Azacitidine low-dose schedule in low-risk myelodysplastic syndromes. Clinical results of a multicenter phase II study

Background: Azacitidine (AZA) at a dose of 75 mg/mq/day subcutaneously for 7 days, every 28 days, induces high hematologic response rates and prolongation of survival in high-risk MDS patients (pts) (Fenaux, 2009). However few data are hitherto available concerning the efficacy and safety of Aza in lower risk MDS. A lower dose regimen, AZA 5 (75 mg/mq daily, subcutaneously, for 5 consecutive days every 4 weeks) have shown to induce response rates consistent with the currently approved schedule (Lyons, 2009), however in this study pts were not classified according to IPSS risk. Aim: In our phase II, prospective, multicentric trial, AZA 5 regimen was administered to IPSS low-or-intermediate-1 risk pts, for a total of 8 courses, in order to evaluate its efficacy and safety. Furthermore pharmacogenomic studies (GEP, SNP) cytokine network and PI-PLCbeta1 methylation and gene expression, before and at the end of 4th and 8th course of Aza treatment, were planned to identify new biological markers to predict the response. Methods: From September 2008 to February 2010, 34 low-risk MDS patients with a median age of 71 (56–84) yrs were enrolled into the study. Results: At present time 30/34 pts are evaluable: 26/30 pts (87%) completed the treatment plan (8 courses). According to the 2006 International Working Group criteria, overall response rate (ORR) was 58% (15/26 pts): 5 pts (19%) achieved complete remission (CR), while 10 pts (39%) showed an hematologic improvement (HI). 11/26 pts (42%) maintained a stable disease (SD). Generally the drug was very well tolerated. The most commonly reported hematologic toxicities were neutropenia (55%) and thrombocytopenia (20%). 4/30 pts (13%) died during treatment. The median duration of response was 5 months (range 1–14 months). Surprisingly, 3/15 patients (2 CR and 1 HI erythroid) showed a long duration of response (11, 13 and 14 months, respectively), still ongoing, after discontinuation of AZA. Preliminary data on the lipid signalling pathways suggested a direct correlation between the demethylating effect on PI-PLC-beta1 and responsiveness to treatment. Conclusion: Our study shows that AZA low-dose schedule may be a feasible and effective treatment for low-risk MDS pts and may induce durable responses. Despite AZA safety, extreme caution is needed in pts with age-related comorbidities and/or with severe neutropenia or thrombocytopenia, especially in low-risk MDS. Furthermore, PIPLC-b1 demethylation and gene expression could represent a new biological marker to predict the clinical response to AZA