Prognostic Value of Measurable Residual Disease after Venetoclax and Decitabine in Acute Myeloid Leukemia
Authors: Maiti Abhishek , DiNardo Courtney D. , Wang Sa A , Jorgensen Jeffrey L. , Kadia Tapan M. , Daver Naval , Short Nicholas J. , Yilmaz Musa , Pemmaraju Naveen , Borthakur Gautam , Bose Prithviraj , Issa Ghayas C. , Ferrajoli Alessandra , Jabbour Elias , Jain Nitin , Garcia-Manero Guillermo , Ohanian Maro , Takahashi Koichi , Montalban-Bravo Guillermo , Masarova Lucia , Burger Jan A. , Thompson Philip A. , Verstovsek Srdan , Sasaki Koji , Andreeff Michael , Rausch Caitlin R. , Montalbano Kathryn , Pierce Sherry A. , Kantarjian Hagop M. , Konopleva Marina , Ravandi Farhad 
Published: November 2020

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&lt;.001; Fig. 1a) and better RFS (median not reached [NR] vs. 6.7, HR 0.26, 95% CI 0.14, 0.47, p&lt;.001). Pts achieving any response who became MRD negative by 1 mo after starting therapy had a 85% reduction in risk of death compared to pts who achieved a response but remained MRD positive, median OS 25.1 vs 3.4 mo, respectively, HR 0.15, 95% CI 0.03, 0.63, p&lt;.001 (Fig. 1b). Pts achieving any response who became MRD negative by 2 mo after starting therapy also had a significantly improved OS compared to those who remained MRD positive (median OS of 25.1 mo vs. 8.0 mo, HR 0.24, 95% CI 0.12, 0.47, p&lt;.001; Fig. 1c) and RFS (median RFS NR vs 6.7 mo, HR 0.28, 95% Ci 0.13, 0.60, p&lt;.001).
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.