Phase I/II study of decitabine in patients with myelodysplastic syndrome: a multi-center study in Japan

Abstract

The management of myelodysplastic syndrome (MDS) remains challenging. We performed a phase I/II study to evaluate the safety and efficacy of decitabine in patients with MDS in Japan. Patients with MDS with red cell transfusion dependence or 5-30% blasts in marrow and with an International Prognostic Scoring System score of intermediate-1 or higher were eligible. Patients received intravenous decitabine at 15 or 20 mg/m(2) daily for 5 days every 4 weeks. A total of 37 patients were enrolled. Three patients received 15 mg/m(2) and experienced no dose limiting toxicity during the first cycle. Thirty-four patients received 20 mg/m(2) . Grade 3 or greater non-hematologic toxicities included cerebral infarction (n = 1), subdural hematoma (n = 1), elevated blood glucose (n = 1), and pulmonary hypertension (n = 1). At 20 mg/m(2) , complete response, partial response, and hematologic improvement were observed in 7 (20.6%), 2 (5.9%), and 7 (20.6%) patients, respectively. Complete cytogenetic response was observed in 30% of evaluable 20 patients. The median number of cycles to clinical response was 4 (range 4-8), and duration of remission was 474+ days (range 294-598+). The 2-year rate of acute myeloid leukemia-free survival was 52%. Correlative studies revealed hypomethylation in multiple genes in peripheral blood cells after treatment. Hypomethylation was generally more profound in CD15 + peripheral blood cells, which reflects myeloid cells, than in peripheral blood mononuclear cells. In summary, decitabine was safe and demonstrated efficacy in Japanese patients with high-risk MDS. This trial was registered at ClinicalTrials.gov (NCT00796003).

© 2012 Japanese Cancer Association.

Figures

Figure 1

Study schema. A total of 37 patients were treated in this study. In the phase I part, three received 15 mg/m2 and six received 20 mg/m2. In the phase II part, 28 additional patients received 20 mg/m2. Toxicity was analyzed in all patients. Efficacy was analyzed in all patients who received 20 mg/m2.

Figure 2

Transfusion independence. Transfusion independence was calculated using all enrolled patients as the denominator (n = 34). (a) Red cell transfusion independence. The transfusion independence rate increased from 26% (baseline) to 41% after five cycles. (b) Platelet transfusion independence. The color indicates the number of transfusions required per cycle. At baseline 85% of patients were transfusion independent. The majority of patients who continued on treatment past cycle 6 did not require platelet transfusion after that cycle.

Figure 3

Time to acute myeloid leukemia or death. Median time to acute myeloid leukemia or death has not been reached. The 2‐year rate was 52%.

Figure 4

Overall survival. Median survival has not been reached. The 2‐year rate was 56%.

Figure 5

Plasma concentrations of decitabine – time profile (Mean ± standard error of mean). Mean plasma concentration is plotted with standard error of mean. The data are from: (a) three patients receiving 15 mg/m2, and (b) five patients receiving 20 mg/m2 (one patient receiving 20 mg/m2 in phase I chose not to participate in the pharmacokinetic analysis).

Figure 6

Changes in the methylation status in five selected genes using peripheral blood mononuclear cells or CD15 + peripheral blood cells (Mean ± standard error of mean). (a) Average methylation changes (0, baseline, and 5, 12 and 28 days after treatment) were compared between peripheral blood mononuclear cells (black lines) and CD15‐positive blood cells (gray lines). The y‐axis shows methylation level (%). (b) Average methylation changes (0, baseline, and 5, 12 and 28 days after treatment) were compared between patients treated with 15 mg/m2 (black lines) and 20 mg/m2 (gray lines). The y‐axis shows relative changes to methylation levels at baseline. (c) DNA demethylation status after decitabine treatment was classified into four groups. (d) Genes in Group 4 show prominent demethylation around 12 days after decitabine treatment. Methylation status of a representative newly identified gene, KLHDC7B, is shown. Methylation changes (at 0, baseline, and 5, 12 and 28 days after treatment) were compared between patients treated with 15 mg/m2 (black lines) and 20 mg/m2 (gray lines). The y‐axis shows relative changes compared to methylation levels at baseline.