A phase II study of 5‐day intravenous azacitidine in patients with myelodysplastic syndromes

Abstract

The approved 7-day schedule of subcutaneous azacitidine for myelodysplastic syndrome is associated with injection site reactions and bruising and may be inconvenient because of the need for weekend doses. Although pharmacokinetic data with IV azacitidine suggests equivalence, there are no efficacy data published. Patients with all myelodysplastic syndromes (MDS) FAB subtypes were enrolled and received 75 mg/m 2 /d of azacitidine by 20-min intravenous infusion for 5 days in every 28 days. Global methylation studies were performed at baseline and prior to Cycle 3. Twenty-five patients were enrolled and 22 were evaluable. Median age was 69.5 years; 9 (41%) patients had lower-risk disease (IPSS Low or Int-1) and 13 (59%) had higher-risk disease (IPSS Int-2 or High). Twenty-seven percent of patients responded (5 CRs and 1 PR). The median time to response was 108 days. The median PFS was 339 days (11.3 months), the median OS was 444 days (14.8 months) and the median duration of response (DOR) was 450 days (15.0 months). Global methylation studies suggest a greater degree of demethylation in responders. This regimen appeared to offer a PR 1 CR rate and median DOR somewhat similar to what has been reported with the 7-day subcutaneous regimen; however, OS was shorter. Am. J. Hematol. 84:560-564, 2009. V

Epigenetic Therapies in MDS and AML

“…In this study the pharmacokinetic profile of intravenous administration was almost identical to that seen with subcutaneous dosing, although the peak drug concentration was higher in patients receiving intravenous drug [38]. Despite these data, published clinical trials using 20 min IV infusion schedules are limited to two studies, one which gave Aza for 5 days and the other for 7 [39, 40]. Both of these studies demonstrated response rates which were similar to those seen with subcutaneous dosing (27% in the 5 day and 56% for the 7 day schedule), but neither of them was powered to detect a survival benefit [39, 40].…”

Targeting DNA methylation for epigenetic therapy

“…More patients who needed red blood cell (RBC) transfusion at baseline became independent of RBC transfusion. Another Phase II trial administered an alternative 5-day 5-Aza-CR intravenous schedule and reported a 27% partial response (PR) + complete remission (CR) rate, comparable to the 7-day subcutaneous regimen[111]. However, future studies are required to illuminate the survival benefit of these modified regimens.…”

“…However, the majority of these studies did not show any clear association between the level of induced demethylation and the clinical response. Two recent papers reported that responders to 5-Aza-CR have more significant decreases in global methylation level and methylated promoters compared to non-responders as detected by the Infinium HumanMethylation array[111, 130]. …”

Hypomethylating Agents in the Treatment of Myelodysplastic Syndromes and Myeloid Leukemia

“…In the second trial, the dose and the schedule were the same, but the drug was given subcutaneously [28]. The Recently, another phase II trial evaluating iv schedule was published [29]. The authors evaluated 22 patients with MDS.…”

“…The most frequent adverse effect was cytopenia [28,30]. The combined results of 3 studies performed by CALGB, evaluating the efficacy of azacytidine in MDS, were reported in 2006 (29). Apart from the randomized study described above, there were 2 single-arm studies taken into account.…”