Hypomethylating Agents Versus Intensive Chemotherapy in Elderly Patients (Age ≥ 70) with Acute Myeloid Leukemia with High White Blood Cell Count

Background

Acute myeloid leukemia (AML) is primarily a disease of older adults, with 40-50% of patients ≥ 70 years old at diagnosis. Optimal frontline therapy for elderly AML patients remains controversial. Intensive chemotherapy (IC) is often favored in those AML patients who present with leukocytosis (P-AML), yet the evidence to support this practice as opposed to lower intensity therapy is scarce. We aimed to investigate the outcomes of older patients with P-AML based on treatment choice of intensive chemotherapy (IC) vs hypomethylating agents (HMA).

Methods

We retrospectively analyzed 983 elderly AML patients (age ≥ 70 years) treated at Moffitt Cancer Center between 1995 and 2016. Patients with prior exposure to HMA for non-AML diagnoses were excluded. We focused on P-AML patients, defined as baseline WBC ≥ 10x10⁹/L, who received initial therapy with either: intensive chemotherapy (IC) (defined as daunorubicin/cytarabine or equivalent) or hypomethylating agents (HMA) (azacitidine (AZA) or decitabine (DEC)). Age, type of AML, history of antecedent hematologic disease, cytogenetics (per European LeukemiaNet (ELN) criteria), Eastern Cooperative Oncology Group (ECOG) performance status, Charlson comorbidity Index (CCI), complete blood counts and myeloblast percentage at time of diagnosis were obtained for each patient. Kaplan-Meier analysis was performed to calculate overall survival (OS) and the log-rank test was used to determine significance where a p-value of 0.05 was defined as significant. Fisher's exact t-test, hazard ratios (HR) and confidence interval (CI) were calculated using GraphPad Prism v7.03. Univariate and multivariate analysis for the baseline characteristics and type of therapy were performed using SPSS v24.0 to determine prognostic impact.

Results

Within the entire cohort of older AML patients, we identified 156 who were treated with either HMA (n=41) or IC (n=115). Baseline characteristics of these patients are described in Figure 1A. Significant baseline differences in age, hemoglobin, WBC, ELN cytogenetic category, marrow blast %, and CCI score were observed between the HMA and IC groups. Most notably, the HMA group were older (median age 77 yrs vs 74 yrs, p=0.0037), had a higher incidence of poor-risk cytogenetics (36.6% vs 7%), and were more likely to have CCI score ≥ 3 (29.3% vs 8.7%).

Median time of initial treatment was 4.3 months (range: 0.10-70.0 months) in the HMA group compared to 0.5 months (range: 0.33-1.90months) in the IC group. Median OS of the entire group was 7.85 mo. Median OS in the HMA-treated patients was superior to IC treated patients (13.7 mo vs. 5.1 mo, HR 0.63, 95% CI 0.443 - 0.886, p=0.0082) (Figure 1B). The 12 month survival rate was 55.0% in the HMA group and 31.0% in the IC group (p=0.0082). Fifty-two (33%) patients achieved CR/CRi. There was no difference in CR/CRi rates between HMA or IC treated cohorts (30.0% vs. 34.8%, p=0.6983). Rate of relapse upon achievement of CR/CRi was not statistically significant between HMA and IC cohort (41.7% vs. 62.5%, p=0.3181). The 30-day mortality rate was lower in the HMA group compared to the IC group (7.3% vs 24.4%, p=0.0217).

Univariate analysis identified treatment type (p<0.0001), cytogenetic risk category (p <0.0001), and ECOG performance status (p<0.0001) as significant prognostic factors for OS. Multivariate analysis identified IC treatment (HR 2.01, 95% CI 1.24-3.26, p=0.005) and poor ECOG performance status (HR 4.30, 95% CI 1.182-15.659, p=0.027) as independent negative predictors of OS.

Conclusions

Elderly patients (age ≥ 70) with proliferative AML appear to achieve a survival advantage with HMA-based frontline therapy compared to IC, despite a disproportionately higher incidence of traditionally adverse prognostic features (poor-risk cytogenetics, high CCI score) in the HMA group. The reasons for this observation are unclear, but could relate to a higher early death rate with IC or biologic/molecular features that induce greater sensitivity to HMAs, which should be studied in future analyses. Although this study was limited by small size and retrospective nature, our findings cast doubt on the notion that intensive therapy should be the standard frontline approach in elderly patients proliferative/high WBC AML.

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