Background: Few therapeutic options exist for older AML patients (pts) in whom induction chemotherapy is not feasible. Encouraged by the marked activity and low toxicity of the demethylating agent DAC in high-risk MDS, we initiated a phase II trial in untreated AML patients >60 years not eligible for induction.

Methods: low-dose DAC was given as for MDS (i.e. 135 mg/m2 i.v. over 72 hrs), repeated q 6 weeks for up to 4 courses, with all-trans retinoic acid (ATRA, 45mg/m2/day for 28 days) given during course 2 in DAC-sensitive pts. Maintenance with 20 mg/m2 DAC i.v. over 1 hour on 3 days (total dose 60mg/m2, outpatient administration) q 8 weeks was offered to pts completing all 4 courses. Pts with a WBC of >20 000/ul received a short course of hydroxyurea (HU) prior to DAC. The primary endpoint was best response: complete (CR) or partial remission (PR) or an antileukemic effect (AE, >25% bone marrow blast reduction). Pts requiring HU beyond day 28 of course 1 and/or showing blast increase had progressive disease (PD). Secondary endpoints were: overall (OS) and progression-free survival, toxicity and hospitalization duration. Accompanying studies included quality-of-life and geriatric assessment, p15/INK4b methylation analyses, and sequential measurement of HbF (a potential marker of DNA demethylating activity).

Results: 51 pts have been recruited, with a median age of 72 years (range 63–85). 33% of pts were > 75 years. Complex karyotype and/or preceding MDS were present in 65 and 51 %, respectively. Median WBC before treatment was 5300/μl (range, 600–241,000, 33% of pts >20 000/μl WBC). Median bone marrow blasts were 70%. The median number of DAC courses given was 2, and 6 pts received a total of 30 maintenance courses (median 4.5). In the 29 fully evaluable pts, the best response was CR in 4 pts (14%), and PR in 5 pts (17%), with a median of 13 weeks to best response. An AE occurred in 9 pts (31%), resulting in a 62% overall response rate. Stable disease (SD) was seen in 3 pts (10%), 7 had PD (24%), 1 pt (3%) died early (day 9 from start DAC). Two pts (1 SD, 1 AE) were taken off study after 2 courses because of prolonged neutropenia. Toxicities of inpatient DAC were very similar to those described for MDS (neutropenia, fever/infection, pancytopenia). No unexpected toxicities or ATRA syndrome were observed with the combination of DAC+ATRA. No hospitalizations occured during maintenance DAC. Median OS from start of treatment was 7.5 months (range, 0.3–21+), the 1-year survival 24%. In CR+PR pts, median OS was not reached, in pts with AE was 7.8 months, in nonresponders 1 month. Geriatric assessment revealed a high maintenance level of capabilities during the study period.

Conclusion: low-dose DAC is very well tolerated by older AML pts ineligible for more aggressive treatment, with myelosuppression being the major toxicity. Objective responses occur in 31 % of pts. A frequent and often prolonged antileukemic effect, limited hospitalization times, the occurrence of late responses, and the good feasibility of outpatient maintenance also support continued DAC treatment.

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