Toxicity and Outcomes in Octo- and Nonagenarians with AML Treated with Venetoclax and Hypomethylating Agent Therapy

Introduction The venetoclax plus hypomethylating agent (VEN-HMA) combination has become the standard treatment for older or unfit patients (pts) with newly diagnosed AML since its approval in 2018. VEN-HMA is associated with significant cytopenias and infectious complications, potentially limiting its use in elderly (>80 years) adults. We explored the toxicity and efficacy of VEN-HMA in octo- and nonagenarians.

Methods This is a multi-center retrospective analysis conducted at 5 institutions in the US and Europe. AML pts ≥80-years-old with or without prior HMA or chemotherapy who received at least 1 day of VEN-HMA between 3/2015 and 4/2022 were included. Dose adjustments for drug interactions with anti-fungals were recorded, and pharmacokinetically equivalent VEN doses are presented. All pts were included in the efficacy and safety analysis. Composite CR (cCR) was defined as CR+CRh+CRi. Baseline characteristics were analyzed by Chi-square/Fisher's exact test. Kaplan-Meier method and multivariate Cox regression for OS as well as logistic regression for CR were used with pre-specified patient variables as predictors.

Results Among 133 AML pts ≥80 years treated with VEN-HMA (75% with AZA, 25% with DEC), 88.7% were newly diagnosed, 11.3% relapsed/refractory (R/R), and 39.1% had prior MDS. Prior HMA was received in 46 pts (35%) and 8 pts (6%) had prior VEN. Median age was 82 years (range: 80-92) and 28.7% of pts had an ECOG PS ≥2. Most pts (52.6%) had ELN adverse risk AML, 36.1% had intermediate, 6% had favorable, and 5.3% were unknown. Molecularly, 22.6% of pts had a TP53 mutation, 22% NPM1, 15.8% IDH1/2, 9.8% FLT3-ITD and 6.8% FLT3-TKD.

Most pts (64%) received the standard dose and schedule of VEN (400 mg [79%] for 28 days [86%]) and HMA (AZA 75 mg/m2 for 7 days [95%], DEC 20 mg/m2 for 5 days [100%]) for the first cycle. Most pts subsequently underwent VEN dose or schedule reductions once response was achieved, with 80% of pts on a reduced schedule by time of analysis. The median final VEN dose and schedule was 400 mg (50-400 mg) for 21 days (4-28 days) with a median cycle length of 35 days (28-70 days). Most pts also had a dose reduction of HMA (51%), most commonly from 7 to 5 days of AZA (71%).

At time of analysis, 38 pts (29%) were still alive and in remission with 26 (20%) still on VEN-HMA. The 30-day and 60-day mortality rates were 8.3% and 15.2 %, respectively. Treatment emergent grade 3-4 anemia occurred in 50%, thrombocytopenia in 48%, neutropenia in 53%, and neutropenic fever in 45.7%.

The cCR rate for the entire population was 54.1% (72/133), with a CR rate of 40.6% (54/133). In patients who had a formal response assessment, the cCR rate was 63.7% (72/113) and CR rate was 47.8% (54/113). In univariate analysis, baseline characteristics associated with a lack of response included R/R disease or prior MDS (cCR for both 50% vs. 76.3% in newly diagnosed, p=0.015) and prior treatment with HMA (cCR 47.4% vs. 72.0% without prior HMA, p=0.01), while patients with an NPM1 or IDH1/2 mutation had higher response rates (cCR 76.9% for NPM1 and 64.7% for IDH1/2, p=0.033). In multivariate analysis (MVA), only prior MDS was associated with a lack of response (OR 0.27 [CI 0.09-0.80], p=0.018).

Median duration of follow-up was 7.5 months in all pts, 6.8 months in deceased pts and 17 months in those still alive. Median OS for all pts was 8.6 months (CI 7.0-11.5) (Figure 1). Median OS by ELN risk was: Favorable NE (4.2-NE), Intermediate 9.5 months (6.6-15.6, p=0.059), and Adverse 8.3 months (4.5-9.4, p=0.038). In patients who achieved a response (cCR), median OS was 13.9 months (CI 10.0-17.8) vs. 3.6 months (CI 0.9-6.6) in non-responders (p<0.001) (Figure 2). Pts who achieved a CR had a median OS of 15.6 months (CI 10.0-39.7) (p<0.001). Only TP53 mutations were associated with shorter OS (HR 2.06 [CI 1.14-3.70], p=0.016) in MVA of baseline characteristics.

Conclusion AML pts ≥80 years old treated with VEN-HMA have high response rates, regardless of performance status and ELN risk. Pts with favorable ELN risk had good outcomes, while those with prior MDS or a TP53 mutation had worse outcomes consistent with clinical trials in younger patient populations. Elderly pts with AML can be treated successfully with VEN-HMA, with a subset (~40%) of responders having long survival. These patients may benefit from significant dose reductions, particularly after achieving response. Further studies of the optimal dose and schedule of VEN-HMA are needed in this age group.

Sekeres:Bristol Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees. Bradley:Geron Corporation: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chandhok:Servier: Consultancy. Taylor:Karyopharm, Inc: Honoraria. Papayannidis:Abbvie: Honoraria; Amgen: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Blueprint: Honoraria; Incyte: Honoraria; GlaxoSmithKline: Honoraria; Bristol Myers Squibb: Honoraria. Kishtagari:CTI Biopharm: Speakers Bureau. Savona:Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Ryvu Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Karyopharm Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Taiho Pharmaceutical: Consultancy; Novartis: Consultancy; Geron: Consultancy; Sierra Oncology: Consultancy, Other: travel expenses; AbbVie: Consultancy, Other: travel expenses; Forma: Consultancy; ALX Oncology: Research Funding; TG Therapeutics: Consultancy, Other: Travel expenses, Research Funding; Incyte Corporation: Research Funding. Sallman:Syntrix Pharmaceuticals: Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Nemucore: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lixte: Patents & Royalties: LB-100; Incyte: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Komrokji:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Honoraria, Other, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees.