Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old

Abstract

Older patients with acute myeloid leukemia (AML) have poor outcomes with standard induction chemotherapy. We retrospectively reviewed our institute's experience with epigenetic (Epi) versus cytarabine-and anthracycline-based intensive chemotherapy (IC) as induction in newly diagnosed AML patients aged 60 years and older. One hundred sixty-seven patients (n 5 84, IC; n 5 83, Epi) were assessed; 69 patients received decitabine and 14 azacitidine. Baseline characteristics between the IC and Epi patient cohorts were not statistically different except for age, initial white blood cell count, and comorbidity index. Overall response rate (ORR, 50% vs. 28%, respectively, P < 0.01) and complete response rate (CRR, 43% vs. 20%, respectively, P < 0.01) were superior following IC vs. Epi. Although univariate analysis demonstrated longer overall survival after IC (10.7 vs. 9.1 months, P 5 0.012), multivariate analysis showed no independent impact of induction treatment. Treatment-related mortality was not statistically different in the two groups. Outcomes of patients with secondary, poor cytogenetic risk, FLT-3 mutated AML, or relapsed/refractory disease after IC or Epi were not significantly different. Outcomes of patients receiving IC versus a 10-day decitabine regimen (n 5 63) also were not significantly different. Our results suggest that IC and Epi therapy are clinically equivalent approaches for upfront treatment of older patients with AML and that other factors (feasibility, toxicity, cost, etc.) should drive treatment decisions. Prospective randomized trials to determine the optimal induction approach for specific patient subsets are needed.

Treating acute myeloid leukemia in older adults

“…13 For this reason, we recently analyzed our own experience with intensive "7ϩ3"-based chemotherapy versus Dec or Aza treatment in 167 consecutive unselected AML patients Ն60 years of age at Roswell Park Cancer Institute. 34 Similarly to Quintas-Cardama, 13 we found that standard intensive chemotherapy resulted in 2-fold higher CR rates than hypomethylating therapy (43% vs 20%; p Ͻ .01). Although univariate analysis demonstrated longer overall survival after intensive versus hypomethylating therapy (10.7 vs 9.1 months; p ϭ .01), multivariate analysis highlighted no independent impact of treatment choice.…”

“…25 Recent studies suggest that, although hypomethylating therapy in AML patients results in lower CR rates (10%-20%) than conventional intensive chemotherapy, an additional 10%-30% of these individuals nevertheless exhibit evidence of some disease response or stabilization and have overall survival rates equivalent or superior to other conventional treatments. 13,26,34 Lastly, and perhaps most importantly, hypomethylating therapy was well tolerated over long periods of time in unfit elderly individuals, with fewer required hospital days and RBC and platelet transfusions. 35,36 To date, the question of which older patients with AML benefit from intensive versus hypomethylating therapy has been addressed only in retrospective analyses.…”

“…Moreover, despite these impressive CR rates, other retrospective analyses have demonstrated no significant overall survival benefit to Dec or Aza therapy compared with intensive chemotherapy in AML with adverse cytogenetics or chromosome 5 and 7 abnormalities. 13,34,36,38 In an intriguing study, Metzeler et al reported a CR rate of 75% after Dec therapy in 8 patients with AML characterized by DNMT3A mutations. 39 However, in a larger study of 68 older patients with AML, Dinardo et al found no direct correlation between DNMT3A, IDH1, or IDH2 mutational status with response, event-free, or overall survival after upfront epigenetic therapy.…”

“…Ten-day Dec induction has also been associated with treatment mortality rates indistinguishable from those of intensive chemotherapy in elderly individuals. 13,34 For these reasons, unfit older individuals desiring largely outpatient therapy and for whom treatment-related mortality is a concern may be considered for subcutaneous Aza, 5-day Dec, or LDAC therapy as an alternative to 10-day Dec induction.…”

“…Subgroup analysis demonstrated similar outcomes after intensive versus Aza or Dec therapy in older patients with adverse karyotype, secondary, or FLT-3-mutated AML. 34 Investigators from the Netherlands analyzed their center's results in 227 AML patients Ն60 years old consecutively treated with intensive chemotherapy (n ϭ 90), Aza (n ϭ 26), or best supportive care (n ϭ 97). Despite the relatively small number of Aza-treated patients in this study, van der Helm et al also found similar overall 1-year (57% vs 56%, pϭ.93) and 2-year (35% vs 35%, p .92) survival rates after intensive versus Aza therapy.…”