Venetoclax Combined with Cladribine, Idarubicin, Cytarabine (CLIA) As Induction Therapy in Patients with Newly Diagnosed Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

Background Addition of the BCL2 inhibitor venetoclax to intensive chemotherapy induction with cladribine, idarubicin, and cytarabine (CLIA) was shown to be safe, with encouraging activity in younger patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) (Kadia TM, et al. Lancet Haematol. 2021). Here we report updated results and longer term follow-up of the phase 2 study of venetoclax combined with CLIA as frontline induction for younger patients with newly diagnosed AML or high-risk MDS.

Methods This is a phase 2 clinical trial (NCT02115295) investigating venetoclax combined with CLIA for patients aged ≤65 years of age with newly diagnosed AML or high-risk MDS. The primary objective was composite complete response rate (CRc; CR+CRi); secondary endpoints were overall survival (OS), event-free survival (EFS), overall response rate (ORR), and toxicity.

Induction was with 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 3 days of CLIA (2 days of idarubicin). Venetoclax was dose modified for CYP3A4 inhibitors. FLT3 inhibitors were allowed for patients with FLT3 mutations. All patients received antibacterial, antiviral, and mold active anti-fungal prophylaxis. G-CSF was allowed. All patients underwent baseline next generation sequencing and MRD testing by multiparameter flow cytometry at the time of response.

Results A total of 67 patients were treated on study with a median age 48 years (range: 18 - 64). 60 patients had a diagnosis of AML, 4 patients had high-risk MDS (either high or very high risk by IPSS-R), and 3 patients had a mixed phenotype acute leukemia (MPAL) with a myeloid predominant clone. 11 (16%) patients had secondary or therapy related AML. 36 (66%) had diploid cytogenetics, 12 (18%) patients had adverse/complex cytogenetics, and only one had favorable risk karyotype at enrollment. By European Leukemia Network (ELN) risk classification, 25%, 35%, and 40% were favorable, intermediate, and adverse risk, respectively. The most commonly mutated genes were DNMT3A in 37%, NPM1 in 34%, FLT3-ITD in 28%, RAS in 24%, TET2 in 18%. TP53 was mutated in 3 (4%) patients. Baseline characteristics are summarized in the table.

All patients were evaluable for response, with a CRc rate of 96%. Best response was CR in 57 (85%), CRi in 7 (10%), no response in 2 (3%), and death in 1 (2%) patient. In responding patients with a bone marrow sample that was evaluable for assessment of measurable residual disease by flow cytometry, 55/61 (90%) were negative for MRD on study. Responses were preserved across ELN risk groups with the CRc (CR/CRi) rate of 94% (88%/6%), 95% (86%/9%), and 96% (84%/12%) for patients with ELN favorable, intermediate, and adverse risk, respectively. The CRc rate was 100% for patients with both MDS and MPAL. 40 (63%) received a subsequent allogeneic stem cell transplantation (alloSCT); among those achieving MRD negative state on study 63% received alloSCT. One patient (2%) died within 4 weeks and 2 patients (3%) died with in 8 weeks.

The most frequent grade 3/4 non-heme adverse events were febrile neutropenia (n=57), alanine transaminase increase (n=11), other infection (n=8), aspartate transferase (n=4), and diarrhea (n=2). No cases of tumor lysis syndrome were observed.

With a median follow up of 22.5 months, median duration of response (DOR) is not yet reached with estimated 12- and 24-month DOR of 82.6% (95% CI: 72.3 - 94.4%) and 80.3% (95% CI: 69.5 - 92.8%), respectively. Median EFS is not yet reached with estimated 12- and 24-month EFS of 71.8% (95% CI: 60.8 - 84.7%) and 69.7% (95% CI: 58.5 - 83.1%), respectively. Median overall survival (OS) is not yet reached with estimated 12- and 24-month OS of 86.5% (95% CI: 78.2 - 95.7%) and 70.7% (95% CI: 58.9 - 84.9%), respectively (figure 1).

Conclusion Among younger patients with newly diagnosed AML deemed fit for intensive chemotherapy, venetoclax with CLIA induced high rates of MRD negative remissions, regardless of ELN risk, allowing a higher rate of patients with MRD negative remissions to proceed with a potentially curative alloSCT. EFS and OS rates are highly encouraging and worthy of further study as a safe and effective induction treatment strategy for younger patients with AML or high-risk MDS.

Kantarjian:Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; ImmunoGen: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Takeda: Honoraria. Borthakur:Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees. Yilmaz:Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Daver:Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Short:Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy; Novartis: Consultancy; Takeda Oncology: Consultancy, Research Funding; Stemline Therapeutics: Research Funding; Astellas: Research Funding; Pfizer: Consultancy. DiNardo:Gilead: Honoraria; Forma: Research Funding; Astex: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Cleave: Research Funding; Jazz: Honoraria; Foghorn: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; LOXO: Research Funding; Takeda: Honoraria; Bluebird Bio: Honoraria; Astellas: Honoraria; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; GenMab: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Jain:Medisix: Research Funding; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; MEI Pharma: Honoraria; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; Beigene: Honoraria; Novalgen: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; TG Therapeutics: Honoraria; Aprea Therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Loxo Oncology: Research Funding; Ipsen: Honoraria; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Newave: Research Funding; Mingsight: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; Dialectic Therapeutics: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Fate Therapeutics: Research Funding; Takeda: Research Funding; ADC Therapeutics: Research Funding; TransThera Sciences: Research Funding; Servier Pharmaceuticals LLC: Research Funding; CareDx: Honoraria; Cellectis: Honoraria, Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding. Alvarado:Sun Pharma: Research Funding; BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; Daiichi-Sankyo/Lilly: Research Funding. Bose:BMS: Consultancy, Research Funding; Cogent: Honoraria, Research Funding; Kartos: Research Funding; Karyopharm: Consultancy; Pfizer: Research Funding; Ionis: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Promedior: Research Funding; Novartis: Honoraria; Pharma Essentia: Honoraria; Sierra Oncology (now GSK): Consultancy; AbbVie: Consultancy; Astellas: Research Funding; Disc Medicine: Research Funding; Telios: Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Honoraria, Research Funding; NS Pharma: Research Funding; Incyte: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding. Jabbour:Amgen: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Pfizer: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding; Takeda: Other: Advisory Role, Research Funding. Andreeff:Senti Bio: Consultancy, Research Funding; Medicxi: Consultancy; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo Inc.: Consultancy, Research Funding; Chimerix: Current holder of stock options in a privately-held company; Glycomimetics: Consultancy; Kintor Pharmaceutical: Research Funding; Reata: Current holder of stock options in a privately-held company; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Brooklyn ITX: Research Funding; Syndax: Consultancy, Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Current holder of stock options in a privately-held company; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI: 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; Pinot Bio: Research Funding; Oxford Biomedical UK: Research Funding; AstraZeneca: Research Funding. Garcia-Manero:BMS: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding; Aprea: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Gilead Sciences: Research Funding; Curis: Honoraria, Research Funding; Acceleron Pharma: Consultancy. Konopleva:AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, Astra Zeneca; Rafael Pharmaceutical; Sanofi, Forty-Seven: Research Funding; Stocks, Reata Pharmaceuticals: Current equity holder in publicly-traded company; Reata Pharmaceuticals, Novartis and Eli Lilly: Patents & Royalties; Forty-Seven; F. Hoffman LaRoche: Honoraria; AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji; Janssen: Consultancy; Stemline Therapeutics, F. Hoffman La-Roche; Janssen: Membership on an entity's Board of Directors or advisory committees. Ravandi:Novartis: Consultancy; Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomea Fusion, Inc.: Research Funding; Xencor: Research Funding; Syos: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Amgen: Honoraria, Research Funding; AstraZeneca: Consultancy. Kadia:Iterion: Research Funding; PinotBio: Consultancy; Regeneron: Research Funding; Servier: Consultancy; Genentech: Consultancy, Research Funding; Delta-Fly: Research Funding; Ascentage: Research Funding; cellenkos: Research Funding; cyclacel: Research Funding; Astellas: Research Funding; Genfleet: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; Astex: Honoraria; Glycomimetics: Research Funding; Pfizer: Research Funding; BMS: Consultancy, Research Funding; Agios: Consultancy; JAZZ: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy.