Hypomethylating Agent and Venetoclax Combination Is a Safe and Effective Alternative to Intensive Chemotherapy in Older (≥ 70 Years) Patients With Newly Diagnosed Favorable Risk Acute Myeloid Leukemia

Abstract

The European LeukemiaNet (ELN) 2017 guidelines defined favorable risk acute myeloid leukemia (AML) as cases with specific genetic characteristics, such as t(8;21), inv (16), NPM1, and biallelic CEBPA mutations [1]. Younger patients with favorable risk AML experience improved outcomes with intensive chemotherapy (IC), but long-term survival remains dismal in older (> 60 years of age) adults with AML [2]. Advanced age, multiple comorbidities, and poor performance status significantly increase the risk of treatment-related adverse events and early mortality with IC in older patients with AML. The less intensive treatment option of hypomethylating agent and venetoclax combination (HMA-Ven) is approved for use in newly diagnosed AML in patients who are IC-ineligible due to advanced age (75 years or older) or coexisting conditions. The randomized phase III trial (VIALE-A) comparing azacitidine-Ven to azacitidine monotherapy demonstrated significant improvement in overall survival (OS) but excluded patients with favorable risk cytogenetics [3]. Hence, it is unclear if HMA-Ven is an effective alternative to IC in all patients aged 70 years or more with favorable risk AML.

In this multicenter retrospective study, adult patients aged 70 years or older, with newly diagnosed AML treated at the H. Lee Moffitt Cancer Center, University of Colorado, Cleveland Clinic, Yale Cancer Center, and Sylvester Comprehensive Cancer Center from January 2004 till December 2021, were considered for inclusion. Patients with newly diagnosed favorable risk AML (ELN 2017) [1], who received IC, HMA-Ven, or HMA alone were eligible. The study protocol was approved by the institutional review boards of all participating institutions. Clinical and genomic data on eligible patients were collected by review of electronic medical records. Response to treatment was assessed per ELN 2017 guidelines [1]. Composite complete remission (cCR) rate included cases with complete remission (CR) and complete remission with incomplete hematologic recovery (CRi). For patients experiencing a CR or CRi, the relapse-free survival (RFS) was calculated from the time of remission until relapse or death due to any cause. We calculated OS from the time of AML diagnosis. Following the univariate Cox regression analysis of relevant factors for RFS and OS, factors with a p < 0.10 were included in a multivariate Cox regression model to identify independent predictors of RFS and OS. All statistical analyses were conducted in SPSS statistics (v.29).

Our study included 111 patients with newly diagnosed favorable risk AML (Figure 1A). IC was the frontline treatment in 57 (51%) patients, whereas 29 (26%) received HMA-Ven and 25 (23%) patients were treated with HMA monotherapy. Patients in the IC group were younger than patients in other treatment groups (median age [range] at diagnosis- IC vs. HMA-Ven vs. HMA: 73 [70–84] vs. 76 [70–89] vs. 76 [71–90] years; p < 0.001). Core binding factor (CBF) abnormalities were noted in 31 (28%) patients, with an equal distribution of t (8;21) and Inv (16) cases. Only four patients with CBF-AML were treated with HMA-Ven, compared to 18 (32%) in the IC group and nine (36%) in the HMA group. In our study cohort, NPM1 (78%) was the most common somatic mutation overall, followed by IDH2 (23%), NRAS (12%), IDH1 (11%), monoallelic CEBPA (10%), FLT3-ITD with a low allelic ratio (10%), and KIT (4%) mutations. Eight (7%) patients had NPM1 and FLT3-ITD co-mutated AML. IC was used more commonly for AML cases with NRAS mutation (IC vs. HMA-Ven vs. HMA: 24% vs. 7% vs. 0%; p = 0.043).

Patients receiving HMA-Ven experienced significantly higher rates of overall response than those in other treatment groups (HMA-Ven vs. IC vs. HMA: 93% vs. 70% vs. 40%; p < 0.001). The use of HMA-Ven led to an improved cCR rate compared to IC (93% vs. 65%; p = 0.006) and HMA monotherapy (93% vs. 33%; p < 0.001) (Table S1). In the NPM1-mutated AML cohort, patients on HMA-Ven (n = 24) had a significantly improved cCR rate compared to those on IC (n = 36) (92% vs. 61%; p = 0.009). In patients with NPM1 and coexistent myelodysplasia-related mutations (ELN 2022), the cCR rate was numerically higher with HMA-Ven versus IC, although the difference was not statistically significant (83.3% vs. 37.5%; p = 0.138). Finally, we observed similar cCR rates with IC (n = 18) and HMA-Ven (n = 4) in patients with CBF-AML (72% vs. 100%; p = 0.53). The rates of 30 and 60-day mortality were 13% and 20% in the entire study population, with a trend toward higher 30-day mortality (19% vs. 3%; p = 0.094) and significantly higher 60-day mortality (17% vs. 4%; p = 0.005) rates in patients treated with IC versus HMA-Ven.

Overall, 38 (34%) patients experienced a relapse during the study follow-up period, including 20% early (< 12 months) and 14% (≥ 12 months) late relapses. There were no significant differences in relapse rates among IC, HMA-Ven, and HMA subgroups (33% vs. 31% vs. 40%; p = 0.77). Nine (8%) patients, including eight in the IC group and seven at first remission, underwent allogeneic hematopoietic stem cell transplant. Overall, after a median follow-up duration of 31.7 months, we observed no significant differences in RFS (15.3 vs. 26.8 months, p = 0.999; Figure 1B) or OS (21.1 vs. 19.6 months, p = 0.916; Figure 1C) between IC and HMA-Ven subgroups. In patients with NPM1-mutated AML, the median RFS (7.5 vs. 26.8 months; p = 0.154) and OS (11.4 vs. 19.6 months, p = 0.254; Figure S1) were comparable between IC (n = 36) and HMA-Ven (n = 24) subgroups. Among patients with NPM1 and myelodysplasia-related mutations, we did not find any significant difference in OS with IC (n = 8) versus HMA-Ven (n = 6) (6.5 vs. 8 months; p = 0.734). On the other hand, in patients with CBF-AML, median RFS and OS were not reached with frontline IC (n = 18) treatment, in comparison to median RFS of 3.5 months (p < 0.001) and median OS of 8.87 months (p = 0.272) in the HMA-Ven (n = 4) cohort (Figure S2).

In a univariate Cox-regression analysis, frontline therapy (IC vs. HMA-Ven) was not a significant predictor of RFS (HR 1.00; p = 0.999). In multivariate analysis, a diagnosis of CBF-AML was associated with improved RFS, whereas patients' age at diagnosis was a significant predictor of worse RFS (Table S2A). Regarding potential predictors of OS on univariate analysis, CBF-AML (HR 0.53; p = 0.026) and attainment of cCR with frontline therapy (HR 0.32; p < 0.001) were associated with an improved OS, whereas older age (HR 1.10; p < 0.001) and FLT3-ITD mutation (HR 2.78; p = 0.007) were associated with worse OS. A multivariate analysis revealed that age at diagnosis (HR 1.07; p = 0.009), cCR with frontline therapy (HR 0.24; p < 0.001), and FLT3-ITD mutation (HR 7.57 p < 0.001) were the independent predictors for OS in our study population (Table S2B).

Management of AML in older adults is challenging due to a significant burden of comorbidities and higher rates of therapy-related complications. In a randomized study comparing different IC regimens in older adults with AML, early death was reported in 19%–37% of patients aged 70 years or older [4]. Treatment with HMA-Ven leads to high rates of flow cytometry and molecular measurable residual disease-negative remission, which correlate with improved long-term outcomes in NPM1-mutant AML [3, 5, 6]. In our multicenter cohort of older patients with NPM1-mutant AML, the cCR rate was significantly higher with HMA-Ven (92%) compared to IC-treated (61%) patients. The median OS with HMA-Ven (19.6 months) was numerically higher than the IC group (11.4 months) in the NPM1-mutant cohort, although the difference did not reach statistical significance. Data is limited on the potential activity of HMA-Ven in patients with CBF-AML, as cases with favorable risk cytogenetics were excluded from the VIALE-A study [3]. Only four patients [one with t(8;21) and three with inv (16)] in our study cohort of CBF-AML received HMA-Ven as frontline therapy, with a cCR rate of 100%. In this subgroup, median OS was not reached with IC compared to 8.87 months with HMA-Ven treatment (p = 0.272), suggesting a trend toward improved long-term outcomes with IC in patients with CBF-AML, who are not at the extremes of older age or frailty.

A large multicenter cohort of older patients with favorable risk AML is a major strength of our study. However, like any other retrospective study with comparison among treatment groups, there is a potential for selection bias. The disparity in the number of RAS-mutant cases between treatment arms could induce a bias, as this group is potentially less likely to benefit from HMA-Ven. To define our study population of favorable risk AML, we used ELN 2017 criteria, which have since been updated. Hence, our study includes a small number of patients (e.g., AML with NPM1 and FLT3-ITD mutations) who would not be considered favorable risk by ELN 2022. Finally, the small sample size of the HMA-Ven treated CBF-AML cohort limits the inference from our study findings for this subgroup.

In conclusion, our study showed that HMA-Ven is safe and efficacious in older (≥ 70 years of age) patients with newly diagnosed NPM1-mutant AML, with outcomes that are at least equivalent to IC and numerically favor HMA-Ven. We noted activity of HMA-Ven in a small number of patients with CBF-AML, including a trend toward improved OS with IC in this subgroup. Patients' age, FLT3-ITD mutation, and the response to frontline therapy were independent predictors of OS in older patients with favorable-risk AML.

Study concept: Rami S. Komrokji. Study design: Somedeb Ball and Rami S. Komrokji. Data acquisition: Somedeb Ball, Najla Al Ali, Akriti G. Jain, Luis E. Aguirre, Jan Philipp Bewersdorf, Ameera Rose, Alexander Hayden, Alexa Siddon, Jill Lykon, Ellen Madarang, and Andrew Kent. Data analysis and interpretation: Somedeb Ball and Rami S. Komrokji. Manuscript preparation: Somedeb Ball. Manuscript review and critical input: David M. Swoboda, Eric Padron, Kendra Sweet, David A. Sallman, Jill Lykon, Justin Watts, Hetty E. Carraway, Amer Zeidan, Daniel A. Pollyea. Study supervision: Rami S. Komrokji.

A.G.J.: Rigel-speaker's bureau, Advisory Board: Sobi, Takeda, Novartis. D.A.S.: Abbvie: Consultancy; Agios: Consultancy; Axiom: Consultancy; Gilead: Consultancy; Celyad: Consultancy; Froghorn: Consultancy; Incyte: Consultancy; Intellisphere LLC: Consultancy; Johnson & Johnson: Consultancy; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; NextTech: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AvenCell: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Jasper Therapeutics: Membership on an entity's Board of Directors or advisory committees; NKARTA: Membership on an entity's Board of Directors or advisory committees; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Apera: Research Funding; Jazz: Research Funding. J.L.: Bristol Myers Squibb: Consultancy, Other: Consultant/Advisory Board; Prelude Therapeutics: Consultancy, Other: Bristol Myers Squibb; Tradewell Therapeutics: Consultancy, Other: Consultant/Advisory Board; HEC: Research funding for clinical trial from Celgene, served on Advisory Board and consultant for BMS, AbbVie, Servier, Stemline, Jazz, Novartis, Daiichi, Kura and has served as DSMB for ASTEX and Syndax and Taiho. J.W.: Incyte: Research Funding; Rafael Pharma: Consultancy; Reven Pharma: Consultancy; Daiichi Sankyo: Consultancy; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Systems Key: Research Funding; Takeda: Research Funding; Celgene/BMS: Consultancy; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Other: safety monitoring or advisory boards, Research Funding. A.Z.: Otsuka: Consultancy, Honoraria, Research Funding; Regeneron: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Kura: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Lava Therapeutics: Consultancy, Honoraria; Sumitomo: Consultancy, Honoraria; Shattuck Labs: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Notable: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Treadwell: Consultancy, Honoraria; Akeso Pharma: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Geron: Consultancy, Honoraria, Research Funding; Vinerx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Hikma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Medus: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Astex: Research Funding; Glycomimetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Schroedinger: Consultancy, Honoraria; Agios: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Research Funding; Faron: Consultancy, Honoraria; Keros: Consultancy, Honoraria. D.A.P.: Research funding and consultant for Abbvie. R.S.K.: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI biopharma: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Research Funding; Servio: Membership on an entity's Board of Directors or advisory committees; Keros: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servio: Honoraria; Taiho: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. The other authors declare no conflicts of interest.