Venetoclax Combined with Cladribine + Low Dose AraC (LDAC) Alternating with 5-Azacytidine Produces High Rates of Minimal Residual Disease (MRD) Negative Complete Remissions (CR) in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)
Authors: Kadia Tapan M. , Cortes Jorge E. , Konopleva Marina Y , Borthakur Gautam M. , Pemmaraju Naveen , Daver Naval G. , Montalban Bravo Guillermo , Issa Ghayas C. , Naqvi Kiran , Short Nicholas J. , DiNardo Courtney D. , Bhalla Kapil N. , Jabbour Elias , Takahashi Koichi , Sasaki Koji , Kornblau Steven M. , Malla Rashmi , Pierce Sherry A. , Wang Xuemei , Estrov Zeev E. , Andreeff Michael , Garcia-Manero Guillermo , Ravandi Farhad , Kantarjian Hagop M. 
Published: November 2019

Treatment of older patients with newly diagnosed AML remains challenging, 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 decitabine for older patients with AML, yielding higher rates of CR and improved outcomes compared to historical experience with hypomethylating agents (HMAs) in this setting (Lancet Haematology 2018). Recently, the combination of the BCL-2 inhibitor venetoclax with HMAs demonstrated significant improvements in response rates and survival over experience with HMAs alone. We hypothesized that the addition of venetoclax to the CLAD/LDAC backbone may further improve response rates and outcomes for this group of patients.
We designed 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). Induction was cladribine 5 mg/m2 IV over 30 minutes on days 1-5 followed by araC 20mg SQ BID on days 1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m2 IV over 30 minutes on days 1-3 + araC 20 mg SQ BID on days 1-10 alternating with 2 cycles of AZA 75 mg/m2 on days 1-7, for up to 18 cycles. Venetoclax was added on days 1-21 of each cycle with dose adjustments (50-400 mg) for concomitant CYP3A inhibitors. One cycle was 4 weeks and up to 2 cycles of induction were allowed. All patients underwent pre-treatment cytogenetic analysis and mutational testing using a customized 81-gene next generation sequencing panel. MRD was assessed using multiparameter flow cytometry in the marrow at the time of remission.
Twenty-six patients have been treated on study, with a median age of 69 yrs (57-84); 11 (42%) pts were ≥ 70 yrs and 1 pt < 60 yrs who was unfit for intensive chemotherapy was enrolled. The baseline patient characteristics are summarized in Table 1. Among 24 evaluable pts, 18 (75%) achieved a complete remission (CR), 3 (13%) had a CR with incomplete platelet recovery (CRp), and 1 (4%) had CR with incomplete neutrophil recovery (CRn) for a CR/CRp rate of 88% an overall response rate of 92%. The median number of cycles to response was 1 (1-3) and 83% of pts were negative for MRD by multi-parameter flow cytometry at the time of CR. Among 9 evaluable pts with diploid karyotype, the CR rate was 100% with full count recovery. Rates of CR/CRp/CRn among other genetic subgroups are summarized in Table 2. The regimen was well tolerated, with a 4-week mortality of 0%. The median time between cycle 1 and 2 was 32 days. The most frequent grade 3/4 non-heme adverse events were neutropenic fever (n=12), lung infection (7), decreased urine output (2), and acute kidney injury (1). Four (18%) of the 22 responding pts went on for allogeneic stem cell transplant, 1 pt (4%) relapsed, 2 (8%) did not respond, and 19 pts continue on treatment. With a median follow-up of 4 months, the median remission duration and overall survival (OS) have not been reached, with an estimated 3- and 6-month OS rate of 95% (Figure).
The combination of venetoclax with CLAD/LDAC alternating with AZA is a lower intensity, well-tolerated, and highly effective regimen for older patients with newly diagnosed AML, producing high rates of MRD negative remission and meaningful blood count recovery. Further study of this approach is warranted.

Disclosures
Kadia: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, 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; AbbVie: Consultancy, Research Funding. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding. Konopleva:Kisoji: Consultancy, Honoraria; Astra Zeneca: Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Agios: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding. Borthakur:AbbVie: Research Funding; Janssen: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Cantargia AB: Research Funding; PTC Therapeutics: Consultancy; Incyte: Research Funding; Merck: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Eli Lilly and Co.: Research Funding; Eisai: Research Funding; Oncoceutics: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Strategia Therapeutics: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic Pharmaceuticals: Research Funding; NKarta: Consultancy; Oncoceutics, Inc.: Research Funding; Arvinas: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; cellectis: Research Funding; Daiichi-Sankyo: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; sagerstrong: Research Funding. Daver:Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Agios: Consultancy; Forty-Seven: Consultancy; Abbvie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas: Consultancy; Novartis: Consultancy, Research Funding; Servier: Research Funding; Glycomimetics: Research Funding; NOHLA: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. DiNardo:abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; medimmune: Honoraria; syros: Honoraria. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Andreeff: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; BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: 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; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; CPRIT: Research Funding; NIH/NCI: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Ravandi:Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding. Kantarjian:Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Astex: Research Funding; Takeda: Honoraria; BMS: Research Funding; Pfizer: Honoraria, Research Funding.