Should “Medically Fit” Older Patients with Acute Myeloid Leukemia (AML) Continue to Receive Intensive Chemotherapy in the Venetoclax (VEN) Era?
Authors: Kapoor Nilesh , Gao Ang , Ikpefan Ruth , Ahn Chul , Anderson Julia , Kalkan F Neslihan , Chen Weina , Germans Sharon , Marinos Velarde Alejandro , Irrizary Gatell Vivian , Alvarenga Thiebaud Julio , Jackson Clayton , Weinberg Olga K. , Cantu Miguel , Collins Robert H. , Chung Stephen , Madanat Yazan F 
Published: December 2024

INTRODUCTION:
Pts ≥ 60 years (y) of age with AML have poor outcomes with a 5-year overall survival (OS) of 5-20%. VEN combined with a hypomethylating agent (HMA) or low dose cytarabine (LoDAC) is standard of care for older pts who are unfit to receive intensive chemotherapy (IC). Our study aimed to determine clinical characteristics, responses, and survival outcomes in older AML pts who received upfront VEN-based therapy vs IC.
METHODS:
We conducted a retrospective study of AML pts diagnosed 1/2013 - 1/2023 at UTSW who received upfront VEN-based therapy or IC. Pts &lt; 60y of age at diagnosis were excluded. Composite complete remission (CRc) was defined as CR, CR with partial hematologic recovery (CRh), and CR with incomplete count recovery (CRi) per 2022 European LeukemiaNet (ELN) criteria. Categorical and continuous variables were compared using Chi-square/Fisher's exact test and two sample T-test/Wilcoxon rank-sum test, respectively. OS was estimated by the Kaplan-Meier method and groups were compared by log-rank tests. Univariate and stepwise logistic and Cox regression models were used to assess factors associated with response and OS, respectively.
RESULTS:
In total, 163 pts were identified; the final analysis included 84 pts per inclusion criteria. Thirty-nine pts (46.4%) received VEN-based therapy (6 VEN/LoDAC; 33 VEN/HMA) and 45 pts (53.6%) received IC. Median age at dx was 71y and was significantly higher in the VEN group vs IC (75y vs 65y, p&lt;0.001). Forty percent were women. Most pts (83.1%) were White, 9.1% were Black, and 6.5% were Asian; 3.8% were of Hispanic/Latino ethnicity.
Thirty-seven percent had de novo AML, 19% had therapy-related AML, and 42% progressed from prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). Twenty-six percent of the VEN group and 18% of IC received HMA prior to their AML diagnosis. Almost half (45%) had myelodysplasia-related (MR) cytogenetics and 59.4% had ≥ 1 MR gene mutation. Baseline bone marrow blasts were higher in pts receiving IC vs VEN (p= 0.028). There was a trend towards a higher WBC count at diagnosis in the IC group (p=0.065).
Per 2022 ELN stratification, 9.5%, 26.2%, and 64.3% had favorable-, intermediate-, and adverse-risk disease, respectively. The IC group had significantly more pts with favorable risk (15.6% vs 2.6%, p=0.043).
The most common mutations were in TET2 (30%), RUNX1 (24%), ASXL1 (18%), DNMT3A (18%), IDH1/2 (18%), NRAS(17%), and TP53 (17%). DNMT3A and IDH1/2 mutations were higher in the VEN group vs IC (28% vs 9%, p=0.021 and 28% vs 11%, p=0.046).
Forty-three percent achieved CR, 6% had CRh, 2% had CRi, and 11% had morphologic leukemia-free state. The IC group achieved a higher CR rate (53.3% vs 30.8%, p=0.037) but there was no difference in CRc. Only 9% of the IC group and 3.2% of the VEN group were transplanted in CR1 (p=0.64).
Univariate analysis identified de novo AML (odds ratio [OR] 4.7, p=0.0018) and favorable/intermediate risk (OR 3.1, p=0.02) as factors associated with CRc. Stepwise selection identified prior MDS/MPN (OR 0.2, p=0.0004) and mutated TP53 (OR 0.2, p=0.03) to be negatively associated with CRc.
Univariate Cox model for OS identified de novo AML (hazard ratio [HR] 0.35, p&lt;0.0001), MR cytogenetics (HR 1.8, p=0.02), and mutated TP53 (HR 2.0, p=0.03) as significant covariates. Stepwise Cox model showed that therapy-related AML (HR 6.12, p&lt;0.0001) and prior MDS/MPN (HR 2.17, p=0.0023) were associated increased HR for death.
Median follow-up time was 12.7 months (mo). Median OS for IC vs VEN was 15.4 vs 9.3mo (p=0.10) in all pts, 18 vs 9.3mo (p=0.086) for favorable/intermediate risk, and 11.9 vs 10mo (p=0.81) for adverse risk, respectively.
CONCLUSIONS:
Older pts with favorable/intermediate risk AML who were offered IC over VEN-based therapy had a trend towards better OS. However, those with adverse risk AML had no difference in OS with either approach; this may support offering VEN-based therapy over IC in pts with adverse risk disease, even to “medically fit” pts, to avoid treatment related toxicity.
Our study had only a few pts proceeding to transplant in CR1, limiting our ability to assess the impact of therapy choice on transplant outcomes. Furthermore, 26% of VEN pts received prior HMA, making this group particularly higher risk and accounting for shortened survival. Our findings should be validated prospectively to optimize therapy choice for “medically fit” older adults with AML.