Outcome with Intensive Chemotherapy Compared to Hypomethylating Agent- Based Induction in Patients Aged 70 Years or Older with Newly Diagnosed Favorable Risk Acute Myeloid Leukemia
Authors: Ball Somedeb , Jain Akriti G , Aguirre Luis E. E. , Al Ali Najla , Bewersdorf Jan Philipp , Hayden Alexander , Siddon Alexa J. , Lykon Jillian , Madarang Ellen , Sallman David A. , Padron Eric , Sweet Kendra , Lancet Jeffrey E. , Watts Justin M , Swoboda David M , Pollyea Daniel A. , Zeidan Amer M. , Komrokji Rami S. 
Published: November 2021

Abstract

Introduction: Elderly fit patients (pts) with favorable risk (ELN 2017) acute myeloid leukemia (FR-AML) are traditionally treated with intensive chemotherapy (IC-most commonly 7+3) as induction treatment, based on data extrapolated from studies in pts &lt;60 years (yrs) old. However, advanced age, comorbidities, and poor performance status significantly increase the risk of treatment-related complications and mortality. Younger pts with FR-AML experience a cure rate of 60% with IC-based induction, but outcome with the same in older pts is not well defined. A recent single center study (Lachowiez et al. 2020) in pts with NPM1-mutant AML (&gt;65 yrs) reported improved outcome (1-yr survival rate- 80%) with the combination of hypomethylating agent and venetoclax (HMA-Ven) compared to HMA alone. However, real world evidence continues to lack on efficacy and long-term outcome of intensive and non-intensive induction strategies in very elderly pts (≥70 yrs) with FR-AML, including core-binding factor (CBF)-AML.
Methods: In this multicenter retrospective study, clinical, demographic, and genomic data were collected by review of records of pts aged ≥70 yrs with FR-AML (ELN 2017), treated at Moffitt Cancer Center, University of Colorado, Yale Cancer Center, and University of Miami. Patients who received IC, HMA-Ven, or HMA alone as induction treatment were included in the final analyses. Survival estimates using Kaplan-Meier statistics and multivariate analysis with Cox regression were performed in SPSS (v.26).
Results: Out of 101 pts included in our study, 45 (45%) received IC, whereas induction regimens were HMA-Ven in 32 (32%) and HMA alone in 24 (24%) pts [Table 1]. Median age at diagnosis was 74 yrs (range 70-92); pts receiving HMA or HMA-Ven were older (p=0.005) than those on IC. Majority of pts were white (90%), and gender was distributed equally. A performance status (PS) of ECOG ≥2 was noted in 18% pts. Abnormalities in CBF were detected in 29% of pts overall (more commonly in IC group), and 26% had secondary AML. Median bone marrow blast counts were comparable across three groups. No significant difference was observed among groups in frequencies of NPM1, CEBPA, IDH1, IDH2, and FLT3-ITD mutations.
Median duration of follow up was 31.7 months (mo). Among evaluable pts (n=95), the composite complete remission [cCR- CR + CR with incomplete count recovery (CRi)] rate was significantly better in pts on HMA-Ven, compared to IC (97% vs. 66%, p= 0.002) or HMA alone [Table 2]. CR was noted in 20 (69%) pts receiving HMA-Ven vs. 22 (50%) with IC- based induction (p= 0.237). Overall, 10 (10%) pts died within 30 days of induction, with a trend for higher 30-day and 60-day mortality (18%) with IC (p=0.059). In our study, 34% pts relapsed, with similar early (&lt;12 mo) and late (&gt;12 mo) relapse rates across groups. In pts achieving a CR or CRi, median relapse free survival was 7.93 mo, with no significant difference between cohorts. Total 9 pts (IC-8, HMA-Ven-1), including 3 with relapsed AML, underwent allogeneic stem cell transplant (allo-SCT).
Median overall survival (mOS) was 25.5 mo in pts with CBF-AML (n=29) and 16.5 mo in NPM1-mutant (n= 67) cohort. Patients on IC had significantly improved mOS than those on HMA alone (24.7 vs. 14.3 mo, p= 0.008, Figure 1); however, it was not an independent predictor in multivariate analysis after adjusting for age, PS, and allo-SCT. No significant mOS difference was observed between pts treated with IC and HMA-Ven as induction regimen (24.7 vs. 19.6 mo, p= 0.836). Estimated 5-yr survival rate was 30% with HMA-Ven, 22% with IC, and 4% with HMA. In pts with NPM1-mutant AML, mOS was not significantly different between IC and HMA-Ven groups (16.6 mo vs. 29.2 mo, p= 0.364). In CBF-AML, mOS was not reached in pts on IC vs. 7.27 mo in HMA-Ven group (p= 0.076).
Conclusions: Induction treatment with HMA-Ven led to a significantly high cCR rate (97%) in elderly (≥ 70 yrs) pts with FR-AML. There was no significant difference in mOS in pts treated with IC and HMA-Ven, both overall and in NPM1-mutant cohort. Among pts with CBF-AML, mOS was not reached in IC group, with a 5-year survival rate of 47%, although small sample size in the HMA-Ven group limits inference from this comparison. NPM-1 mutant elderly FR-AML pts can be treated with HMA-Ven regimen, whereas elderly pts with CBF-AML should be treated with IC if fit, until further data with HMA-Ven combination is available.
Figure 1 Figure 1.

Disclosures
Sallman: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: 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; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magenta: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Incyte: Speakers Bureau. Padron: Stemline: Honoraria; BMS: Research Funding; Incyte: Research Funding; Taiho: Honoraria; Kura: Research Funding; Blueprint: Honoraria. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; BerGenBio: Consultancy; Agios: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Jazz: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy. Watts: Takeda: Consultancy, Research Funding; Genentech: Consultancy; Rafael Pharma: Consultancy; Celgene/BMS: Consultancy. Pollyea: AbbVie: Consultancy, Research Funding; Syndax: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Agios: Consultancy; Glycomimetics: Other. Zeidan: Genentech: Consultancy; Daiichi Sankyo: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Jazz: Consultancy; Amgen: Consultancy, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Geron: Other: Clinical Trial Committees; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Agios: Consultancy; Epizyme: Consultancy; Jasper: Consultancy; BioCryst: Other: Clinical Trial Committees; Janssen: Consultancy; AstraZeneca: Consultancy; Aprea: Consultancy, Research Funding; BeyondSpring: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Astex: Research Funding; Astellas: Consultancy; Ionis: Consultancy; Incyte: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Acceleron: Consultancy, Research Funding; ADC Therapeutics: Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Geron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy.