Deoxycytidine analogs hypomethylating agents

The role of 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine) in the treatment of MDS and, to a lesser degree, in MPD has been investigated for well over a decade. Besides their cytotoxic activity, these agents induce hypomethylation of genes involved in regulating proliferation and differentiation, particularly tumor suppressor genes that are frequently hyperme-thylated in malignant disorders and presumably also in CMML.24 This hypomethylating effect is believed to be particularly active at relatively low doses. The effectiveness of both 5-azacytidine25 and decitabine26'27 in managing MDS is well documented, but their efficacy and usefulness in managing CMML are less clear.

In the randomized trial comparing subcutaneous 5-azacytidine (75 mg/m2/day for 7 days every 4 weeks) with supportive care, seven patients with CMML were included in each group.25 The responses were not analyzed in detail by disease category, but the responses of CMML patients were reported to be "similar" to those with high-risk MDS [refractory anemia with excess blasts (RAEB) and refractory anemia with excess blasts in transformation (RAEBt)]: 8% CR, 15% PR, and 38% HI. Three monthly courses were needed to obtain the best response. Compared with supportive care, the 5-azacytidine regimen provided a significant delay in the disease progression and some survival advantage in patients with MDS; whether these benefits also applied to the small cohort with CMML is unknown.25

The effectiveness of decitabine in managing CMML can be assessed from European clinical trials of this agent. In one study of 66 patients with high-risk MDS,26 subjects were treated with decitabine (15 mg/m2 given as an intravenous infusion over 4 h every 8 h for 3 days, for a cumulative dose of 135 mg/m2 over 3 days) every 6 weeks for a maximum of six courses. The study included nine patients with CMML; the cases were classified by the International Prognostic Scoring System, suggesting that all nine belonged to the category of MDS CMML.2'4 Four (44%) of the nine patients responded: 1 CR, 1 PR, and 2 HI.26 The actuarial median response duration for the entire study cohort of 66 patients was 31 weeks, and it increased from 26 weeks in patients with HI to 39 weeks for patients with a PR to 36 weeks for those with a CR; no information was provided specifically for the nine patients with CMML.26 In a subsequent review, the results of three separate studies of 124 patients, including 16 with CMML, revealed cytogenetic CR in two patients with CMML.27 The response rates and durations were not specifically reported for the CMML patients, how-ever.27 Together, these results suggest a role for both 5-azacytidine and decitabine in managing CMML, but because reports on their effectiveness in treating CMML are sporadic, no conclusion can be reached. Further study and new assessments based on larger and more formal investigations are required before an accurate evaluation can be made.

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