Ten-Day Decitabine with Venetoclax (DEC10-VEN) in Acute Myeloid Leukemia and Myelodysplastic Syndrome: Updated Results of a Phase II Trial
Authors: Maiti Abhishek , DiNardo Courtney D. , Rausch Caitlin R. , Pemmaraju Naveen , Garcia-Manero Guillermo , Ohanian Maro , Daver Naval , Issa Ghayas C. , Borthakur Gautam , Ravandi Farhad , Alvarado Yesid , Kadia Tapan M. , Short Nicholas J. , Jabbour Elias J. , Montalban-Bravo Guillermo , Jain Nitin , Kornblau Steven M. , Masarova Lucia , Wierda William G. , Sasaki Koji , Takahashi Koichi , Yilmaz Musa , Burger Jan A. , Estrov Zeev E. , Verstovsek Srdan , Andreeff Michael , Bose Prithviraj , Ferrajoli Alessandra , Thompson Philip A. , Montalbano Kathryn , Vaughan Kenneth , Bivins Carol A. , Pierce Sherry A. , Qiao Wei , Ning Jing , Welch John , Kantarjian Hagop , Konopleva Marina 
Published: November 2021

Abstract

Background: Older patients (pt) with acute myeloid leukemia (AML) and patients with high-risk myelodysplastic syndrome / chronic myelomonocytic leukemia (HR MDS/CMML) have poor outcomes. We showed that 10-day decitabine with venetoclax (DEC10-VEN) is a safe and effective strategy and offers potentially better outcomes compared to intensive chemotherapy in older pts with newly diagnosed (ND) AML, as well as relapsed or refractory (R/R) AML (DiNardo et al. Lancet Haematol 2020; Maiti et al. Am J Hematol 2021; Maiti et al. Cancer 2021). We here in present updated results of this prospective phase II trial (NCT03404193).
Methods: Eligibility criteria included ECOG PS ≤3, WBC ≤10 x10 9/L, and adequate organ function. Decitabine dose was 20 mg/m 2 IV daily on D1-10 until CR/CRi, followed by 5-day cycles. Venetoclax was given on D1-28 in cycle 1 but was interrupted on C1D21 until count recovery if the D21 bone marrow (BM) had ≤5% blasts. Venetoclax dose was 400 mg PO daily or equivalent with concomitant azole antifungals as previously described (DiNardo et al. Lancet Haematol. 2020). Venetoclax duration could be reduced to 14 to 7 days in subsequent cycles in cases of prolonged myelosuppression.
All pts received cytoreduction prior to start, tumor lysis syndrome (TLS) prophylaxis and antimicrobial prophylaxis. Concomitant FLT3 tyrosine kinase inhibitors were allowed in FLT3-mutated AML. Pts could proceed to allogeneic stem-cell transplantation (SCT) after response, if eligible. Primary objective was overall response rate and secondary objectives included safety and overall survival. Outcomes and endpoints were defined per ELN2017 criteria. Measurable residual disease (MRD) was assessed using multiparametric flow cytometry (sensitivity 0.1%) and reported for all responding pts with evaluable MRD sample.
Results: Between January 2018 and April 2021 we enrolled 219 pts with ND AML (n=83), untreated sAML (n=20), treated sAML (n=25), R/R AML (n=71) and HR MDS/CMML (n=20). This high-risk cohort included 54% of pts ≥70 yrs (n=119), 57% pts were men, 29% pts had ECOG PS ≥2, and 57% pts had adverse-risk AML (Table 1). The 30 mortality was 1% for ND pts and 3.6% for all pts. There were 346 treatment-related adverse events in 181 patients including infections with grade 3/4 neutropenia (40%), febrile neutropenia (29%), and infection with unknown ANC (17%, Table 2). There were 11 grade 5 events including infections with grade 3/4 neutropenia (n=6), infections with unknown ANC (n=4), and renal failure (n=1).
The CR/CRi rate in ND AML was 83%, in untreated sAML was 65%, in treated sAML was 40%, in R/R AML was 42% and in HR-MDS/CMML was 20% (Table 3). Rates of negative measurable residual disease (MRD) by flow cytometry (0.1%) in ND AML was 73%, in untreated sAML was 53%, in treated sAML was 65%, and in R/R AM was 58%. After a median follow-up of 24.7 months (mo), the median OS in ND AML was 16.2 mo, in untreated sAML was 10.7 mo, in treated sAML was 5.8 mo, in R/R AML was 7.8 mo, and in HR-MDS/CMML was 10.1 mo (Fig. 1a). The 1-yr OS in ND AML was 54%, in untreated sAML was 41%, in treated sAML was 36%, in R/R AML was 41%, and in HR MDS/CMML was 35%. Median RFS for pts with ND AML was 10.9 mo, in the untreated sAML was 6.7 mo, in treated sAML was 11.4 mo, and in R/R AML was 8.4 mo (Fig. 1b). 44 pts underwent SCT after achieving response including ND AML (n=17), untreated sAML (n=4), treated sAML (n=3), R/R AML (n=16), and HR-MDS/CMML (n=4). The 100-day post-SCT mortality was 9% (n=4). Median OS after SCT in pts with previously untreated AML was 31.1 mo and in previously treated AML was 15.0 mo (Fig. 1c)
199 pts (91%) have discontinued treatment and 69 pts (32%) are alive. The most common reasons for treatment discontinuation included refractory disease in 49 pts (22%), relapse in 45 pts (21%), SCT in 44 pts (20%).
Conclusions: DEC10-VEN is an effective therapy for older pts with ND and R/R AML. Transition to SCT after response with DEC10-VEN may offer long-term survival advantage in this older/unfit population with both ND and R/R AML. The trial continues to accrue. Based on these findings we have initiated a phase II trial of 10-day oral decitabine (ASTX727) with venetoclax in R/R AML (NCT04975919).
Figure 1 Figure 1.

Disclosures
DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Pemmaraju: DAVA Oncology: Consultancy; 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; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Cellectis S.A. ADR: Other, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Roche Diagnostics: Consultancy; Samus: Other, Research Funding; Blueprint Medicines: Consultancy; Clearview Healthcare Partners: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Celgene Corporation: Consultancy; Incyte: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Plexxicon: Other, Research Funding; Aptitude Health: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Trovagene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Hanmi: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Glycomimetics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; 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. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; Protagonist: Consultancy. Ravandi: Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AstraZeneca: Honoraria; Prelude: Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Alvarado: MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Sun Pharma: Consultancy, Research Funding. Kadia: AbbVie: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Genfleet: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Liberum: Consultancy; Astellas: Other; AstraZeneca: Other; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; BMS: Other: Grant/research support; Dalichi Sankyo: Consultancy; Ascentage: Other; Pulmotech: Other; Novartis: Consultancy; Pfizer: Consultancy, Other; Aglos: Consultancy; Amgen: Other: Grant/research support. Short: Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Astellas: Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Jain: Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Servier: Honoraria, Research Funding; Janssen: Honoraria; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; TG Therapeutics: Honoraria; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Wierda: Janssen: Research Funding; Karyopharm: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta Pharma Inc.: Research Funding; AstraZeneca: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Cyclacel: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; KITE Pharma: Research Funding; Loxo Oncology, Inc.: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Takahashi: Novartis: Consultancy; Celgene/BMS: Consultancy; GSK: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Burger: AstraZeneca: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Verstovsek: CTI BioPharma: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; PharmaEssentia: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Andreeff: Glycomimetics: Consultancy; Aptose: Consultancy; AstraZeneca: Research Funding; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; Syndax: Consultancy; Medicxi: Consultancy; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Breast Cancer Research Foundation: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; ONO Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Senti-Bio: Consultancy. Bose: Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Ferrajoli: AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board . Thompson: Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Jazz: Research Funding; Ascentage: Research Funding; Daiichi-Sankyo: Research Funding; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Konopleva: Agios: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; KisoJi: 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; Cellectis: Other: grant support; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support.