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The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (ClinicalTrials.gov identifier: NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplantation. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days per 28-day cycle. We evaluated relapse-free survival (RFS) and overall survival (OS) in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms; MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data; 137 patients (29.2%) had NPM1 mutations (NPM1mut), 66 patients (14.1%) had FLT3 mutations (FLT3mut; with internal tandem duplications [ITD], tyrosine kinase domain mutations [TKDmut], or both), and 30 patients (6.4%) had NPM1mut and FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.41-0.98) and 45% (HR, 0.55; 95% CI, 0.35-0.84), respectively, vs placebo. Median OS was improved numerically with Oral-AZA among patients with NPM1mut whether without MRD (48.6 months vs 31.4 months with placebo) or with MRD (46.1 months vs 10.0 months with placebo) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR, 0.63; 95% CI, 0.35-1.12) and 49% (HR, 0.51; 95% CI, 0.27-0.95), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 months vs 16.2 months, respectively, for patients with FLT3mut and without MRD and 24.0 months vs 8.0 months for patients with FLT3mut and MRD. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status.

Mutations in the nucleophosmin 1 gene (NPM1) occur frequently in acute myeloid leukemia (AML) and are associated with a favorable prognosis. Applying the new 2022 European LeukemiaNet (ELN) classifier, Angenendt et al tested the prognostic significance of the copresence of NPM1 mutations and adverse-risk cytogenetics among 2426 patients. The authors demonstrate that outcomes for cytogenetic adverse-risk AML are not modulated by the presence or absence of NPM1 mutations, thereby clarifying management for patients.

Background Midostaurin, a multikinase inhibitor with significant activity against FLT3, was approved in combination with chemotherapy (CT) for treatment of pts with newly diagnosed (ND) FLT3-mutated AML based on the CALGB 10603/RATIFY trial (NCT00651261; Stone et al, NEJM 2017). The A2408 study (NCT03379727) confirmed the efficacy/safety of midostaurin in FLT3-mutated AML and extended the findings to older pts (≥60 y) and different CT regimens (Sierra et al, ASH 2020). As midostaurin inhibits both mutant and wild-type (WT) FLT3 (Weisberg et al, Cancer Cell 2002), the UNIFY trial (NCT03512197) was conducted to evaluate midostaurin in FLT3-mutation negative (MN) AML. Here, we report clinical outcomes and MRD results from UNIFY. Methods This randomized, double-blinded, multicenter, placebo (PBO)-controlled, ph 3 study evaluated midostaurin + CT in pts with ND FLT3-MN (mutant to WT signal ratio Results UNIFY was stopped in Sep 2019 on the recommendation of the data monitoring committee, based on an interim analysis of EFS (N = 359; HR, 1.08 [95% CI, 0.78-1.5]; data cutoff, 15 May 2019) that met the futility criterion. Final analysis occurred after the last pt discontinued and the study was closed (data cutoff, 31 Mar 2021). 501 pts were randomized to midostaurin (n = 250) or PBO (n = 251). Median age was 56 y (54% MRD was analyzed irrespective of treatment because no difference in MRD− rates was found between midostaurin and PBO (Table). Among randomized pts, 205 (41%) were MRD− ( Conclusion Results from UNIFY are consistent with the safety/tolerability profile previously reported for midostaurin, but do not show efficacy for midostaurin in FLT3-MN AML; this suggests that the clinical effect of midostaurin in AML is primarily in the FLT3-mutated setting. Exploratory MRD analyses (to be interpreted with caution due to limited follow-up, as the study was stopped 1.2 y after first pt was randomized) suggest a trend toward longer survival for pts in remission who are MRD− at the end of IND and support the utility of assessing MRD via a combined LAIP/DfN approach. Figure 1 Figure 1. Disclosures Cloos: Takeda: Research Funding; Helsinn: Other: MRD assessments; Navigate: Patents & Royalties: Royalties for MRD analyses; DC-One: Other: MRD assessments, Research Funding; Genentech: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Other: MRD assessments, Research Funding; Astellas: Speakers Bureau; Merus: Other: MRD assessments, Research Funding. Montesinos: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Glycomimetics: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Fiedler: Daiichi Sankyo: Consultancy, Other: support for meeting attendance; Pfizer: Consultancy, Research Funding; Celgene: Consultancy; Morphosys: Consultancy; Abbvie: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Other: support for meeting attendance; Amgen: Consultancy, Other: support for meeting attendance, Patents & Royalties, Research Funding; Servier: Consultancy, Other: support for meeting attendance; Stemline: Consultancy; Novartis: Consultancy; ARIAD/Incyte: Consultancy. Müller: GSK: Consultancy; Janssen: Other: Honoraria for educational event; Celgene/BMS: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Amgen: Honoraria; Sandoz/Novartis: Honoraria; Sanofi: Honoraria; Takeda: Honoraria. Sica: Pfizer: Honoraria. Westermann: Astellas: Honoraria; Pfizer: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Stem Cell Line: Consultancy, Honoraria. Döhner: Pfizer: Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Berlin-Chemie: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ulm University Hospital: Current Employment; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria. Levis: Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; BMS: 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; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; Astellas and FujiFilm: Research Funding; Takeda: Honoraria. Ossenkoppele: Jazz: Consultancy, Honoraria; Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; Agios: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Stone: Astellas: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Bristol Myers Squibb: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Innate: Consultancy; Janssen: Consultancy; Jazz: Consultancy; Celgene: Consultancy; Boston Pharmaceuticals: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Gemoab: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Macrogenics: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding. Koenen: Novartis Pharma AG: Current Employment. Bengoudifa: Novartis Pharma AG: Current Employment. Cheng: Novartis Pharmaceuticals Corporation: Current Employment. Medts: Novartis Pharma AG: Current Employment. Heidinger: Novartis Pharma AG: Current Employment. Sachs: Novartis Pharma AG: Current Employment. Sierra: Janssen: Other: Educational grant; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Other: Educational grant; Amgen: Other: Educational grant; Pfizer: Honoraria; BMS Celgene: Honoraria, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Alexion: Other: Educational grant; Jazz Pharmaceuticals: Research Funding.

Background: Alvocidib is an investigational cyclin-dependent kinase-9 (CDK9) inhibitor that can suppress RNA polymerase II-mediated transcription of genes implicated in leukemia cell survival, including myeloid leukemia cell-1 (MCL-1). MCL-1 is an anti-apoptotic BCL-2 family member that is a key mediator of apoptosis in AML. Alvocidib combined in a timed-sequential regimen with cytarabine and mitoxantrone (ACM) has shown clinical activity in newly diagnosed and relapsed/refractory (R/R) AML through Phase I and II clinical trials. Analysis of bone marrow samples from newly diagnosed AML patients (pts) treated with ACM showed an association of complete remission (CR) with MCL-1 dependence by a BH3 profiling biomarker assay. Zella 201 was initiated based on the hypothesis that ACM may have preferential clinical activity in pts with MCL-1 dependence. We report the findings from an exploratory cohort of newly diagnosed high-risk (NDHR) AML pts with MCL-1 dependence treated with ACM. Methods: Zella 201 is a biomarker-driven Phase II study of ACM in R/R AML patients with MCL-1 dependence. Stage 1 included a cohort of R/R AML pts with various levels of MCL-1 dependence and an exploratory cohort of NDHR AML with MCL-1 dependence >40%, as determined by a BH3 profiling assay. Eligibility criteria for the NDHR cohort included pts 18-65 years with high-risk AML defined as one of the following: A) treatment-related AML, B) AML from preexisting MDS/MPN, C) adverse-risk by ELN 2017 criteria. Induction therapy consisted of alvocidib 30 mg/m2 as a 30 minute IV bolus followed by 60 mg/m2 over 4 hours on Days (D) 1-3, cytarabine 667 mg/m2/D by continuous IV infusion D6-8, and mitoxantrone 40 mg/m2 IV on D9. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permitted in responders. The primary endpoint was CR/CRi. Key secondary endpoints were overall survival (OS), relapse-free survival (RFS), overall response rate and safety. Results: Thirteen NDHR pts were treated and evaluable in this cohort (Table 1). One pt received alvocidib on days 1-3 and withdrew from the study on day 6 due to grade 4 diarrhea, cytokine release syndrome, and acute kidney injury. This pt was excluded from the efficacy analysis. Median MCL-1 score was 56% (Range: 42-70%). This cohort was influenced by the following poor risk categories: secondary AML (n= 9; 69%), adverse-risk by ELN (n=8; 62%) and TP53 mutations (n=6; 46%). The most common ≥Grade 3 treatment-emergent non-hematologic AEs (n=14) were diarrhea (29%); TLS, hypocalcemia, sepsis, hypotension (21%), pneumonia, colitis, hyperglycemia, anorectal infection, dyspnea, and left ventricular dysfunction (all 14%). Overall, CR/CRi was 62% with 7 (54%) pts responding following 1 cycle of therapy and another pt achieving CR after a second cycle. Two of six pts with TP53 mutation achieved CR. Although all pts included in this cohort were determined to be MCL-1 dependent, there was no association of CR with increasing MCL-1 dependence. Six (46%) pts went on to an allogeneic stem cell transplant (SCT). Sixty-day mortality was 0%. Median follow-up, OS, and RFS were 8.0, 8.5, and 6.1 months, respectively. Five of 8 (68%) CR/CRi pts have relapsed, and 10 pts (77%) have expired to date. The three pts still alive all received a post-study SCT. Conclusion: ACM has clinical activity in a limited cohort of NDHR AML pts with MCL-1 dependence scores >40% in a biomarker assay. Despite observed CR rates, duration of CR was modest and overall outcomes were poor. These results are comparable to historical controls with conventional chemotherapy regimens given the high-risk subset (62% of pts had adverse-risk and 46% had TP53 mutations). Further study is warranted to better define subgroups of ND AML pts who may benefit from alvocidib-containing induction regimens. Disclosures Zeidner: AsystBio Laboratories: Consultancy; AROG: Research Funding; Forty-Seven: Other: Travel Reimbursement, Research Funding; Merck: Research Funding; Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Daiichi Sankyo: Honoraria; Genentech: Honoraria; Pfizer: Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Reimbursement, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Other: Independent Review Committee; Agios: Honoraria. Lee:Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bayer: Research Funding; AbbVie: Research Funding; Celgene: Consultancy. Fine:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Wang:Bristol Meyers Squibb (Celgene): Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Pfizer: Speakers Bureau; Genentech: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy. Bhatt:Incyte: Consultancy, Research Funding; Oncoceutics: Other; National Marrow Donor Program: Research Funding; Jazz: Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding. Kolibaba:Verastem: Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Compass Oncology: Ended employment in the past 24 months; Seattle Genetics: Research Funding; Atara Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma Oncology, Inc.: Consultancy, Other: Travel, Accommodations, Expenses Paid; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; McKesson Life Sciences: Consultancy; Cell Therapeutics: Research Funding; Pharmacyclics: Research Funding. Anthony:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment; Exact Sciences: Consultancy. Bearss:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background : For patients (pts) with acute myeloid leukemia (AML), preserving and measuring perceptions of health-related quality of life (HRQoL) is important, particularly for those ineligible for intensive chemotherapy and with a poor prognosis, especially when evaluating new treatment regimens. This analysis from 2 Phase 3 trials, Viale-A (NCT02993523) and Viale-C (NCT03069352), evaluated HRQoL, including key symptoms and aspects of functioning, in pts with AML receiving venetoclax (VEN) co-administered with azacitidine (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C). Methods: Viale-A and Viale-C included treatment-naïve pts with AML, ≥18 years of age, and ineligible to receive intensive chemotherapy. Pts were randomized 2:1 to receive VEN +AZA or placebo (PBO)+AZA in Viale-A, and VEN+ LDAC or PBO+LDAC in Viale-C. Pt-reported outcome (PRO) measures included the PROMIS Cancer Fatigue Short Form 7a, the EORTC QLQ-C30 global health status (GHS)/QoL and physical functioning [PF] subscales, and the EQ-5D-5L health status visual analog scale (VAS). PRO data were collected on Day 1 of every 28-day cycle throughout both trials. Time to deterioration (TTD) was assessed to quantify differences between treatment groups. TTD was defined as worsening from baseline in PRO-specific meaningful change thresholds of ≥10, 7, or 5 points for the EORTC-QLQ-C30, EQ-5D-5L VAS, and PROMIS Fatigue, respectively. TTD differences between treatment arms were analyzed using Kaplan-Meier curves, unadjusted log-rank tests, and Cox PH models adjusted for key covariates (age, baseline ECOG and PRO scores, AML type, and cytogenetic risk category). TTD analyses were conducted for all pts in the full dataset who survived up to a given assessment with available data on ≥1 PRO measures from baseline. Results: Viale-A included 431 pts (VEN+AZA: 286, PBO+AZA: 145), of whom 60% were male; median age was 76 years. Compared with PBO+AZA pts, VEN+AZA pts had a non-statistically significant trend to longer TTD in GHS/QoL (median in months [95% CI]: 16.5 [95% CI: 9.8, NE] vs. 9.3 [95% CI: 4.7, 16.6], P=0.066) and fatigue (9.3 [7.2, 16.6] vs. 8.6 [4.2, 16.6], P=0.189) (Figure 1A, B). VEN+AZA pts had significantly longer TTD in PF (9.7 [6.7, 16.0] vs. 6.2 [4.7, 9.5], P=0.028) and health status VAS (10.7 [7.5, 18.6] vs. 3.9 [2.4, 7.4], P Conclusions: Results showed a longer TTD in PRO measures of global health status, VAS, fatigue, and PF for pts receiving VEN combinations vs AZA or LDAC monotherapy, with significantly longer TTD observed for all PRO measures from the unadjusted and adjusted analyses in Viale-C, and for PF and health VAS in Viale-A. These results suggest that VEN conveys meaningful benefit in terms of HRQoL. Limitations included the small sample size beyond early cycles in these studies; however, the early separation of the TTD curves with the initial larger sample size, suggests that these results are not due to chance variability and are statistically valid. Overall the improvements in PROs with VEN are consistent with previous efficacy reports. In summary, VEN appears to have a positive impact on the HRQoL of pts with AML who are ineligible for intensive chemotherapy, leading to a longer preservation of functioning and overall health status. Disclosures Pratz: Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Celgene: Other: Scientific Advisory Board; Boston BioMedical: Consultancy; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy. Panayiotidis:AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Genesis: Honoraria, Research Funding; Takeda: Honoraria; Phizer: Honoraria; ASH: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Jonas:AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Daiichi Sankyo: Research Funding; Genentech/Roche: Research Funding; Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; LP Therapeutics: Research Funding; Forma: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Jazz: Consultancy, Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Hanmi: Research Funding; Takeda: Consultancy. Dinardo:Takeda: Honoraria; Celgene: Research Funding; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Calithera: Research Funding; ImmuneOnc: Honoraria. Novak:Janssen: Other: Travel expenses; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Other: Travel expenses; Takeda: Consultancy. Pejsa:Oktal Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alvogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pliva: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: 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. Stevens:Amgen, MorphoSys: Consultancy. Yeh:Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Kim:AbbVie: Other: Clinical trials investigator. Fracchiolla:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Yamamoto:Takeda: Consultancy, Honoraria, Research Funding; Yakult: Research Funding; Zenyaku: Research Funding; SymBio: Research Funding; Solasia Pharma: Research Funding; Aichi Cancer Center: Current Employment; AbbVie: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; IQIVA/HUYA: Honoraria; HUYA: Consultancy; IQIVA/Incyte: Research Funding; Gilead Sciences: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria; Mochida: Honoraria; MSD: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Sanofi: Honoraria; Sumitomo Dainippon: Honoraria; Stemline Therapeutics: Consultancy. Ofran:AbbVie: Membership on an entity's Board of Directors or advisory committees. Wei:Astra Zeneca: Honoraria, Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Novartis: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Macrogenics: Honoraria; Roche: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Janssen: Honoraria; Abbvie: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau. Bui:AbbVie: Current Employment, Current equity holder in publicly-traded company. Benjamin:AbbVie: Current Employment, Current equity holder in publicly-traded company. Kamalakar:AbbVie: Current Employment, Other: may hold stock or other options. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Mendes:AbbVie: Current Employment, Current equity holder in publicly-traded company. Devine:Genentech: Current Employment, Current equity holder in publicly-traded company. Fiedler:Daiichi Sankyo: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Jazz Pharmaceuticals: Honoraria, Other: support for meeting attendance; Abbvie: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; ARIAD/Incyte: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: support for meeting attendance, Patents & Royalties, Research Funding.

Background: In the Phase 3 randomized, placebo-controlled VIALE-A study, venetoclax (Ven) + azacitidine (Aza) improved overall survival (OS) and complete response (CR) rates vs Aza + placebo (Pbo; DiNardo et al. N Engl J Med. 2020. In Press). Neutropenia and related infections are common in acute myeloid leukemia (AML) and exacerbated by Ven combinations. Antimicrobial prophylaxis is used variably in patients (pts) with AML receiving low-intensity therapies. Ven dose modifications are required for concomitant use of commonly used antimicrobials that are strong or moderate cytochrome P450 3A inhibitors (CYP3Ai). A previous report's findings showed that Ven dose reductions with CYP3Ai do not affect Ven exposure (Wei et al. Blood. 2020;135:2137). This analysis evaluated the use of prophylactic anti-infective CYP3Ai and these agents' effects on infections and efficacy outcomes in the VIALE-A study (NCT02993523). Methods: Pts with newly diagnosed AML, aged ≥75 y or 18-75 yand ineligible for induction therapy were enrolled. Pts were randomized 2:1 to receive Ven (daily, orally) + Aza (75 mg/m2 d 1-7, subcutaneously/intravenously) or Pbo + Aza in 28-d cycles. Anti-infective prophylaxis was required for pts with absolute neutrophil count Results: In total, 286 pts were randomized to Ven + Aza and 145 to Pbo + Aza. Within the first 2 cycles of therapy, concomitant anti-infective prophylaxis agents considered moderate CYP3Ai were received by 41/286 pts (14%) in the Ven + Aza arm and 18/145 (12%) in the Pbo + Aza arm. Concomitant anti-infective prophylaxis agents considered strong CYP3Ai were received in the first 2 cycles by 22/286 pts (8%) treated with Ven + Aza and 13/145 pts (9%) treated with Pbo + Aza. The median duration of each prophylactic CYP3Ai agent use was 12.5 d (range, 1-614) in the Ven + Aza arm and 15 d (range, 1-731) in the Pbo + Aza arm. The rates of CR+CR with incomplete marrow recovery (CRi) as a best response during the study were similar with concomitant use of moderate (61%; CR, 24%; CRi, 37%) or strong (64%; CR, 27%; CRi, 36%) CYP3Ai with adjusted-dose Ven vs no use of CYP3Ai (67%; CR, 39%; CRi, 27%; Table 1). The relatively lower CR and higher CRi rates appear to be due to delay in recovery of peripheral blood counts in pts who received strong CYP3Ai during the first 2 cycles (Table 2). The median time to first CR+CRi was 1.2 mo (range, 0.6-9.9), 1.4 mo (range 1.0-5.5), and 1.4 mo (range, 0.9-5.4) in those receiving no, moderate, and strong CYP3Ai agents, respectively, in the Ven + Aza arm. Median OS was not statistically different regardless of use of moderate or strong CYP3Ai in both arms, as noted by overlapping CIs (Table 1). The 24-month estimated OS was 26.2% (95% CI, 8.1-48.9) for pts receiving strong CYP3Ai vs 37.9% (95% CI, 30.2-45.6) for those receiving no CYP3Ai. Rates of any-grade or Grade 3/4 infections within the first 2 cycles varied between those with or without use of moderate CYP3Ai reported as being given as prophylaxis in both treatment arms (Table 1). Rates of invasive fungal infections were 3%, 12%, and 9% with Ven + Aza and 0%, 0%, and 15% with Pbo + Aza in pts receiving no, moderate, and strong CYP3Ai agents, respectively. Rates of discontinuation from infections were similar in both arms regardless of CYP3Ai use. Conclusions:Antimicrobial prophylaxis with moderate or strong CYP3Ai was used in neutropenic pts in the VIALE-A study, with overall similar composite remission rates with Ven dose reductions. The use of CYP3Ai did not increase rates of discontinuation from infections. Analysis of differences in baseline characteristics, rates of infections, and efficacy outcomes for pts who began anti-infective prophylaxis at the initiation of therapy is ongoing. Disclosures Jonas: Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Genentech/Roche: Research Funding; Sigma Tau: Research Funding; Hanmi: Research Funding; Pfizer: Research Funding; LP Therapeutics: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding. Dinardo:Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Calithera: Research Funding; Celgene: Research Funding; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria. Fracchiolla:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Pristupa:Beigene: Honoraria, Research Funding; State Institution of Health of the Ryazan Regional Clinical Hospital: Current Employment; Pfizer: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Research Funding; Paraxel: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Geron: Honoraria, Research Funding. Ishizawa:Takeda: Honoraria; Ono: Honoraria; Chugai: Honoraria; Eizai: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; SymBio: Research Funding; Bayer: Research Funding; AbbVie: Research Funding. Jin:The First Affiliated Hospital of Zhejiang University: Current Employment. Konopleva:Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding; Calithera: Research Funding; Kisoji: Consultancy; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy; Ascentage: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding. Ofran:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Rambam Health Care: Current Employment; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy. Kovacsovics:Pfizer: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Jazz: Honoraria; Astella: Honoraria; Agios: Honoraria. Kantarjian:Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oxford Biomedical: Honoraria; Janssen: Honoraria; Delta Fly: Honoraria; BioAscend: Honoraria; Jazz: Research Funding; Abbvie: Honoraria, Research Funding; Sanofi: Research Funding; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Ascentage: Research Funding. Hong:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Ainsworth:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Werner:AbbVie: Current Employment, Current equity holder in publicly-traded company. Svensson:AbbVie: Current Employment, Current equity holder in publicly-traded company. Pratz:Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy; Celgene: Other: Scientific Advisory Board; Boston BioMedical: Consultancy; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding.

Background: Evaluation of MRD is standard in patients with AML. However, the role of decentralized MRD assessment for risk stratification in AML remains largely unknown, and so it does which methodological aspects are critical to empower the evaluation of MRD with prognostic significance, particularly if using MFC. Aim: To evaluate the role of decentralized MRD assessment using MFC for risk stratification and putative treatment individualization of patients with AML. Methods: This study was performed on 1,076 AML patients in complete remission (CR) after 7+3 induction chemotherapy, in whom MRD was evaluated by MFC in local laboratories over a period of 20 years in the PETHEMA group. We conducted a survey of technical aspects of MFC based MRD testing in the laboratories of the 60 participating Hospitals, to determine the impact of methodological heterogeneity in the prognostic value of MFC. Results: We first investigated the most effective MRD cutoff to stratify patients' risk at first remission. Patients were segmented into progressively higher cutoffs, starting at 0.01% followed by 0.05%, 0.1%, 0.5% and 1%. Our results showed that 0.1% reached higher statistical significance to discriminate patients with different relapse-free survival (RFS, HR: 0.77; P = .001) and overall survival (OS, HR: 0.73; P = .001). In multivariate analyses together with patients' age, WBC, genetic risk and post-consolidation therapy, MRD status was selected as an independent prognostic factor for OS. To further define the utility of "real-world" MRD assessment using MFC in risk stratification of AML, recursive partitioning was performed using the prognostic and treatment related factors selected in the multivariate Cox model for OS. Of the four variables evaluated, hematopoietic stem cell transplantation (HSCT, regardless of autologous or allogeneic source) vs no transplant emerged as the best single discriminator for OS, followed by genetic risk, age and MRD status. There were two branching points defined by MRD status; the first in patients ≤60 years with intermediate genetic risk who were not transplanted and the second in patients with adverse genetics who were not transplanted, in whom Forty-nine of the 60 hospitals (82%) responded to the survey on questions regarding the measurement of MRD using MFC in the PETHEMA LMA 1999, 2007 and 2010 protocols, providing information corresponding to 966 of the 1,076 (90%) patients regarding the number of markers, preparation of samples, instruments, approach (ie, LAIP, DfN or LAIP+DfN), number of cells to define a cluster, etc. The survey revealed significant heterogeneity intra- and inter-protocols that reflected improvement in MFC assessment of MRD over time, in the absence of harmonization nor standardization at the national level. Accordingly, we investigated if the heterogeneity in methodological, interpretation and reporting aspects of MFC based MRD testing were hampering its ability to predict outcome independently of other patient and treatment related factors. Strikingly, our results showed that except for the denominator used to calculate MRD burden (ie, total nucleated cells vs leukocytes), lack of standardization in all other parameters had an impact on the ability of MFC to predict outcomes in AML (Figure). Namely, panels with ≤4 markers or ≤2 combinations failed to identify patients with significantly different RFS according to MRD status, and MFC-based MRD monitoring was prognostic only when >500,000 cells were measured. Only MRD assessment using patient-specific panels was predictive of outcome. Conclusions: We report here one of the largest studies investigating the role of MRD monitoring using MFC. Our results confirmed that detection of MRD identifies patients in CR/CRi with inferior survival, but uncovered that decentralized MRD testing lacks significance when compared to other baseline risk factors and in the context of risk-adapted post-consolidation strategies. Thus, while this study demonstrated that "real-world" decentralized assessment of MRD using MFC does provide prognostic information in AML patients at first remission, our results question its readiness for risk stratification towards clinical decisions outside trials, at least until adequate standardization of this technique is achieved. Figure Disclosures Paiva: SkylineDx: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Adaptive: Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding. Alonso Dominguez:Celgene: Research Funding; Incyte: Research Funding; Pfizer: Research Funding. Martinez-Lopez:Janssen: Speakers Bureau; Altum: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Roche: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Vivia Biotech: Honoraria; Novartis: Research Funding; BMS: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau. Sossa:Astellas: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novo: Honoraria. San-Miguel:Roche, AbbVie, GlaxoSmithKline, and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, Celgene, Novartis, Takeda, Amgen, MSD, Janssen, and Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: Approximately 40-60% of older patients (pts) with AML achieve complete remission (CR) with IC. Factors influencing the use of consolidation after induction include disease-related considerations, extent of hematopoietic recovery, pt fitness, and physician and pt preference. Most older pts who achieve AML remission will experience disease relapse despite consolidation therapy (Schlenk, Haematologica, 2018). In the phase III, randomized, double-blind QUAZAR AML-001 Maintenance Trial, CC-486, an oral hypomethylating agent, was shown to significantly prolong OS and RFS vs. placebo (PBO) in pts with AML in first remission following induction ± consolidation. Prior to study entry, the use of consolidation chemotherapy and number of consolidation cycles was at the discretion of the treating physician, with study eligibility not contingent on the use of consolidation. Objective: Assess survival outcomes in the QUAZAR AML-001 trial in pt subgroups defined by number of consolidation courses received before study entry. Methods: Eligible pts were aged ≥55 years with newly diagnosed AML, intermediate- or poor-risk cytogenetics, and ECOG PS ≤3. Within 4 months (mo) of attaining first CR or CR with incomplete blood count recovery (CRi), pts were randomized 1:1 to CC-486 300 mg or PBO QD for 14 days per 28-day treatment (Tx) cycle. OS and RFS were compared among pts who received no consolidation ("No Consolidation"), 1 cycle of consolidation ("1 Consolidation"), or ≥2 cycles of consolidation ("≥2 Consolidations"). For these analyses, "induction" and "consolidation" defined regimens received before and after, respectively, the reported date of first CR/CRi. OS was defined as the time from randomization to death, and RFS as time from randomization to relapse or death. Kaplan-Meier OS/RFS estimates were compared for CC-486 vs. PBO using log-rank test. Hazard ratios (HRs) and 95% CIs were generated using a stratified Cox proportional hazards model. These analyses were not powered sufficiently to determine statistical significance. Results: 472 pts were randomized to CC-486 (N=238) or PBO (N=234). Most pts (80%) received consolidation before study entry. The No Consolidation cohort comprised 94 pts (20%; CC-486 52, PBO 42), the 1 Consolidation cohort comprised 212 pts (45%; CC-486 110, PBO 102), and the ≥2 Consolidations cohort comprised 166 pts (35%; CC-486 76, PBO 90), including 19 pts (CC-486 6, PBO 13) who received 3 consolidation cycles. Common agents used for consolidation were cytarabine (377/378 pts), idarubicin (95/378), and daunorubicin (37/378). While most pts received 1 induction, 97 pts received ≥2 induction courses; of them, 21 (CC-486 14, PBO 7) did not receive consolidation and 76 (CC-486 43, PBO 33) received ≥1 consolidation cycle. Baseline characteristics (eg, CR / CRi after IC, ECOG PS, cytogenetic risk at diagnosis) were generally similar among Tx arms and cohorts. Median (range) ages of pts in the 0 / 1 / ≥2 Consolidation cohorts were 71 (58-84), 68 (55-86), and 67 (55-82) years, respectively. In the No Consolidation cohort, median OS from the time of randomization with CC-486 vs. PBO was 23.3 vs. 10.9 mo, respectively (HR 0.55 [95%CI 0.34, 0.89]), and median RFS was 8.4 vs. 3.9 mo (0.55 [0.34, 0.88]) (Figure A). In the 1 Consolidation cohort, median OS was 21.0 vs. 14.3 mo with CC-486 vs. PBO, respectively (HR 0.75 [95%CI 0.55, 1.02]), and median RFS was 10.0 vs. 4.7 mo (0.72 [0.53, 0.99]) (Figure B). In the ≥2 Consolidations cohort, median OS was 28.6 mo with CC-486 vs. 17.6 mo with PBO (HR 0.75 [95%CI 0.50, 1.11]), and median RFS was 13.0 vs. 6.1 mo (0.59 [0.41, 0.87]) (Figure C). Conclusions: CC-486 was associated with consistent survival benefits vs. PBO regardless of number of prior consolidation cycles. Use of consolidation was generally associated with nominal improvements in OS and RFS within each Tx arm; however, in the CC-486 arm, median OS for pts who did not receive consolidation was similar to those who received 1 consolidation cycle (23.3 and 21.0 mo, respectively). Results should be interpreted with caution, as these cohorts were not prospectively defined and the study was not powered to detect significant differences between subgroups. Nevertheless, these data clearly suggest that older pts with AML in first remission after induction can benefit from CC-486, regardless of their fitness to receive consolidation or the number of consolidation cycles received before starting CC-486. Disclosures Wei: AMGEN: Honoraria, Other: Advisory committee, Research Funding; Walter and Eliza Hall Institute: Patents & Royalties; Novartis: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Genentech: Honoraria, Other: Advisory committee; Servier: Consultancy, Honoraria, Other: Advisory committee; Astellas: Honoraria, Other: Advisory committee; Pfizer: Honoraria, Other: Advisory committee; Macrogenics: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Speakers Bureau; Astra-Zeneca: Honoraria, Other: Advisory committee, Research Funding; Janssen: Honoraria, Other. Roboz:Orsenix: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Jazz: Consultancy; Astex: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Array BioPharma: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Jasper Therapeutics: Consultancy; Cellectis: Research Funding; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Amphivena: Consultancy. Dombret:Sunesis: Consultancy; Abbvie: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Janssen: Consultancy; Menarini: Consultancy; Pfizer: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Astellas: Consultancy; Servier: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Cellectis: Consultancy. Döhner:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; AROG: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Sunesis: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Pfizer: Research Funding; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ravandi:Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria.

Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion–based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid– and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.

SARS-CoV-2 infection can impact survival of patients with acute myeloid leukemia (AML). International experts recommend considering delaying or stopping AML treatment, test patients who need intensive induction and s prioritizing outpatient treatment. However there is little published evidence in AML. Objective To analyze the clinical futures and outcome of SARS-CoV-2 infection in AML patients. Methods and patients Observational multicenter study between March and May 2020; 117 patients reported from 47 Spanish centers, but 13 had no PCR or antibody test documented, finally including 104 patients from 45 hospitals. Results The median age was 68 years, men (56.7% vs 43.3%), and the median time from AML diagnosis to SARS-CoV-2 was 4 months. The mean of comorbidities was 1.2, high blood pressure (40.4%), heart disease (17.3%), diabetes (13.5%), smoking (8.8%), chronic obstructive pulmonary disease or emphysema (7.7%), renal failure (6.7%) and liver dysfunction (1.9%). Cytogenetic risk was low in 16.9%, intermediate in 57.1% and high in 26.0%; 55.7% had active disease, 39.2% complete remission and 5.1% partial response. 29.4% were off-therapy and 70.6% under antileukemic treatment at the time of SARS-CoV-2: induction chemotherapy (25.3%), hypomethylating (19.3%), clinical trial (17.0%), consolidation chemotherapy (14.8%), venetoclax (3.4%), FLT3 inhibitors (3.4%) and/or maintenance (1.1%). Overall 3.7% were newly diagnosed (no prior therapy), 77.8% had received one line of treatment, 14.8% two and 3.7% four. 15.4% had prior allogeneic transplantation. Only 4.0% of the patients were asymptomatic, while the main signs and symptoms were fever (77.8%), pneumonia (75.0%), cough (65.3%), dyspnea (52.0%), diarrhea (20.4%), nausea and/or vomiting (12.2%), rhinorrhea (10.2%) and headache (7.4%). Analytical parameters were: neutrophils 3112 cells/µL (1900-7300), lymphocytes 1090 cells/µL (1000-3000), interleukin 6 118 pg/mL (0-100), ferritin 4505 ng/mL (15-150) and D-dimer 2823 ng/mL (20-500), with liver enzymes altered in 23.9% of cases. 84.2% received specific treatment for coronavirus infection: chloroquine or hydroxychloroquine (82.2%), lopinavir/ritonavir (54.0%), corticosteroids (39.6%), azithromycin (33.0%), tocilizumab (15.8%), plasma convalescent (3.0%), clinical trial medication (3.0%), remdesivir (2.0%) and/or anakinra (1.0%). The course was mild in 14.7% (no hospitalization), moderate in 32.0% and severe in 53.3%. The implementation of intensive measures was assessed in 48.2%(14.9% admitted to the ICU and the remaining 33.3% rejected). The mean time to negativization was 20.5 days, duration of symptoms 17.6 days and the hospital stay 11.1 days. In 48.1% of the cases treatment for AML was maintained, in 26.6% delayed and in 25.3% modified due to coronavirus disease.47.5% died, establishing an association between mortality and age over 60 years (58.3% vs 36.4%, p=0.043), ≥2 lines of treatment (72.7% vs 44.3%, p=0.020), active disease (62.5% vs 29.4%, p=0.002) and pneumonia (61.2% versus 22.7%, p=0.002). Overall 47.5% overcame the infection, and in 5.0% SARS-CoV-2 genetic material was still detected at the time of analysis. A non-significant lower mortality rate was observed among: previous transplantation (45.7% vs 64.3%, p=0.19), neutrophil >1900 cells/µL (41.1% vs 60.0%, p=0.09), lymphocyte >1000 cells/µL (42.9% vs 63.6%, p = 0.09) and hydroxychloroquine/chloroquine plus azithromycin (35.3% vs 60.0%, p=0.10). Conclusions SARS-CoV-2 infection produces high mortality among AML patients. Mortality was correlated with age, active disease and pneumonia. Disclosures Martinez-Lopez: Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Research Funding.

Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib - an oral, potent inhibitor of the mutant IDH1 (mIDH1) enzyme - is FDA-approved for adults with relapsed/refractory m IDH1 AML and adults with newly diagnosed m IDH1 AML who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy (IC). Data from a phase 1b study of 23 patients with newly diagnosed m IDH1 AML showed a favorable safety profile and encouraging clinical activity of ivosidenib + azacitidine (IVO+AZA; NCT02677922). Methods: In this global, double-blind, randomized, placebo-controlled, phase 3 study, patients were randomized 1:1 to IVO 500 mg once daily + AZA 75 mg/m 2 subcutaneously or intravenously for 7 days in 28-day cycles, or placebo + AZA (PBO+AZA), and stratified by region and de novo vs secondary AML. Key eligibility: untreated AML (WHO criteria), centrally confirmed m IDH1 status, not eligible for IC, ECOG 0-2. Primary endpoint: event-free survival (EFS; time from randomization until treatment failure, i.e. failure to achieve complete remission [CR] by week 24, relapse from remission, or death from any cause). Key secondary endpoints: CR rate, overall survival (OS), CR + CR with partial hematologic recovery (CRh) rate, and objective response rate (ORR). Results: From 19-Mar-2018 to 18-Mar-2021, 146 patients were randomized: 72 to IVO+AZA (median [interquartile range] age, 76.0 [70.5-79.5] years) and 74 to PBO+AZA (median [interquartile range] age, 75.5 [70.0-80.0] years). Fifty-four (75.0%) patients had de novo AML vs 18 (25.0%) with secondary AML in the IVO+AZA arm. Sixteen (22.2%) patients receiving IVO+AZA had poor-risk genetics per ELN guidelines vs 20 (27.0%) patients receiving PBO+AZA. Thirty-nine (26.7%) patients remain on treatment (27/72 patients in the IVO+AZA arm vs 12/74 patients in the PBO+AZA arm). EFS was statistically significant (HR = 0.33 [95% CI 0.16, 0.69]; P = 0.0011) in favor of the IVO+AZA arm. Median OS with IVO+AZA was 24.0 months vs 7.9 months with PBO+AZA (HR = 0.44 [95% CI 0.27, 0.73]; P = 0.0005). CR rate with IVO+AZA was 47.2% (34/72 patients; 95% CI 35.3%, 59.3%) vs 14.9% (11/74 patients; 95% CI 7.7%, 25.0%) with PBO+AZA (P < 0.0001). Median time to CR was 4.3 months with IVO+AZA vs 3.8 months with PBO+AZA. CR+CRh rate with IVO+AZA was 52.8% (38/72 patients; 95% CI 40.7%, 64.7%) vs 17.6% (13/74 patients; 95% CI 9.7%, 28.2%) with PBO+AZA (P < 0.0001). The CR rate by 24 weeks for IVO+AZA vs PBO+AZA was 37.5% and 10.8%, respectively. ORR with IVO+AZA was 62.5% (45/72 patients; 95% CI 50.3%, 73.6%) vs 18.9% (14/74 patients; 95% CI 10.7%, 29.7%) with PBO+AZA (P < 0.0001). All reported P-values are 1-sided. Common all-grade adverse events (AEs) occurring in > 20% of patients receiving IVO+AZA vs PBO+AZA were nausea (42.3% vs 38.4%), vomiting (40.8% vs 26.0%), diarrhea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), constipation (26.8% vs 52.1%), and pneumonia (23.9% vs 31.5%). Sixty-six (93.0%) patients receiving IVO+AZA vs 69 (94.5%) patients receiving PBO+AZA experienced a grade ≥ 3 AE. Common grade ≥ 3 AEs occurring in > 20% of patients receiving IVO+AZA vs PBO+AZA included febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), and pneumonia (22.5% vs 28.8%). Frequency of all-grade differentiation syndrome (DS) as assessed by investigators was 14.1% with IVO+AZA vs 8.2% with PBO+AZA, and that of grade ≥ 3 DS was 4.2% with IVO+AZA vs 4.1% with PBO+AZA. Based on the recommendation of the Independent Data Monitoring Committee, further enrollment into the study was prematurely discontinued due to evidence of benefit. Conclusions: IVO+AZA significantly improved EFS, OS, and clinical response (CR, CR+CRh, ORR) compared with PBO+AZA in patients with IC-ineligible, newly diagnosed m IDH1 AML. The safety profile of IVO+AZA was favorable and consistent with previous studies. These data demonstrate the clinical benefit of IVO+AZA in this difficult-to-treat AML population. Disclosures Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Forma Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Recher: Incyte: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Takeda: 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. Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Heuser: Tolremo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Astellas: Research Funding; BergenBio: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Calado: AA&MDS International Foundation: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis Brasil: Honoraria; Instituto Butantan: Consultancy; Alexion Brasil: Consultancy. Schuh: Kite/Gilead: Research Funding; GlycoMimetics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, 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; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees. Daigle: Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Servier: Current Employment. Hui: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Boehringer Ingelheim: Ended employment in the past 24 months. Zhang: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Pandya: Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Servier: Current Employment. Gianolio: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. de Botton: Pierre Fabre: Other; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria; Bayer: 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; Syros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Honoraria, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Döhner: Oxford Biomedicals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Ulm University Hospital: Current Employment. OffLabel Disclosure: 1) Ivosidenib (AG-120) is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test in: i) Adult patients with newly diagnosed AML who are 75 years of age or older or who have comorbidities that preclude use of intensive induction chemotherapy ii) Adult patients with relapsed or refractory AML. 2) It is being evaluated in a clinical trial in combination with azacitidine in adults 18 years of age or older with previously untreated acute myeloid leukemia with an IDH1 mutation.

BACKGROUND: BPDCN is a rare, aggressive hematologic malignancy characterized by historically poor overall survival and limited therapeutic options. Despite the recent approval of tagraxofusp-erzs for BPDCN, outcomes remain suboptimal for many patients. Additionally, patients with BPDCN are older and often have co-morbidities at baseline, preventing them from receiving tagraxofusp-erzs. Therefore, novel therapies are needed in the frontline setting for patients with BPDCN. Overexpression of CD123 (IL-3Rα) is present in all BPDCN cases, thereby establishing this surface marker as a target for therapeutic intervention. IMGN632 is a CD123-targeting ADC, comprised of a high-affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. IMGN632 has demonstrated favorable safety and promising clinical activity in relapsed/refractory (R/R) BPDCN [Blood (2020) 136 (Supplement 1): 11-13], leading to the FDA granting IMGN632 Breakthrough Therapy Designation (BTD) for R/R BPDCN (Oct 2020). Following BTD and alignment with FDA, a pivotal cohort in frontline (no prior systemic treatment) BPDCN patients was initiated in addition to a continuing cohort of patients with R/R disease, where we have enrolled 33 patients to date. Here we report the initial experience of three frontline patients who are not part of the pivotal cohort. METHODS: IMGN632 was administered IV at a dose of 0.045 mg/kg on day 1 of a 21-day cycle to all patients. Efficacy was assessed using modified Severity Weighted Assessment Tool (for skin lesions), PET/CT, and blast percentage in bone marrow aspirates. The response criteria were adapted from established BPDCN criteria (Pemmaraju NEJM 2019). RESULTS: Three patients with frontline BPDCN (no prior systemic therapy) received IMGN632. All three of these frontline patients achieved a clinical complete remission (CRc). Patient 1 was a 79yo woman who presented with skin, nodal, and extensive bone marrow disease (80% involvement). After one dose of IMGN632, she cleared her bone marrow (0%), and after 3 cycles, her nodal lesions and skin lesions resolved to achieve a CRc. Upon complete response, treatment was held due to patient co-morbidities. With just 3 cycles of IMGN632, this patient achieved duration of response (DOR) of 10.7 months without further therapy. Patient 2 was a 67yo man who had extensive skin disease covering >20% of the body; over several cycles, he achieved a PR then a CRc and bridged to an allogeneic stem cell transplant (SCT). The patient achieved a DOR of 13.5 months, with no evidence of disease relapse when he died from graft versus host disease. Patient 3 was a 66yo woman who presented with extensive skin and nodal lesions. After improvement over 4 cycles, she achieved a CRc with clearing of most of her skin lesions and all nodal lesions. Unfortunately, while still in CRc, the patient died of COVID-19 pneumonia, with a DOR of 3.7 months. CONCLUSION: Administration of IMGN632 to frontline BPDCN patients resulted in clinical complete remission in the initial three patients with durable responses in the two non-COVID impacted patients. None of these patients progressed while on therapy, and one patient successfully bridged to SCT. Enrollment continues in the pivotal frontline and R/R cohorts. (BPDCNtrial.com; NCT03386513). Disclosures Pemmaraju: Sager Strong Foundation: Other; Daiichi Sankyo, Inc.: Other, Research Funding; Aptitude Health: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Affymetrix: Consultancy, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Springer Science + Business Media: Other; DAVA Oncology: Consultancy; Plexxicon: Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; CareDx, Inc.: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Incyte: Consultancy; LFB Biotechnologies: Consultancy; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Martinelli: Incyte: Consultancy; Daichii Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas: Consultancy, Speakers Bureau; Abbvie: Consultancy; Roche: Consultancy; Pfizer: Consultancy, Speakers Bureau; Stemline Therapeutics: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau. Lane: Qiagen: Consultancy, Honoraria; N-of-One: Consultancy, Honoraria; Stemline Therapeutics: Research Funding; AbbVie: Research Funding. Deconinck: Imunogen: Membership on an entity's Board of Directors or advisory committees; Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Wang: Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Genentech: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; 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. Sweet: Bristol Meyers Squibb: 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; 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. Rizzieri: AbbVie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrotech: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pharmacyclics: Honoraria. DeAngelo: Shire: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Novartis: Consultancy, Research Funding; GlycoMimetics: Research Funding; Agios: Consultancy; Blueprint Medicines Corporation: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Incyte Corporation: Consultancy; Jazz: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy. Montesinos: Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Forma Therapeutics: Consultancy; Stemline/Menarini: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glycomimetics: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding. Konopleva: Ascentage: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; KisoJi: Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Calithera: Other: grant support, Research Funding; Cellectis: Other: grant support; Ablynx: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support. Kantarjian: Novartis: Honoraria, Research Funding; Jazz: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; Astellas Health: Honoraria; Astra Zeneca: Honoraria; NOVA Research: Honoraria; Aptitude Health: Honoraria; Immunogen: Research Funding; Ipsen Pharmaceuticals: Honoraria; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Walter: Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Amgen, Inc.: Consultancy, Research Funding; Amphivena Therapeutics, Inc.: Current equity holder in publicly-traded company; Aptevo Therapeutics, Inc.: Consultancy, Research Funding; Arog Pharmaceuticals, Inc.: Research Funding; Astellas Pharma US, Inc.: Consultancy; BioLineRx, Ltd.: Consultancy, Research Funding; Boston Biomedical, Inc.: Consultancy; Bristol Myers Squibb, Inc.: Consultancy; Celgene, Inc.: Consultancy, Research Funding; Genentech, Inc.: Consultancy; GlaxoSmithKline, Inc.: Consultancy; ImmunoGen, Inc.: Research Funding; Janssen Global Services, LLC: Consultancy; Janssen Research & Development, Inc.: Research Funding; Jazz Pharmaceuticals, Inc.: Consultancy, Research Funding; Kite Pharma, Inc.: Consultancy; Kronos Bio, Inc.: Consultancy; Kura Oncology, Inc.: Research Funding; Macrogenics, Inc.: Research Funding; New Link Genetics: Consultancy; Pfizer, Inc.: Consultancy, Research Funding; Race Oncology Ltd.: Consultancy; Selvita: Research Funding; Stemline Therapeutics, Inc.: Research Funding. Aribi: Seagen: Consultancy. Levy: Beigene: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker. Malcolm: Immunogen: Current Employment. Zweidler-McKay: ImmunoGen: Current Employment. Daver: Astellas: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Novartis: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Novimmune: Research Funding; FATE Therapeutics: Research Funding; ImmunoGen: Consultancy, Research Funding; Hanmi: Research Funding; Pfizer: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Glycomimetics: Research Funding; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding.

Background: Overexpression of CD123 (IL-3Rα receptor) is a hallmark of blastic plasmacytoid dendritic cell neoplasm (BPDCN), thus making this antigen an attractive target for the development of new therapeutics. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprising a novel anti-CD123 antibody coupled, via a highly-stable peptide linker, to a unique DNA-alkylating cytotoxic payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class. Preclinically, IMGN632 has demonstrated potent activity against BPDCN cells with remarkable sensitivity of patient derived xenografts to IMGN632 (Blood 2018 132:3956). IMGN632 has demonstrated a wide therapeutic index in vitro and in vivo (PMIDs: 29661755, 30361418). Importantly IMGN632 has demonstrated favorable safety profile and has demonstrated evidence of promising efficacy in patients with BPDCN (ASH 2020: Blood 2020, vol 136, suppl 1, 11-13) and AML (ASH 2019: Blood 2019, vol 134, suppl 1, 734). Based on this data, IMGN632 was granted FDA Breakthrough Therapy Designation for BPDCN (Oct 2020). Initial experience with 3 frontline BPDCN patients showed clinical complete remissions (CRc) in all three patients. Subsequently an FDA-aligned pivotal cohort enrolling frontline BPDCN patients has been added to this study. Methods: This study is currently enrolling two expansion cohorts for adults with CD123 positive BPDCN. The pivotal cohort is enrolling patients with frontline/untreated (no prior systemic therapy) BPDCN who do not have CNS involvement and meet other basic eligibility. This cohort is designed to support an application for FDA approval for IMGN632 in patients with BPDCN. An additional cohort is enrolling patients with relapsed/refractory BPDCN, which may have had up to 3 prior lines of therapy, including CD123-targeted therapies and prior hematopoietic stem cell transplant (after 120 days) and may have CNS involvement (if cleared with intrathecals), but who must not have prior history of veno-occlusive disease of the liver, or history of grade 4 capillary leak syndrome or non-cardiac grade 4 edema, and other eligibility. Both cohorts are enrolling patients at the RP2D (0.045 mg/kg IV Q 3 weeks) in the US and EU (NCT03386513, https://BPDCNtrial.com). Disclosures Pemmaraju: Clearview Healthcare Partners: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Celgene Corporation: Consultancy; MustangBio: Consultancy, Other; Plexxicon: Other, Research Funding; Blueprint Medicines: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Affymetrix: Consultancy, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Aptitude Health: Consultancy; CareDx, Inc.: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Springer Science + Business Media: Other; Sager Strong Foundation: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Consultancy; Bristol-Myers Squibb Co.: Consultancy; Samus: Other, Research Funding; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Forma Therapeutics: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Stemline/Menarini: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Lane: Qiagen: Consultancy, Honoraria; N-of-One: Consultancy, Honoraria; Stemline Therapeutics: Research Funding; AbbVie: Research Funding. Sweet: AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, 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; Mana Therapeutics: Consultancy, Honoraria; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; DAVA Oncology: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Genentech: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria, Other: Advisory Board; Takeda: Consultancy, Honoraria, Other: Advisory board; 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. Deconinck: Imunogen: Membership on an entity's Board of Directors or advisory committees; Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Rizzieri: AbbVie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrotech: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pharmacyclics: Honoraria. Walter: Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Amgen, Inc.: Consultancy, Research Funding; Amphivena Therapeutics, Inc.: Current equity holder in publicly-traded company; Aptevo Therapeutics, Inc.: Consultancy, Research Funding; Arog Pharmaceuticals, Inc.: Research Funding; Astellas Pharma US, Inc.: Consultancy; BioLineRx, Ltd.: Consultancy, Research Funding; Boston Biomedical, Inc.: Consultancy; Bristol Myers Squibb, Inc.: Consultancy; Celgene, Inc.: Consultancy, Research Funding; Genentech, Inc.: Consultancy; GlaxoSmithKline, Inc.: Consultancy; ImmunoGen, Inc.: Research Funding; Janssen Global Services, LLC: Consultancy; Janssen Research & Development, Inc.: Research Funding; Jazz Pharmaceuticals, Inc.: Consultancy, Research Funding; Kite Pharma, Inc.: Consultancy; Kronos Bio, Inc.: Consultancy; Kura Oncology, Inc.: Research Funding; Macrogenics, Inc.: Research Funding; New Link Genetics: Consultancy; Pfizer, Inc.: Consultancy, Research Funding; Race Oncology Ltd.: Consultancy; Selvita: Research Funding; Stemline Therapeutics, Inc.: Research Funding. Aribi: Seagen: Consultancy. Levy: Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker. Martinelli: Pfizer: Consultancy, Speakers Bureau; Stemline Therapeutics: Consultancy; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Incyte: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau; Daichii Sankyo: Consultancy. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee. Konopleva: KisoJi: Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Rafael Pharmaceuticals: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Stemline Therapeutics: Research Funding; AstraZeneca: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding. Kantarjian: Aptitude Health: Honoraria; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Ipsen Pharmaceuticals: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Astellas Health: Honoraria; Precision Biosciences: Honoraria; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Wang: Immunogen: Current Employment. Malcolm: Immunogen: Current Employment. Zweidler-McKay: ImmunoGen: Current Employment. DeAngelo: Abbvie: Research Funding; GlycoMimetics: Research Funding; Pfizer: Consultancy; Shire: Consultancy; Incyte Corporation: Consultancy; Blueprint Medicines Corporation: Consultancy; Amgen: Consultancy; Agios: Consultancy; Autolus: Consultancy; Takeda: Consultancy; Jazz: Consultancy; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding. Daver: Pfizer: Consultancy, Research Funding; Novartis: Consultancy; FATE Therapeutics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Hanmi: Research Funding; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; ImmunoGen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding.

The outcome of AML patients (pts) ≥ 70 years is poor. Defining the best treatment option remains controversial especially when choosing between intensive chemotherapy (IC) and hypomethylating agents (HMAs). We set up a multicentric European database collecting data of AML pts ≥ 70 y. The primary objective was to compare overall survival in pts selected for IC or HMAs. Individual pt data were collected from 3 European AML registries (DATAML, SAL and PETHEMA). All pts ≥70 y newly diagnosed between 01/01/2007 and 06/30/2018 were included. Variables were age, sex, diagnosis date, AML status, WBC, BM blasts %, cytogenetic risk, NPM1, FLT3-ITD mutations, first-line therapy, response, allo-SCT in first complete remission (CR), date of relapse and/or death. First-line treatments included IC, a semi-intensive regimen (fludarabine, cytarabine, filgrastim), HMAs, low-dose cytarabine (LDAC) or supportive care (SC). 3 700 AML pts ≥ 70y were identified. Pts treated with semi-intensive chemotherapy (n=464), LDAC (n=127) or SC (n=837) were not included in this analysis. Thus, the study population included 1 199 IC pts and 1 073 HMA pts. The median follow-up was 49.5 months. In the HMA group, pts were older, had lower WBC count and BM blast %, and they more frequently had ECOG > 1, secondary AML (sAML) and adverse-risk cytogenetics (CG) compared to the IC group. NPM1 and FLT3-ITD mutations were more frequent in the IC group. IC regimens were daunorubicin-AraC (n=432, 36.0%), idarubicin-AraC (n=381, 31.8%) or ida-AraC-CCNU (n=214, 17.8%). AlloSCT was performed in 70 IC pts (5.8%) and only in 7 HMA pts (0.7%) (P CR/CRi was achieved in 673 (56.1%) and 211 (19.7%) pts in the IC and HMA groups (P 1, adverse-risk CG and WBC >30 giga/L were significantly associated with a lower response rate whereas NPM1 mutation was significantly associated with a higher response rate. HMA treatment was associated with a lower response rate than IC (OR, 0.25; 95%CI : 0.20-0.31 ; P Day-60 death occurred in 247 (20.6%) and 194 (18.1%) pts in the IC and HMA groups (P=0.129). MV analysis showed that age ≥ 75 years, ECOG > 1, adverse-risk CG and WBC > 30 giga/L were significantly associated with a higher d60 death rate. HMA treatment was associated with a lower d60 death rate than IC (OR, 0.69; 95%CI : 0.54-0.88 ; P=0.003). The median OS was 10.9 (95%CI: 9.7-11.6) and 9.2 months (95%CI: 8.3-10.2) in the IC and HMA groups. OS at 1, 3 and 5 y was 46.0 (95%CI: 43.0-48.9) vs. 40.6% (95%CI: 37.6-43.7), 20.8 (95%CI: 18.3-23.4) vs. 8.3% (95%CI: 6.5-10.4) and 12.4 (95%CI: 10.2-14.9) vs 2.8% (95%CI: 1.7-4.4) in the IC and HMA groups. In MV analysis, ECOG > 1, adverse-risk CG, WBC > 30 giga/liter and sAML were significantly associated with a poorer OS. The treatment effect on OS was time-dependent (Fig 1A). To account for the non-proportionality of risks, we used a Royston and Parmar model, which took into account the interactions between time and treatment effect and allowed graphical representation of the adjusted risk of death at all times during follow-up. This model showed that HMA pts had a significantly lower risk of death before 1.5 months of follow-up ; there was no significant difference between both groups between 1.5 and 4.0 months, and OS was significantly better with IC from 4.0 months of follow-up (Fig 1B). There was no significant interaction between treatment (HMAs vs. IC) and all confounding factors (in particular age, performance status or CG risk). We also used the propensity score method. A MV logistic regression model was generated to estimate for each pt a propensity score to receive HMAs or IC. The performance of the model was estimated with the c 2-Hosmer-Lemeshow statistic (P-value= 0.169) and the C-statistic (0.82, 95%CI: 0.81-0.84). The mean propensity score was 0.320 (±0.232) in IC (N=1199) and 0.642 (±0.234) in HMA (N=1073). Based on propensity score, 532 subjects with IC were matched with 532 subjects with HMAs. The mean propensity score was the same in IC and HMA (0.491 ± 0.219) in the matched sample. The results of HMAs vs. IC comparisons on response, early mortality and overall survival (Fig 1C-D) in this subgroup of propensity score-matched pts were similar to those of the MV analysis. With a fairly long median follow-up and a large number of pts, this study shows that IC remains the treatment strategy that offers better chances for prolonged survival compared with HMAs even in AML pts ≥ 70y. Figure 1 Figure 1. Disclosures Recher: Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, 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; Incyte: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: 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; MaatPharma: Research Funding. Bertoli: Astellas: Consultancy; BMS Celgene: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy. Dumas: Daiichi-Sankyo: Consultancy; Astellas: Consultancy; BMS Celgene: Consultancy. Tavitian: Novartis: Consultancy. Platzbecker: AbbVie: Honoraria; Geron: Honoraria; Celgene/BMS: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Müller-Tidow: Janssen: Consultancy, Research Funding; Bioline: Research Funding; Pfizer: Research Funding. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. de la Fuente: Incyte: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Novartis: Research Funding; BMS: Consultancy, Speakers Bureau. Delabesse: Novartis: Consultancy; Astellas: Consultancy. Pigneux: Roche: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Amgen: Consultancy; Novartis: Consultancy, Research Funding. Montesinos: Stemline/Menarini: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glycomimetics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Forma Therapeutics: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

Background: Clonal evolution in AML originates long before diagnosis and is a highly dynamic process. Having a greater understanding of leukemogenesis may contribute to develop treatment strategies that target the tumor evolutionary process. However, dissecting leukemic transformation at the onset of AML is challenging without single-cell sequencing, and most clinical laboratories do not have infrastructure to perform these studies routinely. Patients with newly diagnosed AML may present dysplasia. If these residual, mature, dysplastic cells were generated before the differentiation blockage of blasts preceding leukemic transformation, it could be hypothesized that studying the genetic landscape of dysplastic cells and blasts could uncover the evolutionary process from dysplasia to AML. This hypothesis has never been investigated. Aim: Reconstruct clonal evolution from dysplasia to AML based on the genetic signature of dysplastic cells and leukemic blasts, analyzed using integrated MFC immunophenotyping and sorting with NGS. Methods: Presence of dysplasia according to aberrant phenotypic differentiation of the neutrophil, monocytic and erythroid lineages was investigated using MFC and EuroFlow MDS/AML panels in 283 newly diagnosed AML patients (median age 74; range 29-90). Patient-specific phenotypes were leveraged to isolate a total of 99 cell types from 22 AML cases for targeted (48 MDS/AML related genes) and whole-exome sequencing (WES), with a mean depth of 3246x and 141x, respectively. In patients with measurable residual disease (MRD) by MFC at the time of complete remission, tumor resistant cells were FACSorted for WES using patient-specific aberrant phenotypes. T cells were used as germline control in both approaches. Mutations were considered if ≥0.05 allele frequency in leukemic blasts or dysplastic cells and ≤0.2 in T cells. Results: We first assessed the applicability of our hypothesis by investigating how many patients show dysplasia at the onset of AML. Dysplastic cells were observed in 252 of 283 (89%) cases. Phenotypic abnormalities were more frequently noted in the neutrophil lineage (47%), followed by the monocytic (40%) and erythroid cells (13%). Up to 169/283 (60%) patients showed multi-lineage dysplasia. Only nine cases showed no signs of dysplasia, whereas the remaining 22 had undetectable hematopoiesis. Targeted sequencing of dysplastic cells and blasts in 16 patients uncovered three evolutionary patterns of leukemogenesis. Stable transition in those displaying identical mutational landscapes in blasts and residual mature dysplastic cells (9/16); clonal selection in cases where blasts originated from leukemic stem cells other than the ones driving dysplasia, due to mutations absent in blasts and present in dysplastic cells (4/16); and clonal evolution in cases showing new mutations in blasts onto mutations shared between these and dysplastic cells (3/16). Interestingly, most patients displaying stable transition from dysplasia to AML had mutated ASXL1, RUNX1 and/or TP53 (8/9). Mutations present in dysplastic cells while absent in blasts from patients showing a clonal selection evolutionary pattern, were more frequently detected in genes related to signaling pathways (eg JAK2, KRAS and NRAS). By contrast, clonal evolution was characterized by new mutations affecting FLT3ITD and STAG2. The higher throughput of WES of dysplastic cells and blasts from six patients unveiled a more complex dynamic process of leukemogenesis, with all three evolutionary patterns being detectable in nearly all cases. Most interestingly, we found patients with mutations in dysplastic cells and blasts at diagnosis, but not in MRD cells (eg NBPF1 and ZNF717); and patients showing mutations in dysplastic and MRD cells, but not in blasts at diagnosis (eg MUC2 and KIR2DL3). These findings uncover that genetic alterations that are critical in leukemic transformation and chemoresistance, may not overlap (Figure). Conclusions: We showed for the first time that it is possible to reconstruct leukemogenesis in nearly 90% of newly-diagnosed AML patients, using techniques that are commonly available in clinical laboratories. The possibility to identify the genetic drivers of leukemic transformation and chemoresistance, could be clinically meaningful to develop tailored treatment strategies aiming at the eradication of genetically diverse leukemic clones. Figure 1 Figure 1. Disclosures Prósper: Oryzon: Honoraria; Janssen: Honoraria; BMS-Celgene: Honoraria, Research Funding. Ayala: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Celgene: Honoraria. Perez-Simon: JANSSEN, TAKEDA, PFIZER, JAZZ, BMS, AMGEN, GILEAD: Other: honorarium or budget for research projects and/or participation in advisory boards and / or learning activities and / or conferences. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Montesinos: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; Tolero Pharmaceutical: Consultancy; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Paiva: Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy.

Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare hematologic malignancy affecting 1.5-2.0 per million adults per year worldwide, which corresponds to approximately 1,000 cases in Europe. It is a highly aggressive disease characterized by skin and bone marrow involvement, with secondary sites including lymph nodes and viscera. BPDCN is associated with a poor prognosis, median overall survival of 8-14 months, and has no firm consensus for therapy. Tagraxofusp (TAG, SL-401) is currently the only approved first-line treatment for adult patients with BPDCN in Europe. TAG is a targeted therapy directed to CD123 that has shown efficacy in a controlled, prospective trial with prespecified endpoints. Specifically, TAG is a recombinant cytotoxin composed of human interleukin-3 fused to a truncated diphtheria toxin payload that targets CD123, the α-subunit of interleukin-3 receptor commonly overexpressed on the surface of BPDCN tumor cells. In the past, most adult and pediatric patients in Europe were treated with a plethora of experimental combination chemotherapies often imported from aggressive myeloid and lymphoid malignancy treatment regimens, followed by hematopoietic stem cell transplantation (SCT), as best available treatment. However, there is no robust evidence of the effectiveness and safety of these therapies for BPDCN, due to its rarity, the absence of prospective studies, and the variability in diagnostic criteria, definition of endpoints, and assessment of outcomes. As of July 2021, 65 patients with BPDCN have been treated with TAG in a clinical setting outside the US, as part of an expanded access program. Continued collection of clinical data from the use of TAG in a real-world setting in patients with BPDCN is important to increase the knowledge of clinical outcomes, especially in patient populations commonly underrepresented in clinical trials. This is the first real-world evidence prospective registry in patients with BPDCN receiving TAG. The study is designed to meet the requirements included in the marketing authorization by the European Commission, to further investigate the effectiveness and safety of TAG in the treatment of patients with first-line or relapsed/refractory BPDCN. Study Design and Methods This is a noninterventional, single-arm study (EudraCT: 2021-001684-24) in patients with BPDCN to assess clinical effectiveness and safety of TAG under real-world routine clinical practice conditions (12 mcg/kg intravenously [IV] once daily on days 1-5 of a 21-day cycle, per the summary of product characteristics general recommendation). Up to 125 patients are planned for inclusion in approximately 65 clinical sites in Europe estimated over 3 years. Eligible patients have a diagnosis of BPDCN and are scheduled to start TAG monotherapy, per physician's decision. The primary study objectives are to determine the complete response (CR) rate, defined as CR + clinical CR (CR with residual skin abnormality not indicative of active disease) after 3 months of treatment, and to assess the safety of TAG, in particular the incidence and severity of capillary leak syndrome (CLS). Secondary objectives include analysis of the rate of patients bridging to SCT, progression-free survival, overall survival, best overall response, duration of response, dose interruptions/administration of IV albumin supplementation in patients with CLS or CLS symptoms, incidence and severity of adverse events of special interest (AESIs), overall safety, and TAG treatment administered. AESIs include CLS and hepatic, renal, and cardiac events. Per routine clinical practice, quarterly data collection is anticipated during the study. In addition, data will be collected at screening, enrollment, early discontinuation, and study end (Figure). The end of the registry safety data collection will be 18 months after the last enrolled patient's first visit (LPFV). Interim analyses will be performed annually, and an effectiveness interim analysis is scheduled at 12 months post-LPFV. All effectiveness and safety analyses will be performed using descriptive statistics. Survival data will be summarized using the Kaplan-Meier method. Subgroup analyses for effectiveness and safety may be performed, on the basis of gender, age, or Eastern Cooperative Oncology Group performance status at baseline. Enrollment is planned to start by December 2021. Figure 1 Figure 1. Disclosures Platzbecker: Celgene/BMS: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Geron: Honoraria. Angelucci: Menarini-Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: steering commitee, Speakers Bureau; Vertex Pharmaceuticals: Honoraria, Other: DMC; Celgene BSM: Honoraria, Other: DMC; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Crispr therapeutics: Honoraria, Other: DMC; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Montesinos: Glycomimetics: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy. Lemoni: AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Spyridonidis: Menarini: Current Employment. Casariego: Menarini: Current Employment. Mughal: Stemline: Current Employment, Current holder of stock options in a privately-held company; Oxford University Press, Informa: Other: financial benefit and/or patents . Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Background: The symptom burden for patients (pts) with acute myeloid leukemia (AML) is substantial, and patient reported outcomes (PROs) in pts with newly diagnosed (ND) AML ineligible for intensive induction chemotherapy (IIC) are poor. Baseline health status and conditions (ie, fatigue and physical functioning) are independent prognostic factors for overall survival and pts may benefit from improved quality of life (QoL) while undergoing treatment. To fully evaluate the impact of AML and its treatments, assessing health-related QoL and PROs has become increasingly important. Gilteritinib (GIL), an FMS-like tyrosine kinase 3 gene (FLT3) inhibitor, demonstrated efficacy/safety in pts with FLT3mut+ relapsed/refractory AML. In the phase 3 LACEWING (NCT02752035) trial, GIL was evaluated in combination with azacitidine (AZA) in pts with ND AML with FLT3 mutations who were unable to receive IIC. Aim/Objective: To evaluate prespecified PROs in pts with ND FLT3mut+ AML ineligible for IIC receiving GIL+AZA or AZA in LACEWING. Methods: PROs were obtained from pts in a safety cohort receiving GIL plus AZA and pts randomized (2:1) to GIL (120 mg/day orally on Days 1-28) plus AZA (75 mg/m 2/day SC/IV on Days 1-7) or AZA alone (same regimen) during 28-day cycles. All pts receiving GIL plus AZA (safety cohort and randomized) were included in the 'GIL+AZA' group. Patient reported fatigue, assessed by the Brief Fatigue Inventory (BFI), was a secondary endpoint; other PROs, assessed by the Functional Assessment of Chronic Illness Therapy-Dyspnea Short Form (FACIT-Dys-SF), Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), dizziness and mouth sore symptoms, and EuroQol Group 5-Dimension 5-Level (EQ-5D-5L), were exploratory endpoints. The BFI was administered at Cycle 1 (Days 1, 8, and 15), Cycle 2 (Days 1 and 15), and subsequent cycles on Day 1; all other assessments were administered on Day 1 of each cycle. All assessments were evaluated using analysis of variance models. Results: A total of 15 pts in the safety cohort and 123 randomized pts (GIL+AZA, n=74; AZA, n=49) were included. Median age was 78 years with GIL+AZA and 76 years with AZA; ECOG PS ≥2 was 50.6% and 32.7%, respectively, and FLT3-ITD was the only FLT3 mutation present in 76.4% and 81.6% of pts, respectively. Questionnaire completion rates for the BFI were 73% and 85% for patients in the safety and randomized cohorts, respectively. Baseline scores on assessment scales were similar between groups. A difference in favor of GIL+AZA was seen at Cycle 1, Day 8 on the BFI (least squares mean [LSM] difference [95% CI] -1.0 [-1.9, -0.2]; P=.019); differences were not significant at other time points. On the FACIT-Dys-SF dyspnea subscale score, pts receiving AZA reported improvement in dyspnea compared with pts receiving GIL+AZA (LSM difference [95% CI] 7.7 [0.5, 14.8]; P=.037) at Cycle 3, Day 1. No significant differences were seen at other time points on the FACIT-Dys-SF dyspnea subscale score or at any time for the functional limitation subscale score. On the FACT-Leu at Cycle 2, Day 1, LSM differences in favor of GIL+AZA were observed for physical and emotional well-being but were in favor of AZA on social well-being; at most time points, well-being did not differ between groups. At Cycle 2, Day 1, LSM differences favored GIL+AZA (8.1 [95% CI 0.5, 15.7]; P=.038) on the FACT-Leu Trial Outcome Index. No differences were observed between groups on other measures of the FACT-Leu. At baseline, very little dizziness (mean scores: GIL+AZA, 0.49 vs AZA, 0.63) and mouth sores (mean scores: GIL+AZA, 0.47 vs AZA, 0.48) were reported; no significant differences were observed at any time point while on treatment. A small but significant difference was seen in favor of GIL+AZA at Cycle 2, Day 1 on the EQ-5D-5L utility index (LSM difference [95% CI] 0.1 [0.0, 0.2]; P=.049), but not at other time points. No differences were observed between groups on the EQ-5D-5L visual analog scale scores measuring self-rated health status. Conclusions: Results from analyses of PRO data indicate that the addition of GIL to AZA for the treatment of patients with ND FLT3mut+ AML ineligible for IIC does not result in clinically significant change or worsening of fatigue, leukemia-related symptoms (including dizziness and mouth sores), and QoL compared with AZA treatment alone. From the patient's perspective, combination therapy with GIL+AZA is a feasible and well tolerated treatment strategy. Disclosures Wang: Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Heuser: Tolremo: Membership on an entity's Board of Directors or advisory committees; BergenBio: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Astellas: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Montesinos: Karyopharm: 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, Speakers Bureau; Stemline/Menarini: Consultancy; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Rich: Astellas Pharma Global Development, Inc.: Current Employment. Wu: Astellas: Current Employment. Pandya: Astellas Pharma, Inc.: Current Employment. Shah: Astellas Pharma, Inc.: Current Employment; University of Michigan School of Public Health Department of Health Management and Policy Alumni Board: Other: Chair-Elect.

Background: Gilteritinib (GIL), a FLT3 inhibitor, shows efficacy/safety in patients (pts) with FLT3mut+ relapsed/refractory (R/R) AML. For pts with newly diagnosed (ND) AML with FLT3 mutations unable to receive intensive induction chemotherapy (IIC), survival is limited, and therapy options are few. In preclinical studies, GIL plus azacitidine (AZA) impeded tumor growth and induced apoptosis/differentiation of FLT3-ITD AML cell lines. Antitumor effects appeared synergistic in xenografted mouse models (data on file). We investigated GIL+AZA vs AZA in adults with ND FLT3mut+ AML ineligible for IIC (NCT02752035). Aim/Objective: To compare efficacy and safety/tolerability of GIL+AZA and AZA in pts with ND FLT3mut+ AML ineligible for IIC. Methods: Pts were initially randomized (1:1:1) to GIL (120 mg/day orally on Days 1-28) plus AZA (75 mg/m 2/day SC/IV on Days 1-7), AZA (same regimen), or GIL (same regimen) during 28-day cycles. The GIL arm was removed due to preferred therapy changes. Pts were then randomized (2:1) to GIL+AZA or AZA alone. The primary endpoint was overall survival (OS) and key secondary endpoint was event-free survival (EFS). Treatment failure date was randomization date if complete remission (CR) was not achieved after 6 cycles. Subgroup/sensitivity analyses were prespecified. Response rates, safety/tolerability, and pharmacokinetic endpoints were analyzed. Data from long-term follow-up ≤3 yrs were obtained, including subsequent AML therapy. These results are from an interim analysis at 70 deaths (~50% of total deaths). Results: As of August 26, 2020, 123 pts were randomized to GIL+AZA (n=74) and AZA (n=49); 39 (52.7%) and 31 (63.3%) deaths, respectively, occurred. Median age was 78 yrs with GIL+AZA and 76 yrs with AZA; ECOG PS ≥2 was 47.3% and 32.7%, and FLT3-ITD alone was in 78.4% and 81.6% of pts, respectively (TKD alone 18.9% vs 14.3%; ITD with TKD 2.7% vs 4.1%). Median follow-up was 9.76 mo for GIL+AZA and 17.97 mo for AZA. Median exposure duration was 112 days for GIL in the GIL+AZA arm (n=73); AZA exposure was 98 and 99 days in the GIL+AZA and AZA (n=47) arms, respectively. Subsequent AML therapy was received by 20.3% pts on GIL+AZA and 44.9% pts on AZA; median time to first subsequent therapy was 8.2 and 4.5 mo, respectively. In the AZA arm, 22 pts received subsequent AML therapy, including 10 pts on GIL and 4 pts on other FLT3 inhibitors. Median OS was 9.82 mo for GIL+AZA and 8.87 mo for AZA (HR 0.916 [95% CI 0.529, 1.585]; P=.753). Patient subgroups with improved OS with GIL+AZA vs AZA included pts with ECOG PS 0-1 (HR 0.811 [95% CI 0.409, 1.608]) and high FLT3-ITD allelic ratio ≥0.5 (HR 0.580 [95% CI 0.285, 1.182]). Median EFS was 0.03 mo in both arms (HR 1.175 [95% CI 0.764, 1.807]; P=.459). In sensitivity analyses, median EFS with events based on composite CR (CRc; CR+CRi+CRp) was 5.03 mo for GIL+AZA and 3.29 mo for AZA (HR 0.924 [95% CI 0.576, 1.482]; P=.767). Although CR rates for both arms were similar (16.2% vs 14.3%), CRc rates were significantly higher for GIL+AZA vs AZA (58.1 vs 26.5%, difference 31.4% [95% CI 13.1, 49.7]; P No substantial differences in GIL trough concentrations at steady state (C trough) were seen between GIL+AZA and GIL alone (prior to arm removal). However, on Cycle 1 Day 15, median GIL C trough was 579 ng/mL (GIL+AZA and GIL arms) in contrast to C trough of 279 ng/mL observed with GIL monotherapy in the ADMIRAL trial in pts with R/R AML. Reasons for this difference are being evaluated. No apparent relationship was seen between C trough and response rates/grade of thrombocytopenia or neutropenia. Conclusions: In this trial of pts with ND FLT3mut+ AML ineligible for IIC, GIL+AZA led to significantly higher CRc rates but similar OS vs AZA alone. Pts with ECOG PS 0-1 and high FLT3-ITD allelic ratio appeared to have greater benefit with GIL+AZA. No new safety signals were seen. Curiously, C trough values in pts with ND FLT3mut+ AML ineligible for IIC were 2-fold greater than in pts with R/R FLT3mut+ AML. These results support the safety, tolerability, and activity of GIL+AZA vs AZA. Disclosures Wang: GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Mana Therapeutics: Consultancy, Honoraria; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; 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; DAVA Oncology: Consultancy, Speakers Bureau; 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. Montesinos: Stemline/Menarini: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Minden: Astellas: Consultancy. Lee: Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board. Heuser: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding. Naoe: Fuji Film: Other: Study funding for JAGSE; Astellas Pharma, Inc.: Consultancy, Other: Study funding for JAGSE; Bristol-Myers: Honoraria; Nippon Shinyaku: Honoraria; Daichi Sankyo: Other: Study funding for JAGSE; Otsuka Pharma: Honoraria. Chou: Abbvie: Honoraria, Other: Advisory Board, Research Funding; Celgene: Honoraria, Other: Advisory Board, Research Funding; IQVIA: Honoraria, Other: Advisory Board; Pfizer: Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board; Bristol Myers Squibb: Honoraria, Research Funding; Kirin: Honoraria, Research Funding. Laribi: IQONE: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; AstraZeneca: Other: Personal Fees; BeiGene: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; Jansen: Research Funding; AbbVie: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; Novartis: Other: Personal Fees, Research Funding. Esteve: Jazz: Consultancy; Novartis: Research Funding; Bristol Myers Squibb/Celgene: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy. Altman: ALZ Oncology: Research Funding; Amgen: Research Funding; Biosight: Consultancy, Other: Travel fees, Research Funding; Kartos: Research Funding; Boehringer Ingelheim: Research Funding; Daiichi Sankyo: Consultancy; Syros: Consultancy; BMS: Research Funding; GlycoMimetics: Other: Participation on an advisory board; Aprea: Research Funding; Kura: Research Funding; Kura Oncology: Consultancy; AbbVie: Consultancy, Other: Advisory Board, Research Funding; Theradex: Consultancy, Other: Advisory boards; Fujifilm: Research Funding; Astellas: Consultancy, Other: Advisory Board, Research Funding; Immunogen: Research Funding. Havelange: Astellas Pharma, Inc.: Consultancy; Novartis: Honoraria, Other: Travel fees, Participation on an advisory board; BMS: Other: Travel fees, Participation on an advisory board; Incyte: Other: Advisory board; Abbvie: Other: Advisory board. Watson: Astellas Pharma, Inc.: Consultancy; Roche, Amgen: Other: Travel support. Patkowska: Astellas Pharma, Inc.: Consultancy, Other: Travel fees; Pfizer: Other: Travel fees; Jazz Pharmaceuticals: Other: Travel fees; Angelini Pharma: Honoraria, Other: Travel fees; Novartis: Honoraria, Other: Travel fees; Bristol-Myers Squibb: Other: Travel fees; AMGEN: Honoraria; Servier: Honoraria, Other: Travel fees; KCR US, Inc.: Consultancy. Liu: Astellas Pharma, Inc.: Current Employment. Wu: Astellas: Current Employment. Philipose: Astellas Pharma Global Development: Current Employment. Hill: Astellas Pharma Global Development: Current Employment; Ligacept, LLC: Current holder of individual stocks in a privately-held company, Other: Stockholder. Gill: Astellas Pharma Global Development: Current Employment. Rich: Astellas Pharma Global Development, Inc.: Current Employment. Tiu: Astellas Pharma, Inc.: Current Employment.

Background: Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1). Olutasidenib has previously shown clinical activity in high-risk AML patients (pts) in a Phase 1 clinical trial (Watts, Blood 2019). The planned interim analysis of an ongoing Phase 2 clinical trial (NCT02719574) in R/R mIDH1 AML pts receiving single-agent olutasidenib 150 mg twice-daily showed an overall response rate (ORR) of 46%, including 33% of pts with CR/CRh (de Botton et al., ASCO/EHA 2021). Here we present data analysis on the mutational characteristics of these pts and the relationship between mutations and clinical response. Methods: The Efficacy Evaluable (EE) set comprised mIDH1R132X pts whose first dose was ≥180 days before the data cut-off (18-JUN-20). The primary endpoint was CR/CRh (complete remission [CR] according to modified IWG 2003 criteria plus CR with partial hematologic recovery [CRh]) response rate. CRh was defined as bone marrow blasts 0.5×10 9/L, and platelet count >50×10 9/L. ORR, a secondary endpoint, comprised CR+CRh+CR with incomplete recovery (CRi) + morphologic leukemia-free state (MLFS) + partial remission (PR). IDH1 mutation subtypes were determined by central analysis, co-mutations were reported by investigators. Baseline characteristics and mutation subtypes were tabulated for the safety population and analysis of response rate by mutation type was performed on the EE set. Results: There were 153 R/R AML pts treated with olutasidenib 150 mg BID (safety set). Of those, 123 were in the efficacy evaluable (EE) set (centrally confirmed IDH1R132 mutation and received first dose at least 180 days prior to the data cut off). For the safety population, cytogenetic risk classification was favorable in 6 (4%) pts, intermediate in 109 (71%) pts, and poor in 25 (16%) pts (unknown, 13 [8%] pts). Eighty-five (56%) pts had IDH1R132C mutation subtype, followed by IDH1R132H (n=35 [23%]), IDH1R132G (n=12 [8%]), IDH1R132S (n=11 [7%]), and IDH1R132L (n=4 [3%]). Ninety-four (61%) pts had 1-3 co-mutations reported by the investigator at baseline, with 4-7 co-mutations in 20 (13%) pts, none in 6 (4%) pts, and not done/unknown in 33 (22%) pts. The most common co-mutations at baseline were: NPM1 (n=40 [26%]), DNMT3A (n=36 [24%]), and ASXL1 (n=21 [14%]. Receptor tyrosine kinase (RTK) mutations were reported in 32 (21%) pts (FLT3, n=18 [12%]; NRAS, n=10 [7%]; KRAS, n=3 [2%]; PTPN11, n=3 [2%]; KIT, n=2 [1%]; NF1, n=2 [1%]), with multiple mutations reported in some pts. For the EE population, responses were achieved in all IDH1R132 mutation subtypes, with ORR and CR/CRh response rates ranging from 27%-54% and 17%-50%, respectively (Table 1). The CR/CRh response rate was lower for pts with IDH1R132H mutations; notably, these pts tended to have a higher percentage of co-mutations, particularly mutations in NPM1 and RTK genes, including FLT3. For EE pts with available co-mutation data (n=96), the mean (SD) number of co-mutations was lower (p Conclusions: Responses were observed across IDH1R132 mutation subtypes, with a relatively lower CR/CRh response rate for pts with a R132H mutation as compared to other subtypes. Pts with a best response of CR/CRh had fewer co-mutations than pts who did not achieve CR/CRh. While the ORR was not significantly reduced for pts with RTK mutations, these pts had a lower CR/CRh response rate compared to pts without any RTK mutations. Additional genetic analyses using ddPCR for IDH1 mutations and NGS on a targeted panel of genes at baseline, best response, and end of study will be presented to further explore primary and secondary resistance mechanisms. Figure 1 Figure 1. Disclosures De Botton: Celgene, Agios, Forma Therapeutics, Astella, Daiichi Sankyo, Syros, Abbvie, Bayer, Seattle Genetics, Janssen: Honoraria; Celgene, Agios, Astellas, Daiichi Sankyo, Syros, Abbvie, Bayer, Janssen, Pierre Fabre, Novartis, Pfizer, Servier: Consultancy; Celgene: Speakers Bureau; Agios, Forma Therapeutics: Research Funding. Yee: Forma Therapeutics: Research Funding; Onconova: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Jazz: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Geron: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Otsuka: 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; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: 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. Wei: Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Stemline/Menarini: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Braun: Servier: Research Funding; Daiichi-Sankyo, Celgene: Consultancy, Honoraria. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Esteve: Novartis: Consultancy, Research Funding; Jazz: Consultancy; Pfizer: Consultancy; Astellas: Consultancy; Novartis: Research Funding; Bristol Myers Squibb/Celgene: Consultancy; Abbvie: Consultancy. Grove: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jonas: 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; AbbVie: Other: Travel reimbursement. Khwaja: Pfizer, Abbvie: Honoraria; Novartis, Jazz: Speakers Bureau. Blum: Forma Therapeutics, Xencor; Celyad: Research Funding; Amerisource Bergen; Abbvie, Syndax: Honoraria. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Jurcic: AbbVie, BMS/Celgene, Novartis: Consultancy; AbbVie, Arog Pharmaceuticals, Astellas, BMS/Celgene, Forma Therapeutics, Genentech, Gilead Sciences, PTC Therapeutics, Syros Pharmaceuticals: Research Funding. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding. Xin: Forma Therapeutics, Inc.: Current Employment. Sedkov: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Guichard: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sweeney: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Cortes: Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Fenaux: Syros Pharmaceuticals: Honoraria; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding.

Background and objective. Inotuzumab ozogamicin (InO) was approved for patients (pts) with relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL) based on the results of INO-VATE trial (Kantarjian et al, 2016). There are scarce studies evaluating the results of InO therapy in real life in similar pts as those from the INO-VATE trial. Our objective was to analyze the outcomes of pts included in the compassionate program of InO in Spain (June 2013-April 2018) before definitive approval. Patients and Methods. Inclusion criteria were age >18 yrs., CD22+ ALL, R/R resistant to ≥2 previous lines, Ph+ ALL resistant/intolerant to TKI, ECOG ≤2 or >2 if due to ALL, Bilirubin Results. 34 pts were included in the trial, 21 males, median age 43 yrs (range 19-73), ECOG 50% 15/33 (45%). 25/34 (73%) of pts received >2 previous lines of therapy and 20 (59%) were previously transplanted. The duration of first CR remission before InO was The median number of InO cycles was 2 (1-6). One pt withdrew the study before evaluation, 5 (15%) dead during therapy and 21 (64%) achieved CR/CRi. Ten pts (29%) were transplanted. With a median follow-up for alive patients after InO start of 26 months, the medians (95%CI) of DR, PFS and OS were 4.7 months (2.4-7.0), 3.5 (2.0-5.0) and 4.0 months (1.9-6.1), respectively. CR duration, PFS and OS were significantly shorter in refractory ALL (Figure 1A), pts with first CR (CR1) duration The most frequent adverse events were hepatic (24%), infectious (18%), hematologic (15%) and gastrointestinal (9%). 3/10 transplanted patients showed grade 3-4 VOD/SOS. Grade 5 toxic events were hepatic (n=2), infection (n=2) and hemorrhage (n=1). Conclusion. The results in this series of compassionate use of InO for R/R ALL before approval for clinical use were slightly inferior to that of the INO-VATE trial. However, patients form this series had poorer risk factors than those included in that trial. The frequency and type of AE were similar to that of observed in the INO-VATE trial. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Overall survival according to ALL status at inotuzumab start (A) and to duration of first complete remission (B) Figure 1 Figure 1. Disclosures Ribera: AMGEN: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Hernández-Rivas: Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: 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.

INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), have made it possible to treat more elderly patients with acute myeloid leukemia (AML). Both HMAs have demonstrated efficacy in monotherapy and in combination with targeted therapies. However, there is little direct comparative data on AZA and DEC in first-line treatment, and we do not know which group of patients might benefit from each drug. Results of the full analysis set (FAS) were presented previously (Labrador J, et al. ASH 2020). Here, we report long-term clinical efficacy from prespecified patient subgroup analyses. METHODS We conducted a retrospective study to compare real-life clinical outcomes between AZA and DEC in patients with AML ineligible for intensive chemotherapy included in the PETHEMA registry, and analyzed clinical variables associated with response and overall survival (OS) between AZA and DEC. RESULTS A total of 626 patients were included for the FAS between 2006 and 2019. 487 (78%) received AZA and 139 (22%) received DEC. Baseline characteristics were comparable in both groups, except for the percentage of bone marrow blasts (44% vs. 34% in the DEC group compared to AZA, p=0.010). In the FAS, there was no difference in the CR, CR/CRi or ORR (CR/RCi + PR) rate: 18%, 20.5% and 32% with AZA vs. 23%, 25% and 39.5% with DEC (p=0.20, p=0.27 and p=0.12). In the subgroup analysis, DEC was associated with higher CR/CRi rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.088 - 0.801), bone marrow blast count < 50% (95% CI: 0.293 - 0.965), secondary AML (95% CI: 0.223 - 0.918) and adverse cytogenetics (95% CI: 0.171 - 0.857) (Figure 1A). DEC was associated with higher ORR rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.116 - 0.782), leukocytes < 10 x10 9/L (95% CI: 0.321 - 0.920) and bone marrow blasts < 50% (95% CI: 0.321 - 0.920) (Figure 1B) 120 days-mortality was 25.4% after AZA and 27.1% after DEC, p=0.70. Patients who did not achieve at least a PR had significantly higher 120-day mortality with both HMAs (OR 8.85 and 8.22 for AZA and DEC, respectively). In the subgroup analysis, patients with leukocytes ≥ 10 x10 9/L (95% CI: 1.069 - 4.157) and those with estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73m 2 (95% CI: 1.249 - 4.664) had higher 120-day mortality with DEC than with AZA (Figure 1C) With a median follow-up of 12 months, median OS was 10.4 months (95% CI: 9.2 - 11.7) for AZA vs. 8.8 months (95% CI: 6.7 - 11.0) for DEC (p = 0.455). The subgroup analysis revealed that patients ≥ 80 years (95%: CI 1.005 - 2.341), with leukocytes ≥ 10 x10 9/L (95% CI 1.039 - 2.062), platelet count CONCLUSIONS Our study provides real-life data on the outcomes of AML patients treated with AZA compared to DEC in a large retrospective cohort with long-term follow-up. In addition, we identify for the first time some baseline characteristics that could benefit from AZA or DEC in terms of responses, 120-day mortality and OS. These findings could help us to choose the most appropriate HMA in monotherapy or for the development of new combinations. Figure 1 Figure 1. Disclosures de la Fuente: Novartis: Research Funding; Abbie: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Tolero Pharmaceutical: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Agios: Consultancy; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly patients were historically treated with chemotherapy, with ORRs below 30%. Despite treatment improvements with the recent approval of the combination venetoclax plus azacitidine, with 64% of ORR and overall survival of 14.7 months, 25% of patients continue to be refractory and 50% are estimated to relapse. The management of AML, especially in elderly or unfit patients, remains a major challenge. Lysine-specific histone demethylase 1 (LSD1) contributes to the malignant transformation event in AML. Iadademstat (iada) selectively inhibits LSD1 and has shown efficacy in preclinical models, including promoting differentiation in AML. Iada has been administered so far to +100 oncology patients in different clinical trials, showing good safety. With a favorable ADME profile and high bioactivity allowing low dosing regimens, a low DDI risk is anticipated, making iada suitable for different drug combinations and offering additional therapeutic options for patients. This is a 36-month update of the ongoing Phase II ALICE clinical trial of iadademstat plus azacitidine in front-line AML patients. Methods: ALICE (EudraCT 2018-000482-36) is an open-label, single arm, Phase IIa clinical trial to assess the safety, tolerability, dose finding and efficacy of iadademstat in combination with azacitidine for the treatment of adult AML patients. ALICE includes AML patients, who have not received prior treatment other than hydroxyurea and are considered by the investigator as ineligible for intensive chemotherapy or have refused this treatment option. Secondary end points of the study address the anti-leukemic activity of the combination (overall response rate, time to response and duration of response) along with PK/PD measures. Results: Current unaudited data corresponds to 34 patients enrolled, including 22 evaluable patients (with at least 1 bone marrow disease evaluation). Evaluable patients achieved an 73% objective response rate (ORR): 5 complete remissions (CR), 6 CR with incomplete hematological recovery (CRi) and 5 Partial Remissions (PR). The current median Time to Response is 30 days, with some durable responses, extending for more than one year in five patients, with the longest CR up to date above 930 days (still ongoing, with CR and MRD negative). Moreover, 5 patients became transfusion independent and MRD negative. The number of adverse events (AEs) reported is in line with the usual evolution of the disease and with other AML trials. Only 2 AEs (in 2 patients) were deemed as serious reactions, probably related to treatment: one differentiation syndrome (G3) and one intracranial hemorrhage (G5). The most frequent reported adverse reaction was thrombocytopenia, observed in almost half of patients (47%), although 63% of patients had presented with grade ≥3 thrombocytopenia at baseline, making difficult to unequivocally attribute observed cytopenias to treatment. Of note, patients that showed response experienced platelet recovery within the first 3 cycles of treatment. Other than the hematological events, the iada-azacitidine combination appears to be safe and well tolerated. We have not observed other significant non-hematological toxicities or other organ-related toxicities. We expect to achieve full patient recruitment of the ALICE study (36 subjects) in October 2021 and will report updated safety and efficacy results based on an October data cut-off. Conclusions: Data to date indicate that iadademstat has a good safety profile and produces robust, fast and in some cases durable responses. Iadademstat appears to be an active candidate for combination with azacitidine and other agents. Drug-related toxicity appears to be predictable, manageable, and restricted to hematologic events. Considering the novel mechanism of action of iadademstat, a pro-differentiating agent, combination strategies with iadademstat might increase therapeutic options for AML patients in first line treatment, as well as for refractory, intolerant, or relapsed patients. Disclosures Salamero: Pfizer: Consultancy; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Somervaille: Novartis: Consultancy, Honoraria. Molero: AbbVie: Honoraria; Jansen: Honoraria; BMS-Celgene: Other: Travel, accommodation expenses. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gutierrez: Oryzon Genomics: Current Employment. Buesa: Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

BACKGROUND: Current guidelines for AML ascribe disease-risk partly based on NPM1 and FLT3 mutational status. NPM1 mutations (mut) occur in 25%-30% of patients (pts) with AML and are associated with favorable prognosis in the absence of co-occurring FLT3-ITD. FLT3-ITD alterations are observed in ~15-30% of AML pts and confer poor prognosis, whereas the prognostic implication of FLT3-TKD point mutations (~7% of pts) is less clear. Post-IC, absence of MRD is associated with favorable relapse-free and overall survival (RFS/OS). In the randomized, phase 3 QUAZAR AML-001 trial, Oral-AZA (CC-486) significantly prolonged OS and RFS vs placebo (PBO) in older pts with AML in first remission after IC (Wei, NEJM 2020). It is of high interest to understand the effects of Oral-AZA in pts with NPM1 and/or FLT3 mutations, and whether their outcomes are influenced by post-IC MRD status. OBJECTIVE: Evaluate survival outcomes with Oral-AZA vs PBO in pts with NPM1mut ± FLT3mut at AML diagnosis (Dx), and OS by baseline (BL) MRD status (+/-) in pts with NPM1/FLT3 mutations. METHODS: In QUAZAR AML-001, pts aged ≥55 years with AML and NCCN intermediate or poor-risk cytogenetics at Dx were randomized 1:1 to receive Oral-AZA 300 mg or PBO QD within 4 mo after attaining first CR/CRi with IC (induction ± consolidation). NPM1 and FLT3 statuses (mut or wild-type [wt]) at AML Dx (before IC) were collected from pt diagnostic case report forms. MRD analyses were conducted by MFC (≥0.1% MRD+ cutoff) in bone marrow aspirate samples collected at screening (post-IC; ie, BL). OS and RFS were estimated from the time of randomization using Kaplan-Meier methods. Multivariate (MV) Cox regression analyses of the prognostic effects on OS/RFS were performed, with NPM1 and FLT3 mutational status and cytogenetic risk at Dx; post-IC MRD status (+/-) at BL, and randomized Tx (Oral AZA vs PBO) as variables. RESULTS: Of 472 pts enrolled , 469 (99.4%) had mutational data available at Dx, and the MRD-evaluable cohort comprised 463 pts (98.1%). In all, 137 pts (29%; Oral-AZA n = 66, PBO n = 71) had NPM1mut at AML Dx, and NPM1mut was significantly correlated with MRD- status at BL (post-IC)(P = 0.0178). Among pts with NPM1mut, OS was significantly improved in pts receiving Oral-AZA vs PBO, whether pts were MRD- (median 48.6 vs 26.2 mo, respectively) or MRD+ (median 39.4 vs 10.3 mo) at BL (both P < 0.0001) (Figure). While median OS for NPM1mut pts in the Oral-AZA arm was nominally improved for MRD- pts vs. those MRD+ (48.6 vs. 39.4 mo, respectively), median OS for NPM1mut pts in the PBO arm was substantially influenced by post-IC MRD status (26.2 vs 10.3 mo for MRD- and MRD+ pts, respectively) (Figure). Similarly, median RFS for pts with NPM1mut/MRD- in the Oral-AZA and PBO arms was 24.9 vs 9.9 mo, respectively, and for pts with NPM1mut/MRD+ was 19.4 vs 4.6 mo. In all, 66 pts (14.1%) had FLT3-ITD (n = 46) and/or FLT3-TKD mut (n = 24) at AML Dx; NPM1 and FLT3-ITD status was NPM1mut + FLT3-ITD - in 107 pts, NPM1mut + FLT3-ITD + in 30 pts, and NPM1wt + FLT3-ITD + in 16 pts. In the Oral-AZA arm, median OS in pts with FLT3mut was not meaningfully different from that in pts with FLT3wt (28.2 and 24.7 mo, respectively), but FLT3mut conferred a negative prognosis in the PBO arm (median OS 9.7 mo, vs 15.2 mo for FLT3wt pts). Risk of death was reduced 46% with Oral-AZA vs PBO in pts with FLT3mut (HR 0.54 [95%CI 0.25, 1.14]). When considering MRD status, median OS in FLT3mut/MRD- pts was 28.2 vs. 15.9 mo in the Oral-AZA (n = 14) and PBO (n = 17) arms, respectively, and was 24.0 vs 8.0 mo in FLT3mut/MRD+ pts (Oral-AZA, n = 16; PBO, n = 18). In MV analyses, Oral-AZA significantly improved OS vs PBO when adjusted for other variables (P = 0.035); NPM1 status (P = 0.001), FLT3status (P = 0.035), and cytogenetic risk at Dx (P < 0.001) were each also significantly predictive of OS, as was post-IC MRD status (P < 0.001). All except FLT3 status (P = 0.737) were significantly predictive of RFS. CONCLUSIONS: Oral-AZA prolonged OS and RFS vs PBO in pts with NPM1mut, with improvements beyond the prognostic benefit conferred by MRD-, suggesting that pts with NPM1mut and MRD- can attain substantial OS benefit with Oral-AZA maintenance. An OS benefit was also observed with Oral-AZA vs PBO in pts in FLT3mut at Dx, but outcomes may be confounded by co-occurring NPM1mut, so further investigation is needed. MV analyses confirmed the independent prognostic influence of Oral-AZA, NPM1 and FLT3 mutations at Dx, cytogenetic risk at Dx, and post-IC MRD status on OS. Figure 1 Figure 1. Disclosures Döhner: Janssen: Honoraria; Helsinn: Honoraria; Gilead: Honoraria; GEMoaB: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Berlin-Chemie: Honoraria; AstraZeneca: Honoraria; Astex Pharmaceuticals: Honoraria; Astellas: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Pfizer: Research Funding; Roche: Honoraria. Wei: Astellas: Honoraria; Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees. Roboz: Glaxo SmithKline: Consultancy; Helsinn: Consultancy; AbbVie: Consultancy; Jasper Therapeutics: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Actinium: Consultancy; Agios: Consultancy; Blueprint Medicines: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Jazz: Consultancy; Daiichi Sankyo: Consultancy; Astex: Consultancy; Mesoblast: Consultancy; Amgen: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Bristol Myers Squibb: Consultancy; Janssen: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy. Montesinos: Agios: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy. Thol: Abbvie: Honoraria; Astellas: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Ravandi: AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Astex: Honoraria, Research Funding; Prelude: Research Funding; Taiho: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Sandhu: Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Bioverativ: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Gilead: Consultancy. Skikne: Bristol Myers Squibb: Current Employment. See: Bristol Myers Squibb: Current Employment. Ugidos: Bristol Myers Squibb: Current Employment. Risueño: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Chan: Bristol Myers Squibb: Current Employment. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lopes de Menezes: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

Introduction: Acute myeloblastic leukaemia (AML) is an heterogeneous disease with different molecular and prognostic characteristics. According to the comorbidities and the revised 2017 European Leukaemia genetic risk stratification (ELN17), allogeneic hematopoietic cell transplantation (HCT) is the best therapeutic option for many patients with AML (Grimm, Blood Adv 2020). However, relapse remains the main cause of mortality after transplantation. Impact of MRD on the outcome of patients is well recognized and ELN2017 introduced the new response category complete remission (CR) without MRD (Döhner H, Blood 2017). Detection of measurable residual disease (MRD) by multiparameter flow cytometry (MFC) in AML before allogeneic HCT could be a powerful predictor of outcome and decisive when establishing strategies that modify the prognosis of these patients. Methods: Retrospective multicentre analysis of MRD by MFC of patients undergoing transplantation allogeneic in 4 centres during the period from 2012 to 2020. Both Leukaemia Associated Aberrant Immunophenotype (LAIP) and different from normal (DFN) approach were used to analyse the MRD. The MRD was carried out with 8-color panels based on Euroflow protocols. The samples were acquired in 8-color digital cytometers (FACSCanto II) calibrated and compensated according to Euroflow protocols. Results: 295 of 318 patients were evaluated. Table 1 shows the characteristics of the patients. 285 (96.7%) were in complete remission (CR), 207 had negative MRD, in 21 MRD was less than 0.1% (MRD-low) and in 57 greater than or equal to 0.1% (MRD-high). At 2 years, the overall survival (OS) and leukaemia-free survival (LFS) in the whole group were 69% (95% CI 63.18-74.18) and 58.4% (95% CI 52.4-63.9) respectively. In CR patients, MRD levels significantly influenced on outcomes, with OS and LFS of 76.7% and 67.6% for negative MRD, 68.5% and 49.7% MRD-low and 50 % and 36.6% in MRD-high, p Figure 1 Figure 1. Disclosures Caballero: Celgene: Consultancy. Belén Vidriales: Roche: Consultancy; Novartis: Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau. Montesinos: Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline/Menarini: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Perez-Simon: JANSSEN, TAKEDA, PFIZER, JAZZ, BMS, AMGEN, GILEAD: Other: honorarium or budget for research projects and/or participation in advisory boards and / or learning activities and / or conferences.

Introduction The prognosis of patients with relapsed or refractory acute myeloid leukemia (RR-AML) is very poor, and treatment options are very limited. The exciting results of venetoclax (VEN) in untreated AML have led to its off-label use in RR-AML. However, evidence in RR-AML is still scarce and the available data are mostly from retrospective and single-center studies. The aim of our study was to analyze the effectiveness of VEN use in patients with RR-AML reported to the PETHEMA AML epidemiological registry. Initial results were presented previously (Labrador J, et al. ASH 2020). Here, we report an updated analysis. Methods We conducted a retrospective, multicenter, observational study of a cohort of patients with AML-RR who were treated with venetoclax in the hospitals of the PETHEMA group. We evaluated efficacy, CR/CRi rate and overall survival (OS). We performed a descriptive analysis. Overall survival (OS) was calculated using the Kaplan-Meier method. Results Fifty-one patients were included, 33 men and 18 women, with a median age of 68 years (25-82). The main characteristics of the included patients are shown in Table 1. With a median follow-up of 167 days, 10/51 patients (19%) continued to receive VEN at the time of analyses. Patients received a median of 2 cycles (0-8). VEN was administered with azacitidine (AZA) in 59%, with decitabine (DEC) in 29% and with low-dose cytarabine (LDAC) in 12% of patients, respectively. The CR/CRi and partial response (PR) rates were 12.4% and 10.4%, respectively. The CR/RCi and overall response (ORR, CR/CRi+PR) was higher in patients receiving VEN+AZA (17.9% and 32.1%) than in those receiving DEC + VEN (6.7% and 13.3%) or LDAC + VEN (0%). The presence of NPM1 or CEBPA variants were the only two variables associated with increased CR/CRi with VEN in RR-AML. Median OS was 104 days (95% CI: 56 - 151) (Figure 1A), 120 days in combination with AZA, 104 days with DEC, and 69 days with LDAC; p=0.875. Treatment response (Figure 1B) and ECOG 0 were the only variables that influenced OS in a multivariate model adjusted for age and sex (Table 2). VEN-resistant patients who received subsequent salvage therapy had superior median OS (98 vs. 5 days, p=0.004).Twenty-eight percent of patients required discontinuation of VEN due to toxicity. Sixty-one percent of patients required admission, mainly due to infections (45%), 10% due to bleeding and other causes in 12%. One case of tumor lysis syndrome was described. Conclusions Our real-life series depicts a marginal probability of CR/CRi and poor OS after venetoclax-based salvage. Patients treated with this regimen had very poor-risk features, and were heavily pre-treated, which could explain in part the observed poor outcomes. Although follow-up is still short, the small proportion of responders did not reach the median OS. Further studies will help to identify those patients potentially benefiting from venetoclax-based salvage regimens. Figure 1 Figure 1. Disclosures Belén Vidriales: Roche: Consultancy; Novartis: Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Pérez-Encinas: Janssen: Consultancy. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. OffLabel Disclosure: Venetoclax for Patients with Relapsed or Refractory Acute Myeloid Leukemia

BACKGROUND: Despite improvements in the treatment of "unfit or older" AML patients with the combination of azacitidine (AZA) and venetoclax (VEN), long-term survival for these patients remains poor. Additions to this new regimen may further improve patient outcomes. Overexpression of CD123, the alpha subunit of the IL-3 receptor, is seen in AML blasts. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprised of a high-affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. Preclinical data have demonstrated synergy between IMGN632 and AZA and/or VEN, including overcoming AZA/VEN resistance in murine AML models (Kuruvilla ASH 2020), supporting the clinical exploration of these combinations. Doublets of IMGN632 with both AZA and VEN were studied in AML patients and supported testing of the triplet of IMGN632, AZA, and VEN. Here we report the initial safety and anti-leukemia activity findings from this novel triplet. METHODS: This Phase 1b/2 study was designed to determine the safety, tolerability, and preliminary anti-leukemic activity of IMGN632 combined with AZA and VEN in patients with CD123-positive AML. To date, the triplet combination escalation consists of 5 cohorts of IMGN632 plus AZA and VEN, each agent designated by "C" for IMGN632 dose in mcg/kg, "A" for AZA dose in mg/m2 x7 days, or "V" for VEN # of days at 400mg QD. Four cohorts dosed IMGN632 on Day 7 of each cycle (C15A50V8, C15A50V14, C15A75V21, C45A50V8), and one cohort dosed IMGN632 on Day 1 of each cycle (Day 1 C15A50V14). Responses are determined using modified ELN criteria with a 14-day count recovery window. RESULTS: At the time of this analysis, preliminary safety data are available for 35 relapsed or refractory (R/R) AML patients. The median age was 69y, 23% had secondary AML, 86% received prior intensive therapies, 37% that were refractory to first line therapy, and 51% had received prior VEN. Twenty-three percent of patients had FLT3 mutations. The toxicity profile was manageable in this R/R AML population with multiple prior therapies. The most common treatment emergent adverse events (TEAE) all grades [grade 3+ events] seen in >20% of patients were infusion-related reactions (IRR, 37% [3%]), febrile neutropenia (26% [23%]), hypophosphatemia (26% [3%]), dyspnea (26% [6%]), pneumonia (20% [14%]), and fatigue (20% [0%]). One patient in the Day 1 C15A50V14 cohort discontinued IMGN632 due to a TEAE (DLT IRR, resolved). Cytopenias and infections were consistent with those observed with the AZA+VEN regimen in this R/R population. No TLS, VOD, capillary leak or cytokine release were observed. 30-day mortality was 0%. Efficacy was seen across all cohorts/doses and schedules (efficacy evaluable population, n=29). The objective response rate (ORR) was 55% with a composite complete remission (CCR) rate of 31% (1 CR, 4 CRh, 2 CRp, 2 CRi). Higher intensity cohorts (IMGN632 dose 45 mcg/kg or 14-21 days of VEN) on the Day 7 schedule (n=20) were associated with higher response rates: ORR 75%, CCR rate 40% (Figure 1). At these higher intensity cohorts, in the VEN naïve subset (n=10), ORR/CCR rates were 100%/60%, respectively. Significant activity was also seen in the FLT3 mutant subset (n=7), with ORR/CCR rates of 100%/71%. CONCLUSION: With a manageable safety profile in this R/R AML population, the novel IMGN632 triplet demonstrated compelling anti-leukemia activity. Ongoing escalation cohorts aim to optimize safety and efficacy of the triplet therapy. Expansion proof-of-concept cohorts are planned in both relapsed and frontline AML patients (NCT04086264). Updated safety, efficacy, and PK data will be presented. Figure 1 Figure 1. Disclosures Daver: Trillium: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Hanmi: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Trovagene: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Aribi: Seagen: Consultancy. Montesinos: Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: 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, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Roboz: Astex: Consultancy; Jazz: Consultancy; Glaxo SmithKline: Consultancy; Mesoblast: Consultancy; Blueprint Medicines: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Amgen: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Astellas: Consultancy; Agios: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Janssen: Research Funding; Jasper Therapeutics: Consultancy; Celgene: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Wang: Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; 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. Walter: Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Amgen, Inc.: Consultancy, Research Funding; Amphivena Therapeutics, Inc.: Current equity holder in publicly-traded company; Aptevo Therapeutics, Inc.: Consultancy, Research Funding; Arog Pharmaceuticals, Inc.: Research Funding; Astellas Pharma US, Inc.: Consultancy; BioLineRx, Ltd.: Consultancy, Research Funding; Boston Biomedical, Inc.: Consultancy; Bristol Myers Squibb, Inc.: Consultancy; Celgene, Inc.: Consultancy, Research Funding; Genentech, Inc.: Consultancy; GlaxoSmithKline, Inc.: Consultancy; ImmunoGen, Inc.: Research Funding; Janssen Global Services, LLC: Consultancy; Janssen Research & Development, Inc.: Research Funding; Jazz Pharmaceuticals, Inc.: Consultancy, Research Funding; Kite Pharma, Inc.: Consultancy; Kronos Bio, Inc.: Consultancy; Kura Oncology, Inc.: Research Funding; Macrogenics, Inc.: Research Funding; New Link Genetics: Consultancy; Pfizer, Inc.: Consultancy, Research Funding; Race Oncology Ltd.: Consultancy; Selvita: Research Funding; Stemline Therapeutics, Inc.: Research Funding. Jeyakumar: Jazz: Research Funding; Pfizer: Research Funding. DeAngelo: Abbvie: Research Funding; Blueprint Medicines Corporation: Consultancy; Incyte Corporation: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy; Agios: Consultancy; Amgen: Consultancy; GlycoMimetics: Research Funding; Shire: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy. Erba: Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie, Agios, Amgen, Astellas Pharma, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy; Glycomimetics: Membership on an entity's Board of Directors or advisory committees; Covance (AbbVie): Other: Independent Review Committee ; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, and PTC: Research Funding. Advani: Abbvie: Research Funding; Immunogen: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; OBI: Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinelli: Celgene /BMS: Consultancy, Speakers Bureau; Stemline Therapeutics: Consultancy; Roche: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy; Daichii Sankyo: Consultancy; Incyte: Consultancy; Astellas: Consultancy, Speakers Bureau. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Altman: Biosight: Membership on an entity's Board of Directors or advisory committees, Other: reimbursement for travel, Research Funding; ImmunoGen: Research Funding; Kartos Therapeutics: Research Funding; Kura Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujifilm: Research Funding; Glycomimetics: Other: data monitoring committee; Loxo: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; Astellas: Honoraria, Research Funding; Aptos: Research Funding; Aprea: Research Funding; Amgen: Research Funding; Abbvie: Honoraria, Research Funding; ALX Oncology Inc.: Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees. de la Fuente: Incyte: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Novartis: Research Funding; BMS: Consultancy, Speakers Bureau. Gaidano: Incyte: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Boissel: PFIZER: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Incyte: Honoraria; JAZZ Pharma: Honoraria, Research Funding. Recher: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Incyte: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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; Agios: 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. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Konopleva: Cellectis: Other: grant support; Calithera: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding. Sallman: Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Kantarjian: KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; NOVA Research: Honoraria; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Astra Zeneca: Honoraria; Aptitude Health: Honoraria; Astellas Health: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Precision Biosciences: Honoraria. Malcolm: Immunogen: Current Employment. Zweidler-McKay: ImmunoGen: Current Employment. 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; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: 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.

INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), are a common choice for initial treatment in elderly patients with acute myeloid leukemia (AML). However, about 60% of patients are resistant and most will relapse after a complete response (including CR/CRi). Although relapse or refractoriness to HMAs is very common, very little is known about the therapeutic management of these relapsed or refractory AML (RR-AML) patients after HMAs. METHODS We conducted a retrospective study to describe and compare salvage treatment patterns and real-life clinical outcomes of those AML patients treated upfront with AZA or DEC included in the PETHEMA-AML Registry. RESULTS Between 2006 and 2019, we included 626 AML patients treated in first-line with HMAs, 487 (78%) received AZA and 139 (22%) received DEC. Overall response rate (CR/CRi+PR) was 33.7%, 32% in the AZA vs 39.5% in the DEC group (p=0.120). Patients treated with DEC had a higher median relapse free survival than those treated with AZA (25.6 vs. 17.5 months, p=0.027). No differences were observed in the overall survival between AZA and DEC. We observed 59.7% resistance after HMAs, 60% after AZA and 58.8% after DEC; and 6.5% had other type of response (< PR), 7.9% with AZA and 1.6% with DEC. In addition, 76/121 patients who achieved CR/CRi (62.8%) relapsed, 66/90 in the AZA group (73.3%) vs 10/31 in the DEC group (32.3%) (p=0.000). After relapse or resistance, 74.5% of patients received supportive care only (BSC), which included patients receiving transfusions and other supportive measures, including oral agents to control the white blood cell counts; 71.5% of patients in the AZA group and 84.3% of patients in DEC group (p= 0.004). No differences were observed in baseline characteristics at diagnosis of patients treated with BSC only, except for a higher proportion of patients with adverse cytogenetic risk in the AZA group (46.6% vs. 33.7%, p=0.039). Only 135 patients received a salvage therapy, 116 in the AZA group and 19 in the DEC group. Thirty-five out of 135 RR-AML treated patients (26%) continued receiving HMAs: 31 (26%) in the AZA group and 4 (22%) in the DEC group. In the AZA group, 19 (16%) patients continued with AZA and 12 (10%) switched to DEC, while in the DEC group 2 patients (11%) continued with DEC and 2 (11%) switched to AZA. Fifty-one patients (37.8%) received FLUGA (fludarabine and Ara-C), FLAG-IDA-Lite (fludarabine, Ara-C and idarubicin), Low-dose Ara-C or other non-intensive regimens, 43 patients (37%) in the AZA group and 8 (42%) in the DEC group. Other salvage therapies were administered in 34% of patients (33% in the AZA group and 37% in the DEC group). Salvage therapy was not available in 1% of patients. Response assessment was available in 113/135 of RR-AML treated patients, 98 in the AZA group and 15 in the DEC group. In the AZA group, 13.2% of the patients achieved a CR (n=13), 5.1% achieved CRi (n=5), 6.1% achieved a PR (n=6), 65.3% resistance (n=64) and 8.1% died (n=8). However, no patients in the decitabine group responded to salvage therapy, 86.7% resistance (n=13) and 13.3% died (n=2). If we exclude those patients who died before response was evaluated, the ORR (CR/CRi+PR) after salvage therapy was statistically significant between AZA (n=24/90, 26.7%) and DEC group (n=0/13, 0%), p=0.035. CONCLUSIONS This study shows and compares, for the first time to our knowledge, the patterns of salvage therapy in patients with RR-AML treated upfront with HMAs. Despite the similar response rate with both HMAs, the relapse free survival was lower after AZA. The absence of responses in patients with RR-AML initially treated with DEC could justify the similar OS between AZA and DEC observed. However, we should be very cautious due to the low number of RR-AML patients treated. Disclosures de la Fuente: BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Novartis: Research Funding. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

Background: Genetic information has become critical to understand the development of T-cell acute lymphoblastic leukemia (T-ALL) and to elucidate the origin of disease relapse. Several genetic markers, together with measurable residual disease (MRD), are considered strong predictors of patient outcome. However, the prognostic significance of genetic markers can varie according to treatment. Aim: We used targeted deep sequencing to analyze the genetic profile of 125 T-ALL patients enrolled in three consecutive MRD-oriented trials from the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genomic information was analyzed together with the main clinical and biologic data in a subset of 111 patients with detailed clinical and outcome data to determine the prognostic significance for overall survival (OS) and cumulative incidence of relapse (CIR). Methods: Genetic mutations were detected using a custom gene panel and sequenced on a MiSeq platform. Alignment, variant calling, filtration and annotation of variants were done using standardized pipelines. OS curves were plotted by the Kaplan-Meier method and compared by the log-rank test. CIR was estimated using cumulative incidence functions by competing risks analysis. A Cox proportional hazard regression model was used to identify predictive factors for OS. Statistical significance was set at (two-sided) p-values Results: Recurrently mutated genes found in ≥4/125 patients involved transcription factor tumor suppressor genes (PTEN, BCL11B, RUNX1, GATA3, ETV6), epigenetic regulators (PHF6, DNMT3A, EP300, KMT2C, EZH2, TET2), DNA mismatch repair genes (MSH2), ribosomal (RPL5) and RNA splicing (U2AF1) genes, and genes involved in the RAS/MAPK (NRAS), WNT (FAT1, FAT3), IL7R-JAK-STAT (JAK3, JAK1, IL7R) and NOTCH1 signaling pathways, respectively. Mutations in the latest pathway (NOTCH1 & FBXW7) was found in 88/125 (70%) patients. Clinical-genetic correlations revealed that patients with mutations in JAK3, DNMT3A, N/KRAS, IL7R, MSH2 or in U2AF1 were associated with lower OS (vs unmutated patients). None of the mutated genes had impact on CIR. Upon grouping the mutated genes according to their functional role and potential biological impact on T-ALL, two gene signatures were defined. These included the aging gene signature (DNMT3A and U2AF1) characterized by mutations in genes identified in clonal hematopoiesis of indeterminate potential (CHIP); and the treatment resistance gene signature (JAK3, N/KRAS, IL7R and MSH2), defined by mutations in genes involved in resistance to the ALL therapy. Both clusters identified patients with poorer response to therapy (poorer blast clearance on day 14 of induction treatment and lower CR rates). Therefore, we considered together (worse outcome genetics [WOG] signature) for univariate and multivariate analyses. WOG and MRD level (0.1% cut-off) on day 35 after induction therapy (+35d MRD) showed significant prognostic impact in the univariable and multivariable analyses for OS (3y) with a hazard ratio (95% CI) of 2.4 (1.2; 4.8) and 2.7 (1.4; 5.1), respectively (Table 1). OS according to these two variables allowed risk stratification of T-ALL into low, intermediate- and high-risk (HR) patients with significantly different outcomes (p Conclusion: A genetic signature with independent prognostic significance of MRD has been identified in this cohort of patients included in MRD-oriented trials. This gene signature (WOG) together with MRD could help to improve risk-stratification of adult T-ALL patients and would be of interest in the search for new therapies for HR patients Funding: Support from AECC (GC16173697BIGA); ISCIII (PI19/01828 and PI19/01183), co-funded by ERDF/ESF, "A way to make Europe"/"Investing in your future", CERCA/Generalitat de Catalunya SGR 2017 288 (GRC)/ C González-Gil was supported by AGAUR grant (2020 FI_B2 00210). Figure 1 Figure 1. Disclosures Diaz-Beyá: Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mercadal: Gilead Sciences, Inc.: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tormo: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding. Maciejewski: Regeneron: Consultancy; Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Alexion: Consultancy. Ribera: ARIAD: Consultancy, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau.

Next-Generation Sequencing (NGS) has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia (AML). However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of 7 reference laboratories aimed to deliver molecular results to the clinics. We report the technical cross-validation results for NGS and clinical validation in 2960 AML samples. Three cross-validation rounds (CVR) were performed to establish consensus parameters for NGS analysis and variant reporting. In the first CVR we evaluated the starting situation of the NGS studies. In the second CVR the laboratory network established minimum quality parameters and consensus recommendations to guarantee a valid NGS assay. The third CVR strengthened the established parameters and refined the clinical variant classification. The clinical validation was performed in 2960 samples from 2703 patients: 1530 male and 1173 female with a median age of 67.5 years old. 2522 samples were collected at diagnosis, 275 at relapse and 163 at refractory AML from October 2017 to October 2019. NGS analysis was performed according to already implemented protocols and only variants accomplishing the established quality control parameters were considered. In the first CVR the error rate (ER) was 39% with a high variability in the studied genes. Then, 30 genes were agreed as key genes for AML pathogenesis: 8 were considered mandatory due to their implication in clinical guidelines, targeted therapy and risk stratification and the study of the remaining 22 was recommended based on panel availability (Table 1). In the second CVR the ER was reduced to 14.4% and the NGS quality metrics were 4032X of mean read depth and 98.3% of median uniformity. Therefore, the laboratory network established a minimum read depth of 500X and uniformity >85% as quality control parameters. Due to the high variability in the detection of low VAF variants (1 CVR: ER 8043 variants were reported in the 2960 samples, with 96.5% of patients showing at least 1 mutated gene. The mean number of variants per sample was 2.71 (range 0-9), the number of mutations in ≥65 years old patients (2.9 vs. 2.5, P At least 1 mutation in one of the 8 clinically relevant genes was detected in the 78.7% of patients: 39.8% of patients had targetable mutations (FLT3-ITD/TKD and IDH1/2 mutations) and 35.6% of patients, variants found in ASXL1, RUNX1 and TP53 were the only clinically relevant variant detected. The study of clonal evolution through paired-sample analysis showed that mutations in FLT3, KRAS, NRAS and PTPN11 were particularly unstable at relapse or refractoriness. We show the development of the first national strategy for validation of NGS studies with centralized analysis in an AML cooperative group. We have developed a laboratory network with standardized protocols to ensure technical quality and equity in access to NGS studies. The unification of analysis and interpretation criteria represents a significant increase in the quality of diagnostic tests and translational research. N/A-NI-AML-PETHEMA-007343, PI18/01340, PI19/00730, FI19/00059 Figure 1 Figure 1. Disclosures Ayala: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Celgene: Honoraria. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perez-Simon: JANSSEN, TAKEDA, PFIZER, JAZZ, BMS, AMGEN, GILEAD: Other: honorarium or budget for research projects and/or participation in advisory boards and / or learning activities and / or conferences. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Montesinos: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy.

Introduction: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, accounting for almost 80 percent of the cases. Incidence of AML increases with age and it ranges from 3 to 5 cases per 100,000 persons in the United States. Advances in treatment have led to significant improvements in outcomes for younger patients, while prognosis in the elderly remains poor. There are different sociodemographic and clinical factors that have an impact on survival such as type of leukemia (secondary vs novo), low socioeconomic status, age, gender, health regimen, co-morbidities and performance status Objective: The aim of the study was to describe the impact of sociodemographic and clinical factors on survival of patients with AML in 11 health institutions from Colombia, from 2009 to June 2021. Methods: Population based on RENEHOC (online platform) and PETHEMA (Spanish Program for Hematology Treatments). Kaplan-Meier analysis was used to assess overall survival (OS) and Relapse-Free Survival global (RFS) of the different evaluated factors. Results: A total of 463 patients were included. The median age at diagnosis was 61 years (range, 19-90) and 50.5% were female. According to the FAB classification, 95 (26.6%), 84 (23.6%), and 53 (14.9%) of patients were classified as M2, M0 and M1, respectively. The cytogenetic risk was applied for 227 patients (57%), 135 (59.5%) were intermediate and 78 (34.4%) were high-risk. Secondary AML were 73 (18.2%) and these cases evolved from hematological malignancies in 38 cases (80.8%), the most common were myelodysplastic syndrome (n=16; 34%) and chronic myeloid leukemia (n=7; 50%). For induction therapy, 232 (59.7%) patients received 7+3 (cytarabine/idarubicin), 47 (11.7%) received Azacitidine (AZA) and 23 (5.7%) received FLUGA (Fludarabine/cytarabine low doses). Complete remission (CR) after induction was achieved in 53% of patients, 12% had partial remission, 20.3% had primary refractory AML. Twelve percent died during induction. The most common consolidation regimen was high dose cytarabine (HiDAC), 143 (35,6%) and 36 (9%) of patients received 1 and 2 cycles respectively. Seventy-two (51%) patients that achieved a CR relapsed, and 46 (69.7%) received second line therapy. The most common treatment was FLAG-IDA (27%), followed by best supportive care (23.8%). The response rate was 40% (CR:31.1%/PR:8.9%) with 16 (36.6%) patients being refractory to treatment. Five (11.1%) died during salvage therapy. Thirty-eight (21%) patients had a hematopoietic stem cell transplantation (HCT), 35 (92%) had allogeneic HCT and 3 (8%) autologous HCT, respectively. The median and 5-year OS for the whole population was 19 months and 27.6% (95%CI,19.7- 36.0). The median and 5-year RFS was 14 months and 21.8% (95%CI, 15.2 - 29.2), respectively (Figure 1). Sociodemographic and clinical factors such as age, ECOG PS, co-morbidies (Hypertension, diabetes, and chronic heart failure), AML subtype and leukocytosis at diagnosis were prognostic (Table 1). Conclusion: This is the first multicenter report analyzing real world data from AML patients in Colombia. Results confirm the impact of clinical factors: age, ECOG, secondary LMA on OS and RFS. Challenges includes low alloHSCT rate and low access to complete cytogenetic and molecular classification at diagnosis. Figure 1 Figure 1. Disclosures Sossa: Amgen: Research Funding. Abello: Dr Reddy's: Research Funding; Janssen: Honoraria; Amgen: Honoraria. Peña: Amgen: Research Funding. Salazar: Amgen: Research Funding. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Montesinos: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; Tolero Pharmaceutical: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy.

Background: Overexpression of CD123 is characteristic of a number of hematological malignancies, including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) with a novel anti-CD123 antibody coupled to a unique DNA-alkylating payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class of payloads. In preclinical models of AML, IMGN632 exhibited potent anti-leukemia activity, with a wide therapeutic index. Confirming preclinical expectations, encouraging single-agent activity and favorable tolerability were observed in the Phase I trial (Daver ASH 2019, Blood 2019, vol 134, suppl 1, 734). Preclinical data from AML xenograft models have demonstrated synergy in IMGN632 combinations with azacitidine and venetoclax (Kuruvilla ASH 2020, Blood 2020, vol 136, suppl 1, 32-33), supporting the exploration of these combinations in AML patients. Methods: This Phase 1b/2 study is designed to determine the safety, tolerability, and preliminary anti-leukemia activity of IMGN632 when administered in combination with azacitidine and venetoclax to patients with relapsed and frontline CD123-positive AML, and the single-agent activity of IMGN632 in patients with minimal residual disease (MRD)-positive AML in frontline or 1 st salvage treatment. Study Design: Adult patients with CD123-positive relapsed or refractory AML, who are deemed appropriate for experimental therapy, are eligible to enroll as part of the dose escalation phase. Key exclusion criteria for all regimens include active central nervous system disease, and history of sinusoidal obstruction syndrome/venous occlusive disease of the liver. Current enrollment is focused on the triplet, IMGN632 plus azacitidine and venetoclax (IMGN632+AZA+VEN). Once an RP2D is selected, Phase 2 dose expansion will further characterize the safety profile and assess antileukemia activity in frontline or relapsed AML patients. In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD+ to MRD- and RFS in both fit and unfit AML subpopulations (NCT04086264). IMGN632 is also being tested as a monotherapy in a pivotal cohort for adults with frontline BPDCN (NCT03386513, https://BPDCNtrial.com). Disclosures Daver: FATE Therapeutics: Research Funding; Sevier: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Glycomimetics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novimmune: Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Aribi: Seagen: Consultancy. Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceutical: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Roboz: Novartis: Consultancy; Agios: Consultancy; Helsinn: Consultancy; AstraZeneca: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; Celgene: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Janssen: Research Funding; Blueprint Medicines: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Glaxo SmithKline: Consultancy; Janssen: Consultancy; Bristol Myers Squibb: Consultancy; Astex: Consultancy; Amgen: Consultancy; Actinium: Consultancy; Astellas: Consultancy; Mesoblast: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Wang: DAVA Oncology: Consultancy, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; 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. Walter: Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Amgen, Inc.: Consultancy, Research Funding; Amphivena Therapeutics, Inc.: Current equity holder in publicly-traded company; Aptevo Therapeutics, Inc.: Consultancy, Research Funding; Arog Pharmaceuticals, Inc.: Research Funding; Astellas Pharma US, Inc.: Consultancy; BioLineRx, Ltd.: Consultancy, Research Funding; Boston Biomedical, Inc.: Consultancy; Bristol Myers Squibb, Inc.: Consultancy; Celgene, Inc.: Consultancy, Research Funding; Genentech, Inc.: Consultancy; GlaxoSmithKline, Inc.: Consultancy; ImmunoGen, Inc.: Research Funding; Janssen Global Services, LLC: Consultancy; Janssen Research & Development, Inc.: Research Funding; Jazz Pharmaceuticals, Inc.: Consultancy, Research Funding; Kite Pharma, Inc.: Consultancy; Kronos Bio, Inc.: Consultancy; Kura Oncology, Inc.: Research Funding; Macrogenics, Inc.: Research Funding; New Link Genetics: Consultancy; Pfizer, Inc.: Consultancy, Research Funding; Race Oncology Ltd.: Consultancy; Selvita: Research Funding; Stemline Therapeutics, Inc.: Research Funding. Jeyakumar: Jazz: Research Funding; Pfizer: Research Funding. DeAngelo: GlycoMimetics: Research Funding; Forty-Seven: Consultancy; Abbvie: Research Funding; Autolus: Consultancy; Incyte Corporation: Consultancy; Shire: Consultancy; Blueprint Medicines Corporation: Consultancy; Amgen: Consultancy; Agios: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee. Advani: Abbvie: Research Funding; Macrogenics: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; OBI: Research Funding; Immunogen: Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinelli: Incyte: Consultancy; Pfizer: Consultancy, Speakers Bureau; Daichii Sankyo: Consultancy; Astellas: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Roche: Consultancy; Abbvie: Consultancy; Stemline Therapeutics: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Altman: Biosight: Membership on an entity's Board of Directors or advisory committees, Other: reimbursement for travel, Research Funding; ImmunoGen: Research Funding; Kartos Therapeutics: Research Funding; Kura Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujifilm: Research Funding; Glycomimetics: Other: data monitoring committee; Loxo: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; Astellas: Honoraria, Research Funding; Aptos: Research Funding; Aprea: Research Funding; Amgen: Research Funding; Abbvie: Honoraria, Research Funding; ALX Oncology Inc.: Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees. de la Fuente: Incyte: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Novartis: Research Funding; BMS: Consultancy, Speakers Bureau. Gaidano: Incyte: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Boissel: Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; PFIZER: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; CELGENE: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; SANOFI: Honoraria; Incyte: Honoraria. Recher: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Incyte: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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; Agios: 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. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Wang: Immunogen: Current Employment. Malcolm: Immunogen: Current Employment. Zweidler-McKay: ImmunoGen: Current Employment. 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.

BACKGROUND. SEL24/MEN1703 is a first-in-class, orally available, dual PIM/FLT3 kinase inhibitor investigated in unselected AML patients in the First-in-Human, Dose Escalation (DE) and Cohort Expansion (CE) CLI24-001 trial (DIAMOND-01, ClinicalTrials.gov identifier: NCT03008187). The study has completed both the DE and CE part showing an acceptable safety profile up to the recommended dose (RD), with initial evidence of single agent efficacy particularly clustering in patients with IDH mutant disease. Previous studies conducted on a limited number of patients in the DE cohort indicated pS6, a downstream target in the PIM/FLT3 signaling pathway, as a biomarker of target engagement. AIM. To assess the relevance of pS6 as a pharmacodynamic (PD) biomarker in SEL24/MEN1703-treated patients. Moreover, patients were characterized on the basis of genetic profile to identify mutations which might cluster in patients' samples that demonstrated significant target engagement. Finally, longitudinal assessment of Variant Allelic Frequency (VAF) has been implemented. METHODS. S6 phosphorylation has been longitudinally monitored in the DIAMOND-01 study through an optimized assay for multiparametric analysis of phospho-protein activation. The assay allows a quantitative assessment of pS6 at the single cell level among blast cells as well as the identification of blast subpopulations in peripheral blood (PB). CD34+ Blast cells % was monitored to assess whether target engagement translated into blast reduction. Genotype analysis was performed by NGS using the Oncomine Myeloid Research Assay. RESULTS. PB samples from DE and CE patients, treated at 125 mg (RD) were analyzed, for a total of n= 27 assessable patients. At screening, we observed a heterogeneous positivity for pS6 marker in blast cells (range: 0.9%-79%), consistent with the unselected AML patient population recruited in the trial. Overall, 14/27 (51.8%) patients showed pS6 inhibition in blast cells at the end of Cycle 1 in comparison with screening (range: 70%-94%) (Figure 1). When SEL24/MEN1703 treatment continued beyond Cycle 1 (n=11 patients), pS6 inhibition was maintained and long-lasting in 6/11 (54.5%) patients. While pS6 inhibition did not translate into CD34+ blast decrease in all patients, long-lasting pS6 inhibition was observed in 2 out of 3 responding patients (including CRi as best response) evaluable for pS6 levels. Genetic characterization of these two patients treated at 125 mg (RD) showed that they harbored IDH mutations. CONCLUSIONS. The longitudinal PD assessment through the modulation of pS6 activation by flow cytometry confirmed that meaningful target engagement was achieved in more than 50% of patients treated with SEL24/MEN1703 at the RD. In most patients, including 2 out of 3 responders evaluable for pS6, its inhibition was maintained during the entire treatment. Preliminary genotyping showed that responding patients with strong pS6 inhibition harbored IDH mutations. In-depth analysis of genomic profiling and of the longitudinal assessment of VAF is ongoing in order to identify potential correlation with pS6 modulation and blast depletion in specific AML subsets, with the aim to define patient population(s) more likely to respond to SEL24/MEN1703. Figure 1. pS6 (%pS6*MFI) assessment in peripheral blast cells at screening and at C1D14-4H in CE patients treated at RD of 125 mg. Figure 1 Figure 1. Disclosures Paoli: Menarini Group: Current Employment. Bellarosa: Menarini Group: Current Employment. Bressan: Menarini Group: Current Employment. Bertolini: Gilead: Research Funding; Emercell: Research Funding. Montesinos: Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline/Menarini: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Mukherjee: Eusa Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Teaching and Speaking; McGraw Hill: Honoraria, Other: Editor of Hematology Oncology Board Review (ongoing); Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; AAMDS in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria; Genentech: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; BioPharm: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; Bristol-Myers Squibb Co.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acceleron: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Partnership for Health Analytic Research: Honoraria. Strickland: AbbVie, ArcherDx, Genentech, Incyte, Kura Oncology, Novartis, Pfizer, and Syros: Consultancy; Sunesis: Research Funding. Santoro: Takeda: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Arqule: Consultancy, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Speakers Bureau; Eli-Lilly: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Walter: 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; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Fazal: Taiho: Consultancy, Honoraria, Speakers Bureau; Stemline: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Tolero: Consultancy. Ravandi: Novartis: Honoraria; AstraZeneca: Honoraria; Xencor: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Prelude: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Brzozka: Ardigen: Current Employment, Membership on an entity's Board of Directors or advisory committees; Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Selvita SA: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Rzymski: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mazan: Ryvu Therapeutics: Current Employment; Selvita SA: Current Employment. Baldini: Menarini Group: Current Employment. Ravenni: Menarini Group: Current Employment. Binaschi: Menarini Group: Current Employment. Laurent: Menarini Group: Current Employment. Pellacani: Menarini Group: Current Employment.

Background and objective. The combination of HyperCVAD and ponatinib resulted in a high molecular response rate and survival in adults with Ph+ ALL, suggesting improved outcome compared with combinations of chemotherapy with first- or second-generation tyrosine kinase inhibitors (TKI) (Jabbour E, et al, Lancet Haematol. 2018;5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same chemotherapy as that of the ALL Ph08 trial that used imatinib as TKI (Ribera JM et al. Cancer 2019;125:2810-17). Final results of this trial are reported. Patients and method. PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin, prednisone) followed by consolidation (high-dose methotrexate, high-dose ARA-C, mercaptopurine, etoposide) and allogeneic hematopoietic stem cell transplantation (alloHSCT). Ponatinib was scheduled after alloHSCT only for patients (pts) with persistence/reappearance of MRD. Response to therapy (complete morphological [CR], molecular [complete -CMR- or major -MMR-] after induction and before alloHSCT) (assessed by centralized BCR-ABL1/ABL1 ratio), disease-free survival (DFS), overall survival [OS]) and toxicity were analyzed. The following genetic studies were performed: 1. Additional gene abnormalities (Copy Number Alteration [CNA] analysis by SNP array Affymetrix 750K), 2. ABL1 mutation status at diagnosis (Sanger sequencing), 3. T315I mutation at diagnosis (allele-specific PCR). A propensity score comparison with the results of the ALL Ph08 trial was performed. Results. Median age was 49 (19-59) years (y), and 13/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score was Among 7/16 pts without CMR after consolidation and genetic material available, 4 showed IKZF1 deletion (IKZF1 plus in 2), 1 showed CDKN2A/B and PAX5 deletion and 2 did not show any CNA. Among 5/19 pts with molecular relapse, 3 showed IKZF1 deletion (1 being IKZF1 plus), and 2 pts did not show any CNA. No ABL1 mutations or T315I mutation at diagnosis were found. Propensity score with 1:1 matching identified 30 pts in each cohort (variables: age, gender, ECOG, WBC, CNS involvement, cytogenetic risk and BCR/ABL isoform). 2y DFS rates for PONALFIL and ALL Ph08 trials were 97% and 62%, (p=0.005), and 2y OS rates were 97% and 66% (p=0.001) (Figure 2). 107 adverse events (AE) were registered in 20 pts (21 severe in 11 pts), prompting to withdrawn of the trial in 3 (thrombosis of central retina artery, severe bowel infection, grade IV hepatic toxicity). The most frequent AE were hematologic (28%), gastrointestinal (14%), hepatic (11%), infections (7%), and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina). Conclusions. The results of the PONALFIL trial show a high antileukemic efficacy with acceptable toxicity profile and compare favorably with the same chemotherapy schedule and imatinib. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. OS (A) and DFS (B). PONALFIL. Figure 2. OS (A) and DFS (B). PONALFIL vs. ALL Ph08. Figure 1 Figure 1. Disclosures Ribera: AMGEN: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Esteve: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Novartis: Research Funding; Jazz: Consultancy; Astellas: Consultancy. Mercadal: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Honoraria, Speakers Bureau. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. OffLabel Disclosure: This trial includes Ponatinib in off-label indication.