-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

25 Phase II Study of Venetoclax Added to Cladribine + Low Dose AraC (LDAC) Alternating with 5-Azacytidine Demonstrates High Rates of Minimal Residual Disease (MRD) Negative Complete Remissions (CR) and Excellent Tolerability in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Novel combination therapies in treatment of newly diagnosed AML
Hematology Disease Topics & Pathways:
AML, Adult, Diseases, Therapies, Combinations, Elderly, Study Population, Myeloid Malignancies, Clinically relevant
Saturday, December 5, 2020: 7:45 AM

Tapan M. Kadia, MD1, Gautam Borthakur, MD1, Naveen Pemmaraju, MD1, Naval Daver, MD2, Courtney D. DiNardo, MD, MSc3, Koji Sasaki, MD4, Ghayas C. Issa, MD5, Maro Ohanian, DO1*, Guillermo Montalban Bravo, MD1, Nicholas J. Short, MD1, Nitin Jain, MD6, Alessandra Ferrajoli, MD1, Kapil N. Bhalla, MD7, Elias Jabbour, MD1, Rashmi Kanagal-Shamanna, MD8, Koichi Takahashi, MD, PhD9, Rashmi Malla, RN, BSN1*, Kelly Marek1*, Mark Brandt, BS1*, Uday R. Popat, MD10, Michael Andreeff, MD, PhD11, Jorge E. Cortes, MD12, Guillermo Garcia-Manero, MD1, Marina Konopleva, MD, PhD13, Farhad Ravandi, MBBS14 and Hagop M. Kantarjian, MD15

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX
3Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, Universit Y of Texas At Houston, Houston, TX
6Associate Professor of Medicine Department of Leukemia The University of Texas MD Anderson Cancer Center, Houston, TX
7Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
8Department of Hematopathology, Division of Pathology/Lab Medicine, University of Texas MD Anderson Cancer Center, Houston, TX
9Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
10Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
11Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
12Georgia Cancer Center Augusta University, Augusta, GA
13Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX
14Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
15Department of Leukemia, Professor and Chairman, Department of Leukemia, Samsung Distinguished University Chair in Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Background
Treatment of older patients with newly diagnosed AML has been limited by modest response rates with low-intensity therapy and higher levels of toxicity with intensive therapy. We previously reported on a low-intensity backbone of cladribine + LDAC (CLAD/LDAC) alternating with hypomethylating agent (HMA) for older patients with AML, yielding higher rates of CR and improved outcomes compared to HMAs alone. Recently, addition of the BCL-2 inhibitor venetoclax to HMAs was shown, in a randomized study, to improve survival over HMAs alone. We hypothesized that the addition of venetoclax to the low intensity CLAD/LDAC backbone may further improve response rates and outcomes for this group of patients.

Methods
This is a phase II clinical trial studying the combination of venetoclax with CLAD/LDAC alternating with 5-azacytidine (AZA) in older (age ≥ 60y) or unfit patients with newly diagnosed AML (excluding APL, CBF). Induction was cladribine 5 mg/m2 IV over 30 minutes on D1-5 followed by araC 20mg SQ BID on D1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m2 IV on D1-3 + araC 20 mg SQ BID on D1-10 alternating with 2 cycles of AZA 75 mg/m2 on D1-7, for up to 18 cycles. Venetoclax 400 mg was added on days 1-21 of each cycle with dose adjustments for concomitant CYP3A inhibitors. One cycle was 4 weeks and up to 2 cycles of induction were allowed.

Results
A total of 48 patients were treated on study, with a median age of 68 yrs (57-84); 18 (38%) pts were ≥ 70 yrs and 1 pt < 60 yrs who was unfit for intensive chemotherapy was enrolled. 12 (25%) patients had secondary AML (sAML) and 12 (25%) had adverse karyotype. The baseline patient characteristics are summarized in Table 1. Among 48 evaluable pts, 37 (77%) achieved a complete remission (CR), 8 (17%) had a CR with incomplete count recovery (CRi) for a CR/CRi rate of 94%. The median number of cycles to response was 1 (1-3) and 36 (80%) pts were negative for MRD by multi-parameter flow cytometry at the time of CR/CRi. Among the subset of patients who had CR with complete count recovery, the MRD negative rate was 92% (34/37). Among pts with sAML or with adverse karyotype, the CR/CRi rate was 83% (58%/25%) and 83% (50%/33%), respectively. The regimen was well tolerated, with 4- and 8-week mortality rates of 0% and 6%, respectively. The most frequent grade 3/4 non-heme adverse events were neutropenic fever (n=20), lung infection (9), decreased urine output (2), nausea (1), acute kidney injury (1), dizziness (1), and mucositis (1). Eleven (24%) of the 45 responding pts proceeded with allogeneic stem cell transplant (SCT). With a median follow-up of 11+ months, the median overall survival (OS) has not been reached (NR), with 6- and 12-month OS rates of 86% and 70%, respectively (Figure 1). The median OS of pts with or without MRD at CR were 10.7m and NR, respectively (P=0.056). For pts with sAML vs. de novo AML, the median OS was 10.6m vs. NR, respectively (P=0.09). OS by cytogenetic risk is shown in Figures 2. OS among different subgroups are summarized in Table. The median RFS was not reached, with 6- and 12-month RFS rates of 79% and 64%, respectively.


Conclusion
CLAD/LDAC plus venetoclax alternating with AZA plus venetoclax is an effective, lower-intensity regimen that is well tolerated among older patients with newly diagnosed AML, producing high rates of durable MRD negative remission and meaningful blood count recovery. With approximately 1-year follow-up, the rates of overall and relapse-free survival are encouraging in this cohort of older AML patients. Further study of this backbone in combination approaches is warranted.

Disclosures: Kadia: Incyte: Research Funding; Novartis: Honoraria; Cellenkos: Research Funding; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; Celgene: Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Borthakur: Treadwell Therapeutics: Consultancy; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; BioTherix: Consultancy; Incyte: Research Funding; PTC Therapeutics: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; GSK: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Novartis: Research Funding; Nkarta Therapeutics: Consultancy. Pemmaraju: Samus Therapeutics: Research Funding; Cellectis: Research Funding; Roche Diagnostics: Honoraria; Celgene: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; DAVA Oncology: Honoraria; SagerStrong Foundation: Other: Grant Support; AbbVie: Honoraria, Research Funding; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria; Incyte Corporation: Honoraria; Blueprint Medicines: Honoraria; Novartis: Honoraria, Research Funding; Affymetrix: Other: Grant Support, Research Funding; Daiichi Sankyo: Research Funding; MustangBio: Honoraria. Daver: Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; 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. DiNardo: AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; MedImmune: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Novartis: Consultancy. Sasaki: Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Otsuka: Honoraria; Pfizer Japan: Consultancy. Issa: Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Short: Astellas: Research Funding; Amgen: Honoraria; Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy. Jain: BMS: Research Funding; Incyte: Research Funding; Fate Therapeutics: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: 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; Verastem: 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; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Research Funding; Cellectis: Research Funding. Jabbour: BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Popat: Bayer: Research Funding; Novartis: Research Funding. Andreeff: Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; 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; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding. Cortes: Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Merus: Research Funding; Takeda: Consultancy, Research Funding; Arog: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Sun Pharma: Research Funding; Telios: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Garcia-Manero: AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding. Konopleva: Rafael Pharmaceutical: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Amgen: Consultancy; Kisoji: Consultancy; Ablynx: Research Funding; Genentech: Consultancy, 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; Cellectis: Research Funding; Forty-Seven: Consultancy, Research Funding; Ascentage: Research Funding; Sanofi: Research Funding; AbbVie: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Eli Lilly: Research Funding; Agios: Research Funding. Ravandi: Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Kantarjian: Astex: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria.

OffLabel Disclosure: This combination is investigational.

*signifies non-member of ASH