gt;60 yrs) who received VEN 400 mg daily or equivalent with DEC for 10 days until CR/CRi, followed by 5-day cycles. FLT3 inhibitors (FLT3i) were allowed in FLT3mut pts. Overall survival (OS) was measured from date of diagnosis of refractory AML or relapse after VEN+HMA therapy, till death or censored at last follow-up. The data cut-off date was 07.08.19. Results: Between November 2014 and February 2019, out of 103 ND AML pts treated with VEN+HMA, 41 pts were identified to have refractory AML, or relapse after VEN+HMA. The median age was 74 yrs (range 62-85), 12 pts (29%) had sAML, 7 pts (17%) had therapy-related AML, 33 pts (81%) had ELN adverse risk AML, 16 pts (39%) had TP53mut, 12 pts (29%) had N/KRASmut, and 5 pts (12%) had FLT3-ITD (Table 1, Fig 1). Pts had received a median of 4 cycles of VEN+HMA (range 1-29). The median follow-up duration for all pts was 21.2 months (mo). With frontline VEN+ HMA, 19 pts (46%) achieved CR, 11 pts (27%) achieved CRi, 3 pts (7%) achieved morphologic leukemia free state (MLFS), and 8 pts (20%) had primary refractory disease. Pts obtaining initial response relapsed after a median duration of response (DOR) of 5.3 mo (range 0.9-34.1). After VEN+ HMA failure, median OS for all 41 pts was 2.4 mo (range 0.1-21.2, Fig 2a). Pts who received salvage therapy (n=24) had longer OS compared to pts who did not receive salvage therapy (n=17, 2.9 vs 1.3 mo, HR=0.41, 95% CI 0.19-0.88, p=0.003, Fig 2b). Median OS for de novo AML at relapse/failure was 2.5 mo, for sAML was 2.8 mo, and for t-AML was 1.1 mo (Fig 2c). Pts with primary refractory AML vs relapsed AML had comparable OS of 1.7 mo vs 2.3 mo, respectively (Fig 2d). Of the 24 pts who received salvage therapy (Table 2, Fig 2e), 5 pts (21%) responded; CR in 1 pt, CRi in 2 pts and MLFS in 2 pts. Among 3 pts with primary refractory AML, 1 pt achieved CR and 1 pt achieved MLFS. Among 21 pts with relapse after VEN+HMA, 2 pts achieved CRi and 1 pt achieved MLFS. 8 pts received IC, and 2/8 pts (notably both with NRASmut) achieved CR and CRi with CLIA, and CLIA + gemtuzumab ozogamicin, respectively. 7 pts received HMA-based regimens, and 2/7 pts responded with CRi and MLFS with AZA + quizartinib, and AZA + nivolumab + ipilimumab, respectively. The former pt had FLT3-ITD and NRASmut and the latter pt had TP53mut. Of the remaining 9 pts receiving other therapies, 1 pt with FLT3-ITD achieved a MLFS with quizartinib + low-dose ara-c. These 5 responding pts continue in remission with median DOR not reached (NR, range 0.7-20.1, Fig 2f) and OS also NR (range, 2-21.2). All pts with NPM1mut and IDH1/2mut who relapsed had adverse-risk cytogenetics or co-occurring mutations in TP53, N/KRAS, FLT3, and/or KIT. Of FLT3-ITDmut pts, 2 of 5 pts (40%) responded to salvage therapy including a FLT3i. Of 11 RASmut pts, 3 pts (27%) responded to salvage therapy including both IC and HMA-based regimens. 1 of 6 TP53mut pts receiving salvage therapy achieved MLFS with AZA + nivolumab + ipilimumab. This pt was also the only one among 7 pts with complex cytogenetics who responded to salvage therapy. Conclusion: Older IC-ineligible pts with ND AML who fail frontline VEN+HMA have high-risk disease biology including t-AML, sAML, complex cytogenetics, FLT3-ITD, TP53mut, N/KRASmut. These known high-risk features decrease likelihood of response and confer poor OS, confirmed in this analysis. The median OS after frontline VEN+HMA failure was 2.4 mo. Notably some pts with FLT3-ITD responded well to salvage regimens with FLT3i. Novel therapies to abrogate VEN resistance, especially in high risk genotypes, are urgently needed. Disclosures Maiti: Celgene: Other: research funding. Cortes:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Daver:Immunogen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Servier: Research Funding; Abbvie: Consultancy, Research Funding; Forty-Seven: Consultancy; Glycomimetics: Research Funding; Celgene: Consultancy; Astellas: Consultancy; Immunogen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; Celgene: Consultancy; NOHLA: Research Funding; Agios: Consultancy; Otsuka: Consultancy; BMS: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Servier: Research Funding; Glycomimetics: Research Funding; Pfizer: Consultancy, Research Funding; NOHLA: Research Funding; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Agios: Consultancy; Karyopharm: Consultancy, Research Funding; Forty-Seven: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Borthakur:AstraZeneca: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; NKarta: Consultancy; Cyclacel: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Strategia Therapeutics: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; GSK: Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; AbbVie: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jain:Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Cyclacel: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Astex: Research Funding; BMS: Research Funding. Konopleva:Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding. DiNardo:jazz: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; medimmune: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; daiichi sankyo: Honoraria.

Abstract: Background: Elderly patients (pt) with acute myeloid leukemia (AML) or pts with relapsed/refractory (R/R) AML have dismal outcomes. Venetoclax (VEN) synergizes with hypomethylating agents (HMA) and is now an approved combination for newly diagnosed (ND) AML in older/intensive chemotherapy (IC)-ineligible patients. We hypothesized that VEN with 10-day decitabine (DEC) may offer superior efficacy in AML. Methods: Between January and November 2018 we enrolled 101 pts with ND AML (n=40), untreated secondary AML (sAML, n=9), treated sAML (n=19) and R/R AML (n=33). Eligibility included ECOG PS ≤3, WBC ≤10 x109/L, and adequate organ function. DEC was given 20 mg/m2 IV daily on day 1-10 until CR/CRi, followed by 5-day cycles. VEN was given on day 1-28 in cycle 1 but was interrupted on C1D21 until count recovery if the day 21 bone marrow (BM) had ≤5% blasts. VEN could be reduced further to 14, 10 or 7 days in subsequent cycles for pts with ongoing cytopenias/myelosuppression. VEN dose was 400 mg PO daily (reductions allowed for concomitant CYP3A4 inhibitors) All pts received tumor lysis syndrome (TLS) prophylaxis. Cytoreduction prior to start, and concomitant BCR-ABL1 (n=1) and FLT3 inhibitors (n=15) were allowed as indicated. Primary objective was overall response rate and secondary objectives included safety and overall survival. The data cut-off date was 03.08.19. Results: This high-risk cohort included 52% of pts ≥70 yrs (interquartile range [IQR], 61-74), 54% pts were men, 28% pts had ECOG PS ≥2, and 67% pts had adverse-risk AML (Table 1). 30 and 60-day mortality were both 2.5% for ND pts, and 5% and 9%, respectively, for all pts. Notable treatment-emergent adverse events were infections with grade 3/4 neutropenia (61%), febrile neutropenia (35%), and TLS (4%, Table 2). Four pts developed grade 3 or 4 reversible TLS; their median WBC count was 7.1x109/L (1.6, 2.1, 12, 28) and median peripheral blasts was 64% (IQR 39-83) and led to a subsequent requirement for WBC ≤10 x109/L prior to start. The CR/CRi rate in ND AML was 95%, in untreated sAML was 67%, in treated sAML was 37%, and in R/R AML was 27% (Table 3). Out of 67 pts with C1D21±3 BM, ≤5% blasts was achieved in 57%, and 74% of ND pts. In previously untreated AML (defined as ND AML + untreated sAML), CR/CRi rate in ELN favorable, intermediate and adverse risk pts were 100% (n=11), 100% (n=6), and 84% (n=32). CR/CRi rate in t-AML was 100% (n=7). In previously treated AML (treated sAML + R/R AML), CR/CRi rate in HMA refractory pts was 39% (n=18), in pts with prior IC was 21% (n=33), in pts with prior HMA and IC was 17% (n=12), in pts with prior stem cell transplantation (SCT) was 22% (n=18). At median follow-up of 8.1 months (mo), the 6-mo OS in ND AML was 90%, in untreated sAML was 56%, in treated sAML was 62%, and R/R AML was 53% (Fig. 1). Among all pts, achievement of CR conferred better duration of response (DOR) and OS compared to CRi/MLFS (median DOR not reached [NR] vs 4.0 mo, censored at SCT, hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.09-0.49, p=0.002, and median OS NR vs 7.8 mo, censored at SCT, HR 0.31, 95% CI 0.13-0.74). 70% of all responding pts were minimal residual disease negative (MRD-) by flow cytometry and MRD- status was associated with longer OS (NR vs 7.8 mo, censored at SCT, HR 0.35, 95% CI 0.14-0.88, p=0.01, Fig. 2a). Median DOR in pts achieving CR/CRi in ND AML was 8.5 mo, in the untreated sAML was 6.3 mo, in treated sAML was 4.8 mo, and in R/R AML was 6.6 mo. Among ND AML pts achieving CR/CRi, median time to count recovery after 1st, 2nd and 3rd cycles for ANC 〉 0.5x109/L was 42 days (95% CI 37-46), 40 days (95% CI 35-44), and 38 days (95% CI 32-NR), respectively; and for platelet ≥50 x109/L was 28 days (95% CI 25-32), 25 days (95% CI 0-34), and 26 days (95% CI 19-33), respectively. 78 pts (77%) discontinued treatment, and 59 pts (58%) are alive. Common reasons for discontinuation were non-response in 24 pts (24%), SCT in 20 pts (20%), and relapse in 18 pts (18%). Pts receiving SCT (n= 20) had excellent outcomes with 100-day post-SCT mortality of 0% (Fig 2b and c). Baseline BCL2 expression in CD34+ blasts showed a trend between higher BCL2 expression and MRD- rate (Fig. 2d). Conclusions: DEC10-VEN is an effective therapy for ND elderly pts, as well as in R/R AML as an effective bridge to SCT. Trial continues to accrue (NCT03404193). Disclosures Maiti: Celgene: Other: research funding. DiNardo:jazz: Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Daver:Pfizer: Consultancy, Research Funding; Servier: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jazz: Consultancy; Servier: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Astellas: Consultancy; Incyte: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Glycomimetics: Research Funding; Agios: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Incyte: Consultancy, Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Celgene: Consultancy; Agios: Consultancy; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Otsuka: Consultancy; Pfizer: Consultancy, Research Funding. Ravandi:Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding. Garcia-Manero:AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding. Borthakur:BMS: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Novartis: Research Funding; Strategia Therapeutics: Research Funding; Cyclacel: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; PTC Therapeutics: Consultancy; Arvinas: Research Funding; Oncoceutics: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Xbiotech USA: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Cantargia AB: Research Funding; NKarta: Consultancy; Agensys: Research Funding; Polaris: Research Funding; Oncoceutics, Inc.: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi:Symbio Pharmaceuticals: Consultancy. Jain:Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff:Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Bose:Blueprint Medicine Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Ariad: Research Funding. Konopleva:Forty-Seven: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Ablynx: Research Funding; Kisoji: Consultancy, Honoraria; Astra Zeneca: Research Funding; Ascentage: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding.

Abstract: Background: Acute myeloid leukemia (AML) remains a therapeutic challenge in elderly or unfit patients (pts) and high-risk subgroups. DEC10-VEN has shown high efficacy in these pts. However, outcomes in specific mutational subgroups are unknown. Here we present the results in mutational subgroups and resistance patterns in pts treated with DEC10-VEN (NCT03404193). Methods: This single-institution phase II study enrolled pts with newly diagnosed (ND) AML ( & gt;60 years) ineligible for intensive chemotherapy, relapsed or refractory (R/R) AML, and secondary AML (sAML) with or without prior therapy. DEC was given 20 mg/m2 IV daily on day 1-10 until CR/CRi, followed by 5-day cycles. VEN was given for 21-28 days in cycle 1 and day 1-21 or shorter duration thereafter. BCR-ABL1 and FLT3 inhibitors (FLT3i) were allowed as appropriate. Amplicon-based next-generation sequencing targeting the entire coding regions of 81 myeloid genes was performed on screening bone marrow aspirate with a MiSeq platform. The analytical sensitivity was established at 5% mutant reads in a background of wild type reads. Previously described somatic mutations registered in COSMIC were considered as potential driver mutations. Results: High response rates were noted across mutational subgroups of both previously untreated and previously treated AML (Table 1 and 2). The median follow-up for the entire cohort was 8.1 months (mo). In previously untreated AML (ND AML and untreated sAML, n=49), the CR/CRi rate in NPM1mut pts was 100% (n=13), in RUNX1mut pts was 100% (n=8), in IDH1/2mut pts was 92% (n=12), in TP53mut pts was 85% (n=13), and in N/KRASmut pts was 77% (n=13, Table 1). The median overall survival (OS) among previously untreated NPM1mut pts was not reached (NR), for RUNX1mut pts was NR, for IDH1/2mut pts was 12.4 mo, for TP53mut pts was 5.8 mo, and for N/KRASmut was 12.4 mo. The median DOR for NPM1mut pts was 8.5 mo, for RUNX1mut pts was NR, for IDH1/2mut pts was NR, for TP53mut pts was 5.7 mo, and for N/KRASmut pts was 6.7 mo (Table 1). The one pt with NPM1mut who relapsed had co-occurring ASXL1mut and NRASmut at screening. In previously treated AML (treated sAML and R/R AML, n=52), the CR/CRi rate in NPM1mut pts was 60% (n=10), in IDH1/2mut pts was 50% (n=8), and in TP53mut pts was 21% (n=14, Table 2). The median OS for NPM1mut pts was NR, for IDH1/2mut pts was 7.8 mo, and for TP53mut pts was 4.5 mo. The median DOR for NPM1mut pts was NR, for IDH1/2mut pts was NR, and for TP53mut pts was 3.2 mo (Table 2). The only grade 4 TLS event occurred in a pt with NPM1mut and IDH2mut and baseline WBC of 28x109/L. 2 other pts with high % of PB blasts and FLT3mut experienced grade 3 TLS. Among 15 pts with FLT3-ITD/TKD, 8 pts received sorafenib, 5 pts received midostaurin, and 2 pts did not receive FLT3i (1 insurance non-approval and 1 very low ITD ratio). Among ND FLT3mut AML pts (n=7), the CR/CRi rate was 100% (n=5) in pts receiving FLT3i with negative MRD by flow cytometry (FCM) in 80% pts, with median OS of 8.8 mo and median DOR not reached (Table 1). Of the 2 FLT3-ITD pts not receiving FLT3i, 1 pt with FLT3-ITD of 0.47 did not respond, and 1 pt with low FLT3-ITD of 0.02 achieved CR MRD-. Among previously treated FLT3mut pts (n=8), all received FLT3i with a CR/CRi rate of 38% (n=5) and negative MRD by FCM in 75% pts tested (3/4). The median OS was 6.4 mo and the median DOR was 6.6 mo (Table 2). 2 pts had received prior FLT3i, 1 pt achieved morphologic leukemia-free state (MLFS), and the other pt did not respond. 1 pt with new t(9;22) identified at 4th relapse achieved a MLFS after 1 cycle with addition of ponatinib and transitioned to allogeneic transplant. Overall, pts with durable CR/CRi/MLFS sustained without relapse till data cut-off, had significantly higher proportion of mutations in NPM1 and DNA methylation pathways (DNMT3A, TET2, IDH1/2) compared to pts refractory to, or relapsing after DEC10-VEN (Table 3, Fig. 1). Pts with relapsed or refractory disease to DEC10-VEN had significantly higher frequency of N/KRASmut, ASXL1mut, and TP53mut compared to pts with durable CR/CRi/MLFS (Table 3, Fig. 1). TP53mut associated with worse OS on multivariable analysis (HR 2.9, 95% CI 1.4-5.7, p=0.003). Conclusion: DEC10-VEN is an effective regimen for AML. Addition of FLT3i to DEC10-VEN was safe and may improve upon responses in FLT3mut pts. Mutations in NPM1 and DNA methylation pathways were associated with more durable responses while mutations in ASXL1, RAS and TP53 were associated with refractory disease or relapse. Disclosures Maiti: Celgene: Other: research funding. Cortes:BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria. Pemmaraju:samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria, Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding. Daver:Servier: Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Immunogen: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz: Consultancy; Jazz: Consultancy; NOHLA: Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy; NOHLA: Research Funding; Celgene: Consultancy; Otsuka: Consultancy; Glycomimetics: Research Funding; Novartis: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Pfizer: Consultancy, Research Funding. Ravandi:Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Borthakur:Cyclacel: Research Funding; AbbVie: Research Funding; Eli Lilly and Co.: Research Funding; Xbiotech USA: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Janssen: Research Funding; NKarta: Consultancy; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; Incyte: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Oncoceutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; GSK: Research Funding; BMS: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Novartis: Research Funding; Eisai: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:AbbVie: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi:Symbio Pharmaceuticals: Consultancy. Jain:Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff:NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; AstaZeneca: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Bose:CTI BioPharma: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; BMS: Consultancy, Research Funding. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Daiichi-Sankyo: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding. DiNardo:agios: Consultancy, Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria; jazz: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria. OffLabel Disclosure: FLT3 inhibitors, used in combination with decitabine and venetoclax