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INTRODUCTION: The current WHO definition requires presence of persistent absolute monocytosis for the diagnosis of chronic myelomonocytic leukemia (CMML). Oligomonocytic CMML (O-CMML), defined by presence of clinical and pathological features of CMML in the presence of an absolute monocyte count (AMC) of 0.5-0.9x109/L and ³10% monocytes, has been proposed as a unique entity. To date, there is scarce data on the clonal architecture, optimal therapeutic management and survival outcomes of these patients (pts) compared to those with classical CMML. METHODS: We evaluated all untreated pts who met proposed diagnostic criteria of O-CMML treated at the University of Texas MD Anderson Cancer Center from 2000 to 2020. Whole bone marrow DNA was subject to 81 gene targeted next-generation sequencing (NGS) analysis in a subset of patients. Variant allele frequency (VAF) estimates were used to evaluate clonal relationships within each individual sample using Pearson goodness-of-fit tests and VAF differences. Response to therapy was assessed following MDS/MPN IWG response criteria. RESULTS: A total of 30 pts met criteria for O-CMML. Compared to a cohort of 271 pts with classical CMML, there were no significant differences in cytogenetic abnormalities based on CMML-specific prognostic scoring system (CPSS). NGS was available in 10 (33%) patients with O-CMML. Frequency of identified mutations and their VAFs are shown in Figure 1A and compared to that of the CMML cohort. Frequencies of mutations in ASXL1 (50% vs 49.1%, p=0.958), SRSF2 (60% vs 39.4%, p=0.198), TET2 (70% vs 49.1%, p=0.199) and RUNX1 (20% vs 19.4%, p=0.965) were similar in O-CMML and CMML with RAS pathway mutations (NRAS, KRAS, CBL, NF1, SETBP1, PTPN11) being more frequent in CMML compared to O-CMML (51.4% vs 20%, p=0.053). The median number of mutations was 4 (range 1-12), and 4 (range 0-8) in O-CMML and CMML (p=0.578), respectively. No significant differences in median VAFs for ASXL1 (28.2% vs 33.5%, p=0.503), SRSF2 (41.1% vs 45.7%, p=0.743), TET2 (30.4% vs 42.6%, p=0.342), RUNX1 (26.9% vs 32.7%, p=0.837), and RAS pathway mutations (21.6% vs 23%, p=0.197) were observed between both groups. Frequencies at which each mutation appeared as a dominant or minor clone are shown in Figure 1B. Mutations in RAS pathway were more likely to appear as minor clones in patients with O-CMML (71% vs 50%, p CONCLUSIONS: This data supports the revision of AMC threshold for the diagnosis of CMML. This data also supports that clinical and mutational features should guide confirmation of the diagnosis of CMML. Figure Disclosures Sasaki: Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. DiNardo:Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Syros: Honoraria; Novartis: Consultancy. Konopleva:Genentech: Consultancy, Research Funding; Sanofi: Research Funding; Rafael Pharmaceutical: 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; Kisoji: Consultancy; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Forty-Seven: Consultancy, Research Funding; Ablynx: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Eli Lilly: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Ascentage: Research Funding; Amgen: Consultancy; Calithera: Research Funding; Agios: Research Funding. Pemmaraju:Affymetrix: Other: Grant Support, Research Funding; DAVA Oncology: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; SagerStrong Foundation: Other: Grant Support; Celgene: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Pacylex Pharmaceuticals: Consultancy; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding; Cellectis: Research Funding; Samus Therapeutics: Research Funding; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding. Kadia:Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Cellenkos: Research Funding; Novartis: Honoraria; JAZZ: Honoraria, Research Funding; Cyclacel: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Pulmotec: Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Research Funding. Ravandi:Macrogenics: Research Funding; Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: 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; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Borthakur:Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; Abbvie: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; BioLine Rx: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Aptitute Health: Honoraria; Immunogen: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Janssen: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Delta Fly: Honoraria; Adaptive biotechnologies: Honoraria; Jazz: Research Funding; Oxford Biomedical: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BioAscend: Honoraria; Sanofi: Research Funding; Abbvie: Honoraria, Research Funding. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding; Novartis: Research Funding; Amphivena Therapeutics: Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy.

Background: Detection of measurable residual disease (MRD) has been shown to provide important prognostic information in patients (pt) with acute myeloid leukemia (AML) receiving standard cytotoxic chemotherapy. The predictive value of MRD detection after low intensity regimens is less well established. Methods: We conducted a post-hoc analysis of a phase 2 trial to determine the prognostic value of MRD after frontline therapy with venetoclax (VEN) plus decitabine (DEC; DiNardo CD, et al, Lancet Haematology, 2020). MRD was assessed on bone marrow (BM) specimens using 8-color multiparametric flow cytometry (FCM) that was validated to a sensitivity level of 0.01-0.1%. Negative results were considered valid only if there had been acquisition of at least 200,000 events or a minimum of 200 CD34+ myeloid precursors. Pts were treated with DEC 20 mg/m2 for 10 days for induction followed by DEC for 5 days after CR/CRi with cycles repeated every 4-6 wks. Response and relapse were defined using the ELN 2017 criteria. Overall survival (OS) was determined from start of treatment until death or censored at last follow-up (LFU). Relapse-free survival (RFS) was determined from date of CR/CRi till morphologic relapse, death, or censored at LFU. Results: Between January 2018 and April 2020 we enrolled 121 pts in the frontline cohort including de novo AML (n=74), untreated secondary AML (sAML, n=16) and sAML with prior therapy for antecedent hematological disorder (n=31). No pts had received prior therapy for AML. The median age was 72 yrs (interquartile range [IQR] 68-77) and 34 pts (28%) had ECOG PS ≥2 (Table 1). The overall response rate was 81% with CR/CRi rate of 71%. Over half (53%) of responding pts achieved MRD negative status at any time point. (Table 2). The median time to response was 1.4 mo (IQR 1.1-2.6) and median time to MRD negativity was 2.0 mo (IQR 0.9-3.1). 16 pts (13%) underwent allogeneic hematopoietic stem cell transplant after achievement of response. The median OS was 11.7 mo (95% CI 9.1, 14.8) and the median RFS was 9.0 mo (95% CI 6.7, 15.0). After a median FU of 20.2 mo (95% CI 15.7, 23.0) 51 pts are alive. Pts achieving negative MRD at the time of morphologic response (CR/CRi/MLFS) had significantly longer OS compared to pts who were MRD positive, median OS 25.1 vs 11.6 mo, respectively, hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.24, 0.85, p=.02. Pts achieving CR MRD- per ELN guidelines at any time point had longer OS compared to those with an inferior response i.e. CR MRD+ or CRi/MLFS MRD± (median OS 25.1 mo vs 10.9 mo, HR 0.31, 95% CI 0.18, 0.55, p Conclusion: Achievement of negative MRD status at 1- and 2-month time points is associated with significantly better OS and RFS in older pts with AML receiving frontline therapy with VEN and DEC. Disclosures Maiti: Celgene: Research Funding. DiNardo:Novartis: Consultancy; Calithera: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Agios: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Honoraria; Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding. Kadia:Cyclacel: Research Funding; Astra Zeneca: Research Funding; Astellas: Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Ascentage: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Abbvie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding. Daver:Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: 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; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Amgen: Honoraria. Yilmaz:Pint Pharma: Honoraria; Daicho Sankyo: Research Funding; Pfizer: Research Funding. Pemmaraju:LFB Biotechnologies: Honoraria; Plexxikon: Research Funding; DAVA Oncology: Honoraria; Pacylex Pharmaceuticals: Consultancy; Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; Celgene: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Affymetrix: Other: Grant Support, Research Funding; Daiichi Sankyo: Research Funding; Cellectis: Research Funding; Incyte Corporation: Honoraria; SagerStrong Foundation: Other: Grant Support; Samus Therapeutics: Research Funding. Borthakur:Argenx: Consultancy; Treadwell Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; BioTherix: Consultancy; FTC Therapeutics: Consultancy; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Cyclacel: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; PTC Therapeutics: Consultancy; PTC Therapeutics: Research Funding; BioLine Rx: Consultancy; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; Novartis: Research Funding. Bose:Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; NS Pharma: Research Funding; CTI BioPharma: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kartos Therapeutics: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Jabbour:Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Pharmacyclics: 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; BMS: Research Funding; BeiGene: 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; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Pfizer: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Novartis: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Burger:Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding; Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Consultancy. Thompson:AbbVie: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria; Adaptive Biotechnologies: Consultancy, Research Funding. Verstovsek:Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; NS Pharma: Research Funding. Sasaki:Daiichi Sankyo: Consultancy; Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding. Andreeff:Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding. Kantarjian:BioAscend: Honoraria; Abbvie: Honoraria, Research Funding; BMS: Research Funding; Immunogen: Research Funding; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Research Funding; Ascentage: Research Funding; Jazz: Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Delta Fly: Honoraria; Amgen: Honoraria, Research Funding. Konopleva: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; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Cellectis: Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Forty-Seven: Consultancy, Research Funding; Amgen: Consultancy; AstraZeneca: Research Funding; Agios: Research Funding; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Kisoji: Consultancy; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding.