Efficacy of the hypomethylating agents as frontline, salvage, or consolidation therapy in adults with acute myeloid leukemia (AML)

Abstract

Background The hypomethylating agents (HA), azacitidine and decitabine, have emerged as an alternative to initial and salvage therapy in patients with AML. Little is known about how AML responds to hypomethylating agents after standard therapy and the activity of these agents in a real world setting is not well studied. Methods We retrospectively examined data for 75 consecutive AML patients at Wake Forest from 2002–2011 treated with HAs either as 1st line (n=34), salvage (n=28) or consolidation (n=13). We collected data on age, gender, race, Charlson Comorbidity index (CCI), cytogenetics, type of treatment, Complete Remission (CR), Complete Remission with incomplete count recovery (CRi), and survival. Statistical analysis was performed using Kaplan-Meier estimates and cox proportional hazards models. Results Frontline response rate (CR+CRi) was 26.5%, median overall survival (OS) was 3.4 (95% CI 1.3–7.4) months, with 18% alive at one year. In the salvage cohort, the response rate was significantly lower compared to frontline (3.6% versus 26.5%, p=0.017). Despite the reduced response, OS from time of HA treatment was longer than frontline at 8.2 (CI 4.8–10.3) months. In the consolidation cohort OS was 13.8 (CI 8.0 – 21.6) months with one patient in remission more than 30 months from diagnosis. Conclusion These data suggest prior cytotoxic therapy decrease marrow response rates to HAs but not survival. Furthermore, use of hypomethylating agents for consolidation resulted in a median overall survival over one year in a cohort of older patients. This suggests that hypomethylating agents have activity in all phases of AML treatment.

RETRACTED ARTICLE: 5-Azacitidine for treating acute myelogenous leukemia

“…Hypomethylating therapy has also been used as consolidation or maintenance therapy in older patients with AML in CR and, retrospectively at least, has been shown to prolong overall disease-free survival in some individuals [69]. In a Phase Ib study, Wei et al studied the safety and tolerability of maintenance therapy, comprising lenalidomide in combination with azacitidine, in 40 patients with AML in complete remission after chemotherapy.…”

“…Azacitidine-based combinations have recently been investigated in early phase clinical trials in relapsing/refractory AML [76][77][78] and in retrospective cohorts of limited size [60,69,79,80]. Subgroups of relapsed/refractory patients likely to benefit from such azacitidine-based regimens have not been identified to date.…”

Treating acute myeloid leukemia in older adults

“…35 Dec or Aza therapy has also been used as consolidation or maintenance therapy in older patients with AML in CR and, retrospectively at least, has been shown to prolong overall disease-free survival in some individuals. 51 …”

Biochemical, Epigenetic, and Metabolic Approaches to Target IDH Mutations in Acute Myeloid Leukemia

“…hypomethylating agents)Azacitidine and decitabine are DNA methyltransferase inhibitors (DNMTI) approved by the Food and Drug Administration (FDA) for the treatment of patients with MDS42,43 . Off-label, these agents have been used widely as an alternative to high-dose induction chemotherapy for AML patients who cannot tolerate or whose disease has failed aggressive induction therapy44 .Based on the hypothesis that the presence of DNA hypermethylation secondary to IDH1/2 mutations would predict a favorable response to hypomethylating agents, we performed a retrospective analysis of outcome for patients with AML bearing IDH1/2 mutations who were treated with DNMTIs 45 . Of the 42 samples (mean patient age 76.0±7.4 years) analyzed, three harbored IDH1 and four had IDH2 mutations.…”