Cladribine, Idarubicin, Cytarabine (ara-C), and Venetoclax in Treating Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome
Authors: Reville Patrick K , Kantarjian Hagop M. , Borthakur Gautam , Yilmaz Musa , Montalban-Bravo Guillermo , DiNardo Courtney D. , Andreeff Michael , Daver Naval , Jain Nitin , Kornblau Steven M. , Jabbour Elias , Short Nicholas J. , Alvarado Yesid , Ohanian Maro , Bose Prithviraj , Masarova Lucia , Wang Sa A , S Tidwell Rebecca S. , Estrov Zeev E. , Garcia-Manero Guillermo , Konopleva Marina , Ravandi Farhad , Kadia Tapan M. 
Published: November 2020

Background
Addition of the BCL2 inhibitor venetoclax to lower intensity therapy improved survival (OS) for older and unfit patients with newly diagnosed AML. We have previously reported the safety and efficacy of the nucleoside analogue cladribine combined with high dose ara-C and idarubicin (ida) as an intensive induction regimen (CLIA) in patients with newly diagnosed AML. Here, we report the results of the combination of venetoclax with the CLIA regimen for younger, fit patients with newly diagnosed AML.
Methods
Patients &lt; 65 years of age with newly diagnosed AML or high-risk MDS were enrolled (NCT02115295). Induction was cladribine 5 mg/m2 IV on D1-5, ara-C 1.5 g/m2 IV on D1-5, and idarubicin 10 mg/m2 IV on D1-3; venetoclax was given at an effective dose of 400mg PO on D2-8 without ramp up with every cycle. Consolidation consisted of 3d of CLIA (2d of ida). AML patients with FLT3-ITD or FLT3 point mutations could receive midostaurin on D6-19 or gilteritinib on D1-14 for induction, and continuously thereafter. Venetoclax dose modifications for CYP3A4 inhibitors were made. All patients underwent baseline next generation sequencing and MRD testing by multiparameter flow cytometry at the time of response.
Results
A total of 31 patients have been enrolled. The median age was 48 years (range, 18-64). Baseline characteristics are shown in Table 1. Median follow up is 8.8 months. All patients were evaluable for response, with 28 of 31 (90%) achieving a remission, including 23 (74%) complete remission (CR) and 5 (16%) CR with incomplete count recovery (CRi) (Table 1). Of the 2 patients that did not respond, one was ELN adverse risk with TP53 mutation and complex karyotype, the other was ELN favorable risk with a t(8;21) translocation and mutations in IDH1 and JAK2. At time of initial response assessment 19 of 30 (63%) had undetectable MRD, with another 4 patients (77%) becoming MRD negative overall. Median cycles until response was 1 (range: 1 - 2), and patients have received a median of 2 cycles (range: 1 - 5). Median time to absolute neutrophil count ≥ 1000/µL was 32 days (range: 18 - 49) and platelet count ≥ 50k and 100k/µL were 29 days (range: 17 - 61) and 32 days, respectively after induction. 8 patients received FLT3 inhibition (FLT3i) in addition to CLIA and venetoclax, 7 (88%) with gilteritinib and 1 (12%) with midostaurin. Within this subset, there were 6/8 (75%) CR and 1 CR (12%) (Table 2). Median overall survival (OS) for those receiving FLT3i is not yet reached (95% CI: 0.79 - NE months). Median duration of response for the entire cohort is not reached. At 6 and 12 months 87% of responders had an ongoing response (SE=9%). 18 of 28 (64%) of responders received an allogeneic stem cell transplant. Median OS has not been reached, with 6- and 12-month rates of OS 93% (SE=5%) and 81% (SE=9%), respectively (Figure 1). Median OS in all ELN risk categories has not yet been reached, with 6 month OS of 91% (SE=9%), 100% (SE=NA), and 83% (SE=15%) in favorable, intermediate, and adverse risk groups, respectively (Figure 2). Median event free survival (EFS) has not been reached, with 6- and 12-month rates of EFS are 90% (SE=5%) and 79% (SE=9%), respectively. Overall the regimen was well tolerated, with an acceptable toxicity profile. Tumor lysis syndrome was not seen. The most common Grade &gt;/= 3 adverse events were neutropenic fever, pneumonia, nausea, and liver transaminitis. There was one induction death in the FLT3i cohort and none with CLIA + venetoclax.
Conclusion
Venetoclax added to CLIA was safe and highly effective in newly diagnosed pts with AML and high risk MDS, including patients with FLT3-mutated AML and adverse risk by ELN or IPSS-R. The addition of FLT3i may be associated with delayed count recovery. CLIA plus venetoclax provided high rates of durable MRD negative remissions and encouraging event-free and overall survival across prognostic subgroups.

Disclosures
Kantarjian: BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Delta Fly: Honoraria; Ascentage: Research Funding; Janssen: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Oxford Biomedical: Honoraria. Borthakur:Abbvie: Research Funding; BioLine Rx: Consultancy; FTC Therapeutics: Consultancy; BioTherix: Consultancy; Jannsen: Research Funding; GSK: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Argenx: Consultancy; AstraZeneca: Research Funding; Cyclacel: Research Funding; PTC Therapeutics: Consultancy; PTC Therapeutics: Research Funding; Novartis: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; Incyte: Research Funding; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding. Yilmaz:Daicho Sankyo: Research Funding; Pint Pharma: Honoraria; Pfizer: Research Funding. DiNardo:ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Honoraria; MedImmune: Honoraria; Syros: Honoraria; Novartis: Consultancy. 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; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy. Daver: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; 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. Jain:Aprea Therapeutics: 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; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: 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; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jabbour:Takeda: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding. Short:Astellas: Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding. Alvarado:Daiichi-Sankyo: Research Funding; BerGenBio ASA: Research Funding; Tolero Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Research Funding. Bose:Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Astellas Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Promedior, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kartos Therapeutics: Honoraria, Research Funding. Garcia-Manero:Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Amphivena Therapeutics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Onconova: Research Funding; Novartis: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Konopleva:Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Ablynx: Research Funding; Genentech: Consultancy, Research Funding; Ascentage: Research Funding; Amgen: Consultancy; Agios: Research Funding; AstraZeneca: Research Funding; Eli Lilly: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; Calithera: Research Funding; Kisoji: Consultancy; AbbVie: 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; Forty-Seven: Consultancy, Research Funding. Ravandi:Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Kadia:Amgen: Research Funding; Cellenkos: Research Funding; Cyclacel: Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria, Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Pulmotec: Research Funding; Incyte: Research Funding; Pfizer: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding.