Continued Treatment with An Outpatient Maintenance Schedule of Decitabine in Older AML Patients Ineligible for Induction Chemotherapy: Results of the 00331 Phase II Multicenter Trial

Introduction: In older patients with AML in whom conventional chemotherapy is not indicated (comorbidities, performance status, poor cytogenetics etc.), treatment with low-dose azanucleoside DNA demethylating agents may be a less intensive alternative. In MDS, these drugs need to be administered over a prolonged time period in order to gain full benefit, since delayed responses are common, and thus occur not infrequently after more than 6 months of treatment. In a phase II multicenter trial (00331) of low-dose decitabine (DAC, 135 mg/m² administered over 3 days in 9 intravenous 3-hour infusions, with 15 mg/m²/infusion, repeated every 6 weeks) patients benefiting from this treatment were offered an outpatient maintenance with the drug given at an even lower dose and as one-hour infusions on 3 consecutive days.

Patients and Methods: Patients having completed 4 courses of DAC according to the study protocol and being in complete or partial remission (CR, PR), having achieved an antileukemic affect or stable disease were offered continued DAC treatment with 20 mg/m² given intravenously over one hour on 3 consecutive days, repeated every 6 to 8 weeks. Maintenance treatment was continued until relapse or progression.

Results: Of the 235 patients included in the 00331 study, 57 (25%) received the 3-day DAC maintenance. Median age of these 57 patients before study inclusion was 71 years (range 60 – 81), the median white blood count 4200/μl (range 0.2–285,000/μl), 59% had preceding MDS, with a median of 16 months duration. Performance status before initial treatment with DAC: ECOG 0, 1 and 2 in 29%, 58% and 13% of the patients, respectively. 60% had intermediate-risk cytogenetics, 28 % poor-risk cytogenetics, no metaphases were obtained or cytogenetics not done in 12 %. Remission status at maintenance start, i.e. response to 4 courses of DAC, was CR+PR in 71 % of the patients. A median number of 4 maintenance courses was administered (range, 1–16), with 24 patients (42 %) receiving 5 or more courses. Treatment was overall very well tolerated, with dose reductions because of cytopenia necessary in <10 % of courses given. There was no clear effect upon the treatment duration (≥4 versus < 4 courses of maintenance) of patients’ age, sex, WBC, serum LDH, preceding MDS or cytogenetic risk group.

Conclusions: Since the relapse rate in MDS and AML after stopping of azanucleoside treatment is very high, continued dosing, e. g. as a maintenance treatment may significantly prolong disease control. This 3-day “very low-dose” DAC regimen (60 mg/m2 total dose per course) could be given over 4 or more courses in the majority of these AML patients already pretreated with higher doses of the drug, even in the presence of poor-risk cytogenetics. The good tolerance and feasibility of the schedule indicates that it may also be useful in maintaining remissions obtained by a standard treatment of AML/MDS.