Poster Board III-16
Epigenetic silencing of tumor suppressor genes (TSGs) is among the most common acquired abnormalities observed in AML and is prototypically linked to DNA methylation. Aberrant DNA methylation is most prevalent in adverse risk AML patients (Melki, Vincent et al. 1999; Toyota, Kopecky et al. 2001). Reactivated expression of TSGs is commonly implicated in the clinical activity of DNA hypomethylating agents since these genes often have roles in cellular differentiation, apoptosis, DNA repair, and checkpoint control (Jones and Taylor 1980; Pinto, Zagonel et al. 1989; Petti, Mandelli et al. 1993; Schimmer, Pedersen et al. 2003; Schmelz, Sattler et al. 2005; Schmelz, Wagner et al. 2005; Tamm, Wagner et al. 2005). We, and others, have demonstrated that DNA hypomethylating agents can sensitize resistant cancer cells to cytotoxic agents in vitro (Avramis, Mecum et al. 1989; Anzai, Frost et al. 1992; Plumb, Strathdee et al. 2000; Fulda, Kufer et al. 2001; Niitsu, Hayashi et al. 2001; Arnold, Goel et al. 2003; Eramo, Pallini et al. 2005; Kanda, Tada et al. 2005; Qiu, Mirkin et al. 2005) yet this approach has been sparsely studied in clinical trials. We hypothesized that pre-treatment with a hypomethylating agent would increase the efficacy of standard induction chemotherapy for AML.
We conducted a phase I dose-escalation study of decitabine administered just prior to a single, standard induction with infusional cytarabine (100 mg/m2 for 7 days) and daunorubicin (60 mg/m2 × 3 doses) as initial treatment for patients with less-than favorable risk AML. Three dose levels of decitabine (20 mg/m2 for 3, 5 or 7 days), delivered either as a bolus (Arm A) or by continuous infusion (Arm B), were used as priming for standard induction chemotherapy.
At current data cut-off, 25 (of 30 patients planned) were fully evaluable: median age was 56 (range 23–60); 21 (84%) patients had adverse risk AML because of karyotype (No. 15, 60%), or other adverse features (FLT3-ITD or antecedent hematologic disorder, No. 11, 44%), and the remaining 4 (16%) patients had intermediate risk AML. Toxicity was similar to that of standard induction chemotherapy alone. Two patients treated at the highest dose level had grade 3 mucositis that resolved prior to count recovery. We observed no excess hematologic toxicity and all patients had peripheral blood count recovery within 30 days or were found to have persistent AML. There was no induction mortality and no patients required ICU transfer. A maximum tolerated dose was not achieved.
Twenty-one patients (84%) responded to therapy: 14 CR (56%), 7 PR (28%). Of the patients with PR to protocol treatment, 5 achieved remission with a second, standard induction bringing the overall CR rate to 76%. The final cohort of patients is currently accruing. All patients went on to receive additional AML therapy and 14 have received an allogeneic HSCT. Pharmacodynamic analyses of DNA hypomethylation prior to and immediately following priming demonstrate genome-wide DNA hypomethylation at all dose levels. Detailed analyses of DNA methylation are ongoing.
Complete remission is requisite for the cure of AML and this study demonstrates that it is safe to combine the epigenetic modifier, decitabine, with full-dose, standard, cytotoxic chemotherapy as an approach to improve remission rates. Our results suggest that epigenetic priming is potentially superior to standard induction therapy alone as initial therapy for patients with less than favorable risk AML and provide the foundation for a subsequent phase II study.
Off Label Use: Phase I study of decitibine use in AML.
Asterisk with author names denotes non-ASH members.