Ten-Day Decitabine with Venetoclax (DEC10-VEN) in Acute Myeloid Leukemia: Updated Results of a Phase II Trial
Authors: Maiti Abhishek , DiNardo Courtney D. , Rausch Caitlin R. , Cortes Jorge E. , Pemmaraju Naveen , Daver Naval G. , Ravandi Farhad , Garcia-Manero Guillermo , Borthakur Gautam M. , Naqvi Kiran , Ohanian Maro N. , Short Nicholas J. , Alvarado Yesid , Benton Christopher B. , Kadia Tapan M. , Takahashi Koichi , Yilmaz Musa E. , Jain Nitin , Kornblau Steven M. , Sasaki Koji , Andreeff Michael , Bose Prithviraj , Ferrajoli Alessandra , Issa Ghayas C. , Jabbour Elias , Masarova Lucia , Rytting Michael E. , Thompson Philip A. , Wang Sa A , Konoplev Sergej , Chen Zhining , Goswami Maitrayee , Maduike Rita , Guerrero Julio A , Zhang Qi , Cavazos Antonio , Ma Helen , Bivins Carol A. , Wade Allison , Adewale Shadiat L , Tse Susan , Thomas Robin , Vaughan Kenneth , Pierce Sherry A. , Ning Jing , Qiao Wei , Welch John S. , Kantarjian Hagop M. , Konopleva Marina Y 
Published: November 2019

Background: Elderly patients (pt) with acute myeloid leukemia (AML) or pts with relapsed/refractory (R/R) AML have dismal outcomes. Venetoclax (VEN) synergizes with hypomethylating agents (HMA) and is now an approved combination for newly diagnosed (ND) AML in older/intensive chemotherapy (IC)-ineligible patients. We hypothesized that VEN with 10-day decitabine (DEC) may offer superior efficacy in AML.
Methods: Between January and November 2018 we enrolled 101 pts with ND AML (n=40), untreated secondary AML (sAML, n=9), treated sAML (n=19) and R/R AML (n=33). Eligibility included ECOG PS ≤3, WBC ≤10 x109/L, and adequate organ function. DEC was given 20 mg/m2 IV daily on day 1-10 until CR/CRi, followed by 5-day cycles. VEN was given on day 1-28 in cycle 1 but was interrupted on C1D21 until count recovery if the day 21 bone marrow (BM) had ≤5% blasts. VEN could be reduced further to 14, 10 or 7 days in subsequent cycles for pts with ongoing cytopenias/myelosuppression. VEN dose was 400 mg PO daily (reductions allowed for concomitant CYP3A4 inhibitors) All pts received tumor lysis syndrome (TLS) prophylaxis. Cytoreduction prior to start, and concomitant BCR-ABL1 (n=1) and FLT3 inhibitors (n=15) were allowed as indicated. Primary objective was overall response rate and secondary objectives included safety and overall survival. The data cut-off date was 03.08.19.
Results: This high-risk cohort included 52% of pts ≥70 yrs (interquartile range [IQR], 61-74), 54% pts were men, 28% pts had ECOG PS ≥2, and 67% pts had adverse-risk AML (Table 1). 30 and 60-day mortality were both 2.5% for ND pts, and 5% and 9%, respectively, for all pts. Notable treatment-emergent adverse events were infections with grade 3/4 neutropenia (61%), febrile neutropenia (35%), and TLS (4%, Table 2). Four pts developed grade 3 or 4 reversible TLS; their median WBC count was 7.1x109/L (1.6, 2.1, 12, 28) and median peripheral blasts was 64% (IQR 39-83) and led to a subsequent requirement for WBC ≤10 x109/L prior to start.
The CR/CRi rate in ND AML was 95%, in untreated sAML was 67%, in treated sAML was 37%, and in R/R AML was 27% (Table 3). Out of 67 pts with C1D21±3 BM, ≤5% blasts was achieved in 57%, and 74% of ND pts. In previously untreated AML (defined as ND AML + untreated sAML), CR/CRi rate in ELN favorable, intermediate and adverse risk pts were 100% (n=11), 100% (n=6), and 84% (n=32). CR/CRi rate in t-AML was 100% (n=7). In previously treated AML (treated sAML + R/R AML), CR/CRi rate in HMA refractory pts was 39% (n=18), in pts with prior IC was 21% (n=33), in pts with prior HMA and IC was 17% (n=12), in pts with prior stem cell transplantation (SCT) was 22% (n=18).
At median follow-up of 8.1 months (mo), the 6-mo OS in ND AML was 90%, in untreated sAML was 56%, in treated sAML was 62%, and R/R AML was 53% (Fig. 1). Among all pts, achievement of CR conferred better duration of response (DOR) and OS compared to CRi/MLFS (median DOR not reached [NR] vs 4.0 mo, censored at SCT, hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.09-0.49, p=0.002, and median OS NR vs 7.8 mo, censored at SCT, HR 0.31, 95% CI 0.13-0.74). 70% of all responding pts were minimal residual disease negative (MRD-) by flow cytometry and MRD- status was associated with longer OS (NR vs 7.8 mo, censored at SCT, HR 0.35, 95% CI 0.14-0.88, p=0.01, Fig. 2a). Median DOR in pts achieving CR/CRi in ND AML was 8.5 mo, in the untreated sAML was 6.3 mo, in treated sAML was 4.8 mo, and in R/R AML was 6.6 mo.
Among ND AML pts achieving CR/CRi, median time to count recovery after 1st, 2nd and 3rd cycles for ANC >0.5x109/L was 42 days (95% CI 37-46), 40 days (95% CI 35-44), and 38 days (95% CI 32-NR), respectively; and for platelet ≥50 x109/L was 28 days (95% CI 25-32), 25 days (95% CI 0-34), and 26 days (95% CI 19-33), respectively.
78 pts (77%) discontinued treatment, and 59 pts (58%) are alive. Common reasons for discontinuation were non-response in 24 pts (24%), SCT in 20 pts (20%), and relapse in 18 pts (18%). Pts receiving SCT (n= 20) had excellent outcomes with 100-day post-SCT mortality of 0% (Fig 2b and c). Baseline BCL2 expression in CD34+ blasts showed a trend between higher BCL2 expression and MRD- rate (Fig. 2d).
Conclusions: DEC10-VEN is an effective therapy for ND elderly pts, as well as in R/R AML as an effective bridge to SCT. Trial continues to accrue (NCT03404193).

Disclosures
Maiti: Celgene: Other: research funding. DiNardo:jazz: Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Daver:Pfizer: Consultancy, Research Funding; Servier: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jazz: Consultancy; Servier: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Astellas: Consultancy; Incyte: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Glycomimetics: Research Funding; Agios: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Incyte: Consultancy, Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Celgene: Consultancy; Agios: Consultancy; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Otsuka: Consultancy; Pfizer: Consultancy, Research Funding. Ravandi:Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding. Garcia-Manero:AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding. Borthakur:BMS: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Novartis: Research Funding; Strategia Therapeutics: Research Funding; Cyclacel: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; PTC Therapeutics: Consultancy; Arvinas: Research Funding; Oncoceutics: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Xbiotech USA: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Cantargia AB: Research Funding; NKarta: Consultancy; Agensys: Research Funding; Polaris: Research Funding; Oncoceutics, Inc.: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi:Symbio Pharmaceuticals: Consultancy. Jain:Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff:Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Bose:Blueprint Medicine Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Ariad: Research Funding. Konopleva:Forty-Seven: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Ablynx: Research Funding; Kisoji: Consultancy, Honoraria; Astra Zeneca: Research Funding; Ascentage: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding.