Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML

Abstract

We conducted an open-label phase 1 study exploring the feasibility, safety, and biologic activity of epigenetic priming with decitabine before standard induction chemotherapy in patients with less-thanfavorable risk of acute myelogenous leukemia (AML). We directly compared the clinical and DNA-hypomethylating activity of decitabine delivered at 20 mg/m 2 by either a 1-hour infusion (Arm A) or a continuous infusion (Arm B) for 3, 5, or 7 days before a single, standard induction with infusional cytarabine (100 mg/m 2 for 7 days) and daunorubicin (60 mg/m 2 ؋ 3 doses). Toxicity was similar to that of standard induction chemotherapy alone. Although we did not identify a maximum tolerated dose, there was more gastrointestinal toxicity with 7 days of decitabine priming. Decitabine induced DNA hypomethylation at all dose levels and there was a trend toward greater hypomethylation in CD34 ؉ bone marrow cells when decitabine was delivered by a short pulse (Arm A). Twenty-seven subjects (90%) responded to therapy: 17 with complete remission (57%) and 10 with partial remission (33%). Of the patients with partial remission to protocol treatment, 8 achieved remission to their next therapy, bringing the overall complete remission rate to 83%. We conclude that epigenetic priming of intensive chemotherapy can be safely delivered in an attempt to improve response rates. This trial was registered at www.clinicaltrials. gov as NCT00538876. (Blood. 2011;118(6): 1472-1480) IntroductionComplete remission (CR) is required for the cure of patients with acute myelogenous leukemia (AML). Modern treatment has improved the survival of patients with AML and favorable molecular features, but the majority of patients do not have these favorable features. Standard therapy for younger patients with suboptimalrisk AML is associated with only 19%-37% long-term survival, and 17%-38% of these patients have persistent AML after standard induction chemotherapy. 1-3 Accordingly, new treatment strategies to improve induction success rates are needed to increase survival.Aberrant DNA methylation is a common means by which tumor suppressor genes (TSGs) are inactivated during carcinogenesis. 4,5 Unlike genetic mechanisms of inactivation such as gene deletion or mutation, the epigenetic silencing of TSGs by DNA methylation is potentially reversible. This has led to broad interest by cancer biologists and oncologists in the study of DNA methylation and provides the rationale for incorporating DNA-hypomethylating agents into cancer therapy.Acquired abnormalities of DNA methylation are frequently observed in AML and are particularly prevalent among patients with adverse risk features. 6,7 Decitabine has single-agent activity in patients with poor-risk, relapsed, and resistant AML. [8][9][10][11][12] This antileukemic activity is believed to result from the epigenetic induction of differentiation and cytotoxicity, 13,14 but a link between clinical outcomes and the decitabine-induced hypomethylation of specific genomic loci has not yet been established. 10,[15]...

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How to manage high-risk acute myeloid leukemia

“…While I would have no problem with such approval, I think it would be unfortunate if these drugs were regarded as the 'standard of care' for such patients if this phrase meant not a standard of comparison for future trials, but a mandate to use these drugs as initial therapy, rather than placing a patient on a clinical trial, such as one using these drugs as 'epigenetic priming'. 47 Because the results noted above likely reflect an average of results from more and less sensitive patients it is important to identify patients who are more likely to respond. Administering decitabine at 20 mg/m 2 for 10 days, Blum et al 48 noted a CR rate of 67% in 27 patients with unfavorable cytogenetics, a much higher rate than with the usual 5-day schedule.…”