Introduction: Hypermethylation of tumor suppressor genes (TSG) has been recognized as an important factor in the pathogenesis of malignancies, including myelodysplastic syndromes (MDS). Decitabine (trade name Dacogen; 5-aza-2'-deoxycytidine) is a cytosine analog which inhibits the enzyme DNA methyltransferase (DNMT), inducing hypomethylation and activates TSG, leading to tumor cell growth inhibition. In clinical trials with hypomethylating agents in advanced MDS, a total response rate of 30-73% has been observed, with a complete response (CR) of 9-37%, partial response (PR] of similar rate and a hematologic improvement (HI] in 20-48% of the patients.
Aim: We report the results of a national Israeli compassionate program of decitabine administration to patients with advanced MDS.
Patients and methods: From July 2007 through August 2008, under the joint sponsorship of The Israel Society of Hematology and Blood Transfusions and Janssen, Israel, a compassionate program was conducted. Decitabine was administered to patients with advanced MDS who were not candidates for any other anti-MDS treatment, except for supportive care. The selected regimen was a 5-day intravenous administration of 20 mg/m/d, every 28 days. After the program had been completed, an approval of the institutional Helsinki committees was obtained, and the data were collected in an attempt to evaluate the results of this novel treatment. The standard response criteria, i.e. total response, CR, PR and HI were applied. Toxicity, survival and leukemic transformation rate were also analyzed.
Results: Twenty-four patients with advanced MDS participated in the program but evaluable information could be collected only on 17 patients. The median number of therapeutic cycles was two per patient. Twelve patients were transfusion-dependent at program onset, of whom 7 either benefited from reduced transfusion requirements or became transfusion-free. The overall response rate was 26%, with 23% PR and 13% HI. Two patients (13%) demonstrated leukemic transformation. The median overall survival was 17 months and the median event-free survival was 13 months. Nine out of 12 patients, who could be evaluated, experienced 3-4 degree bone marrow suppression. A single patient suffered from vocal cord paralysis, apparently, unrelated to the treatment.
Discussion and conclusions: The overall response rate was 26% in this national compassionate program of decitabine administration to patients with advanced MDS. Although somewhat low, this is similar to other reports. Possible reasons for the relatively low response rate include a small number of patients, the nature of a compassionate program, the limited number of therapeutic cycles, and the very advanced degree of the disease in most patients who had been on several treatment lines prior to the program. Nevertheless, understanding the role of epigenetics in the pathogenesis of neoplasms and MDS, which led to the introduction of hypomethylation agents such as decitabine into clinical practice, is an encouraging step towards better care of cancer, including MDS.