Venetoclax Added to Cladribine (CLAD) + Low Dose AraC (LDAC) Alternating with Azacitidine (AZA) Is Highly Active As Frontline Therapy in Older Patients with Newly Diagnosed Acute Myeloid Leukemia in a Phase 2 Study

Background The combination of venetoclax with AZA for patients with newly diagnosed AML who are older or unfit for intensive chemotherapy significantly improves remission rates and survival compared to AZA alone. A low-intensity backbone combining venetoclax with cladribine (CLAD) plus low-dose araC (LDAC) alternating with HMA has demonstrated encouraging results in older patients with newly diagnosed AML (Kadia TM, et al. J Clin Oncol. 2022). Here we report an updated cohort of patients with longer-term follow up treated on the phase 2 clinical trial of venetoclax added to CLAD/LDAC alternating with AZA.

Methods This is a phase 2 study (NCT03586609) investigating the combination of venetoclax with CLAD/LDAC alternating with AZA in older (age ≥ 60 years) or patients <60 years that are unfit for intensive chemotherapy with newly diagnosed AML (excluding APL, CBF). The primary objective was composite complete response rate (CRc; CR+CRi); secondary endpoints were overall survival (OS), disease-free survival (DFS), overall response rate (ORR), and toxicity.

Induction was with cladribine 5 mg/m2 IV on D1-5 and araC 20mg SQ BID on D1-10. Consolidation/maintenance consisted of 2 courses of cladribine 5 mg/m2 IV on D1-3 and araC 20 mg SQ BID on D1-10 alternating with 2 cycles of AZA 75 mg/m2 on D1-7, for up to 18 courses. Venetoclax 400 mg was added for each course with dose adjustments for concomitant CYP3A inhibitors. Venetoclax was given for 21 days during induction and for 7-14 days for consolidation depending on measurable residual disease (MRD) and tolerability. One cycle was 4 weeks and up to 2 cycles of induction were allowed.

Results A total of 93 patients were treated on study with a median age was 68 years (range: 57 - 84); 28 (30%) patients were ≥ 70 yrs and 1 patient <60, unfit for intensive chemotherapy was enrolled. 29 (31%) patients had secondary or therapy related AML. 52 (56%) had diploid cytogenetics with 11 (12%) having adverse cytogenetics at enrollment. By European Leukemia Network (ELN) risk, 24%, 24%, and 53% were favorable, intermediate, and adverse risk, respectively. The most commonly mutated genes were DNMT3A in 28 (30%), NPM1 in 26 (28%), RAS in 23 (25%), TET2 in 22 (24%), and IDH2 in 20 (22%). TP53 was mutated in 8 (9%) patients.

Among 93 evaluable patients the CRc rate was 92%. Best response was CR in 72 (78%), CRi in 13 (14%), no response in 5 (5%), and death in 2 (2%) patients. In responding patients with a bone marrow sample evaluable for assessment of MRD by flow cytometry, 71/85 (84%) achieved MRD negativity while on study. Responses were preserved across ELN risk groups with the CRc (CR/CRi) rate of 95% (86%/9%), 95% (82%/14%), and 90% (73%/17%) for patients with ELN favorable, intermediate, and adverse risk, respectively. CRc rate for TP53 mutated disease was 88% (7/8, 86% MRD negative) and for NPM1 mutated disease was 96% (25/26, 100% MRD negative). 35 (41%) responders received a subsequent allogeneic stem cell transplantation (alloSCT). Early mortality was low with two patients (2%) dying within 4 weeks and five patients (5%) dying with in 8 weeks.

The most frequent grade 3/4 non-heme adverse events were febrile neutropenia (n=12), infection (n=7), atrial fibrillation (n=2), and allergic reaction (n=2). One patient developed grade 4 tumor lysis syndrome.

With a median follow up of 22.8 months, the median duration of response (DOR) is not reached (95% CI: NE - NE months). Estimated 12- and 24-month DOR are 88.4% (95% CI: 81.0 - 96.4%) and 81.0% (95% CI: 71.0 - 92.4%), respectively. Median disease-free survival (DFS) is not yet reached (95% CI: 24.5 - NE months). Estimated 12- and 24-month DFS are 76.0% (95% CI: 66.8 - 86.4%) and 63.4% (95% CI: 52.1 - 77.1%), respectively. Median overall survival (OS) is not yet reached (95% CI: 25.4 - NE months). Estimated 12- and 24-month OS are 75.7% (95% CI: 66.9 - 85.7%) and 68.3% (95% CI: 58.1 - 80.1%), respectively (Figure).

Conclusion Venetoclax added to CLAD/LDAC alternating with AZA is a highly effective, lower-intensity regimen which is well tolerated among older patients with newly diagnosed AML, producing high CRc and MRD negative remission rates and is effective in transitioning older adults to alloSCT. The rates of DFS and OS are encouraging. Further study of this non-anthracycline containing regimen is warranted in older patients both fit and unfit for intensive chemotherapy as a safe and effective induction treatment strategy.

Kantarjian:Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Research Funding; ImmunoGen: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVA Research: Honoraria; Daiichi-Sankyo: Consultancy, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria. Borthakur:Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy. 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. 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. DiNardo:Cleave: Research Funding; Forma: Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kura: Honoraria, 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; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; LOXO: Research Funding; AbbVie: Consultancy, Research Funding; Jazz: Honoraria; Bluebird Bio: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Astellas: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Astex: Research Funding; Takeda: Honoraria; GenMab: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding. 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Ferrajoli:Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy; Ostuka Pharmaceuticals: Honoraria; Agios: Consultancy; Celgene/BMS: Consultancy; GSK: Consultancy; Novartis: Consultancy; Mission Bio: Honoraria; Illumina: Honoraria. Popat:Bayer: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Iovance: Consultancy. Konopleva:Forty-Seven; F. Hoffman LaRoche: Honoraria; Stocks, Reata Pharmaceuticals: Current equity holder in publicly-traded company; Reata Pharmaceuticals, Novartis and Eli Lilly: Patents & Royalties; AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, Astra Zeneca; Rafael Pharmaceutical; Sanofi, Forty-Seven: Research Funding; AbbVie, Genentech, F. 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