PROLONGED HEMATOLOGIC AND MOLECULAR RESPONSE AFTER A LIMITED NUMBER OF AZACITIDINE CYCLES IN LOW-RISK MYELODYSPLASTIC SYNDROMES

Background. Azacitidine (AZA), at a dosing schedule of 75 mg/m2/d subcutaneously for 7 days every 4 weeks, induces high hematologic response rates (60-80%) in patients with Myelodysplastic Syndromes (MDS), and prolongs overall survival in high-risk MDS patients (Silverman, 2002; Fenaux, 2009). However limited data are available concerning the efficacy and safety of AZA in low- risk MDS. Moreover, although continuation of AZA treatment is generally recommended in all responder patients, the optimal duration of therapy has not been clearly defined, especially for low-risk patients. Recently, a community-based study mainly involving low-risk MDS (Lyons, 2009), showed that the lower dose AZA 5 regimen (75 mg/m2/d subcutaneously for 5 days), which avoid week-end dosing, can induce therapeutic responses consistent with the currently approved schedule. Aims. These data prompted us to investigate the therapeutic effect of the AZA 5 regimen, administered as induction treatment for a total of 8 courses, in low-risk MDS patients with symptomatic anemia refractory to erythropoietin (EPO). Methods. From September 2008 to February 2010, 34 patients with low-risk MDS (IPSS score low or intermediate-1) were enrolled into the study. Age at diagnosis ranged between 56 and 84 years. Moreover, as our group (Follo, 2009) previously demonstrated that the inositide signalling pathways, in particular phosphoinositide-phospholipase C (PI-PLC) beta1, may represent a target for AZA, we quantified the degree of PI-PLCbeta1 methylation and gene expression before and during AZA administration. Results. According to the 2006 International Working Group criteria (Cheson, 2006), overall response rate (ORR) was 61% (14/23 evaluable patients), including Complete Remission (CR) (22%), and Hematologic Improvement (HI) (39%). Unexpectedly, in 3/14 responder patients we observed a long duration of response, still ongoing, after discontinuation of AZA. Patient 1, a 77 yr male, (WHO diagnosis: Refractory Anemia; IPSS risk: low; karyotype: normal) started AZA on September 2008. He showed a 1st response (HI, erythroid response), with a significant reduction of transfusions, after 3rd course of AZA, and became completely transfusion-independent from August 2009, 3 months after the completion of the 8th course (duration of response: 18 months). Patient 2, a 61 yr female, (WHO diagnosis: Refractory Anemia with Excess of Blasts-1; IPSS risk: intermediate-1; karyotype: normal) started AZA on October 2008, became transfusion-independent after 5th course, and achieved CR after 8th course (duration of response: 24 months). Patient 3, a 70 yr female, (WHO diagnosis: Refractory Cytopenia with Multilineage Dysplasia; IPSS risk: intermediate-1; karyotype: normal) started AZA on February 2009, and achieved HI (erythroid response) after 2nd course (duration of response: 22 months). All the patients showed an increase in PI-PLCbeta1 expression, in association with the hematologic response, and still maintain the molecular response. Summary/Conclusions. Our clinical and biological results support the feasibility and effectiveness of AZA treatment in low-risk MDS, especially in the case of EPO refractoriness. After achievement of hematologic response, discontinuation of AZA might be attempted, especially in lowrisk MDS, where the risk of leukemic evolution is lower. However, the effectiveness of AZA resumption, in case of relapse, is still unknown.