Preliminary Results of a Multicenter Phase II Trial of 5-Day Decitabine as Front-Line Therapy for Elderly Patients with Acute Myeloid Leukemia (AML)

Introduction: More than half of patients diagnosed with AML are over 60 years old and have few effective treatment options due to both patient-related factors such as co-morbidities and poor performance status, and high-risk disease features such as complex cytogenetics and preceding myelodysplastic syndrome (MDS). Decitabine, a potent DNA hypomethylating agent, has been approved for the treatment of patients with all FAB subtypes of MDS, including those with secondary MDS and those who have received prior therapy for MDS. In AML, decitabine may target the frequent aberrant DNA methylation patterns and is a lower intensity therapy that may be better tolerated in this challenging patient population.

Study: The primary objective of this multicenter, open label Phase II trial was establishing the morphologic complete response (CR) rate in patients 60 years and older with newly diagnosed, untreated AML, who were not candidates for standard induction chemotherapy. Decitabine was administered at a dose of 20 mg/m² intravenously over 1-hour for 5 consecutive days every 4 weeks.

Results: Fifty-five patients were enrolled in the trial [27 men, 28 women; median age: 74 years (range, 61–87); ECOG Score: 0 (47%), 1 (35%), or 2 (18%)]. Most patients had intermediate (53%) or poor (42%) risk cytogenetics. Fifty-six percent had de novo AML, 35% were transformed from MDS, 7% had AML secondary to prior therapy, and 2% had other. According to the AML response criteria (Cheson, JCO 2003), the expert-reviewed overall response rate in the intent-to-treat (ITT) population was 26%, with 13 (24%) morphologic complete responses (CR) and 1 (2%) CR with incomplete blood count recovery (CRi) (Table). The median time to response was 3 months (range, 51–164 days). Responses were seen in all subgroups of patients, including 5 of 19 patients with a prior history of MDS (CR or CRi, 26%) and 5 of 23 patients with poor-risk cytogenetics (22%). A median of 3 cycles (range, 1–25) was administered to the ITT population. Sixty-four percent of patients received 3 or more cycles of therapy. Twenty-four patients (44%) maintained stable disease during a median 5 cycles of therapy. With 1-year duration of follow-up, the overall median survival was 9.6 months. Besides myelosuppression, the most commonly reported adverse events considered possibly related to decitabine treatment were febrile neutropenia (24%), fatigue (24%), pneumonia (11%), sepsis (9%), dyspnea (9%), and bacteraemia (7%). Three deaths occurred on study and were attributed to sepsis. The 30-day mortality rate on this trial was 4%, which compares favorably to the ~20% mortality rate typically seen in this population treated with standard induction therapy (

Conclusion: These preliminary results suggest that decitabine given daily for 5 days demonstrates efficacy in patients with newly diagnosed AML, with a toxicity profile that was manageable in this elderly patient population. This study supports the investigation of decitabine in an ongoing Phase III survival trial (n=480) of the 5-day regimen in elderly patients with AML.

Table