Abstract

DNA hypermethylation of promoter-specific CpG islands is a well known mechanism of epigenetic silencing, and has been implicated in the pathogenesis and progression of disease in MMM. We are evaluating 5-aza-2′deoxycytidine (Decitabine), a potent DNA methyltransferase inhibitor in a Phase II trial in patients (pts) with MMM. Decitabine was administered subcutaneously at a dose of 0.3mg/kg/d on days 1–5, and days 8–12 and cycles were repeated every 6 weeks, in the absence of dose limiting toxicities. Response was determined every 12 weeks, and defined as an improvement in cytopenias and/or splenomegaly. Pts who had no response after 2 cycles were eligible for dose escalation to 0.4mg/kg/d. Elevated levels of circulating CD34+ cells are associated with advanced stage and evolution to the blast phase of the disease in MMM. Therefore, CD34+ cells were measured in peripheral blood at baseline, and at days 1, 5 and 12 of the first 2 cycles of therapy as a surrogate marker of disease activity. Seven pts (5 males, 2 females) have been enrolled, median age 71 (range 42–89), median baseline absolute CD34+ cell count 27× 106/L (11–4959), Dupriez score of 2, 1 and 0 in 72%, 14% and 14% respectively. Median number of cycles administered was 4 (range 1–7). Median WBC and platelet (plt) count at baseline were 3.6K/uL (range 1.5–29), and 188K/uL (range 62–446K/uL) and 3 pts were red cell transfusion dependent. Grade 4 neutropenia (ANC) occurred in all pts, and grade3/4 thrombocytopenia in 5 pts. Nadir ANC and plts occurred at a median of 31 days (range 24–44) and 23 days (range 17–31) respectively. Recovery to ANC >0.5K/uL and plts >50K/uL occurred at a median of 43 (range 35–58) and 26 days (23–36) respectively. Two pts required a dose reduction for prolonged myelosuppression, and in 1 pt the dose was escalated to 0.4mg/kg/d for lack of a response after 2 cycles. Two pts have developed febrile neutropenia; one of these pts had a documented infection. Grade 3–4 non-hematologic toxicities were rare and include a variceal bleed in a patient with baseline portal hypertension, occurring in the setting of a platelet count of 486K/uL. There have been no injection site reactions. Five pts are evaluable for response. Of these, two pts have had a response including 1 pt with a CR (normalization of blood counts including transfusion independence). One pt in the blast phase of the disease has had a hematological improvement as evidenced by a normalization in platelet counts (from 62K/uL to 200K/uL) associated with a significant decrease (from 2.58K/uL to 0.03K/uL) in peripheral circulating blasts. The other 3 pts have had stable disease; 2 of these remain on treatment and have received 4 and 7 cycles of treatment, respectively. A trend towards a decrease in spleen size has been observed in 3 of 4 patients with palpable splenomegaly at baseline. Overall, there was a significant reduction in circulating CD34+ levels, with a mean decrease of approximately 70% at day 12 of cycles 1 and 2 (p=0.01)

We conclude that low dose decitabine administered subcutaneously is feasible in MMM and is associated with minimal non-hematologic toxicity. Myelosupression is significant, though reversible and requires close monitoring. To our knowledge this is the first report demonstrating the potential clinical activity of decitabine in MMM. This observation requires confirmation in a larger group of patients, and accrual is ongoing to this multi-center Phase II study.

Disclosure: No relevant conflicts of interest to declare.

Author notes

*

Corresponding author