A 10 Day Schedule of Azacitidine Induces More Complete Cytogenetic Remissions Than the Standard Schedule In Myelodysplasia and Acute Myeloid Leukemia with Myelodysplasia-Related Changes: Results of the E1905 US Leukemia Intergroup Study

In recent years, azacytidine (AZA) has become the standard of treatment for high risk myelodysplasia (MDS). The approved schedule of AZA uses a 75mg/m²/d s.c. regimen for 7 days based on the CALGB-9221 (Silverman, JCO 2002) and the AZA-001 studies (Fenaux, Lancet Oncol 2009). The clinical response rates after AZA have been extensively presented but there is only limited data on the rates of cytogenetic response (CyR). Based on the review of the literature, there are no specific cytogenetic data published on prospective trials.

We based our analysis on a randomized phase 2 study from the US Leukemia Intergroup (E1905 study, NCT00313586) testing 10 days of AZA (50mg/m²/d s.c.) vs 10 days of AZA+ the histone deacetylase inhibitor entinostat (4 mg/m²/d PO days 3 and day 10). MDS, CMML, and AML with myelodysplasia-related changes were included. This analysis includes all patients with cytogenetic abnormalities (at baseline or acquired following treatment) with available cytogenetic follow-up (cycle 6). Of 150 patients, 70 demonstrated baseline cytogenetic abnormalities. To date, forty patients (27 MDS and 13 AML) were evaluable for both time points. Karyotypes were performed at local laboratories, and reviewed centrally (RPK and GH). Cytogenetic response was assessed using IWG 2000 (Cheson et al, Blood 2000) criteria.

The clinical response rate (CR+PR+ trilineage HI) according to IPSS cytogenetic risk stratification were of 20%, 33%, and 35% for favorable, intermediate and poor cytogenetic risk groups respectively (p=NS). Patients with Chr 7 abnormalities (i.e. -7 or -7q, n=18) had a response rate of 28% including 17% CR. Of patients with complete cytogenetic data, the rate of overall CyR was 52% (n=21): 22% (n=9) complete CyR, 30% (n=12) partial CyR. This represents a complete CyR of 13% and a partial CyR of 23% as a proportion of all treated patients with initial cytogenetic abnormalities (including those who did not receive six cycles of therapy). To date, confirmatory FISH analyses were available for 4 patients with CyR (2 CCyR and 2 PCyR). All four had complete clearance of their cytogenetic clone. Among the cytogenetic responders, 15 had MDS and 6 had AML (p=NS). CyR did not differ between the two treatment arms. CyR and clinical response were highly correlated (p<0.001): all patients with complete CyR and 7/10 partial CyR had a clinical CR. Only 3 patients (1 CCyR and 2 PCyR) had a CyR without associated clinical response. Among 8 patients with cytogenetic progression, 3 pts showed increased frequency of a known aberration and 5 showed new or additional aberration including 2 cases involving Chr7.

65 AZA-treated patients from AZA001 had comparable cytogenetic results available. Only 3 patients experienced complete CyR 4.6% with 33.8% partial CyR (n=22). In contrast, the reported rate of clinical response was similar in the two studies. Complete CyR were more frequent in the E1905 10 days AZA schedule compared to the 7 days AZA schedule (p=0.007). There was no difference in overall CyR between the two studies.

Both the standard AZA schedule and the 10 day schedule administered on E1905 lead to high rates of cytogenetic response. The novel schedule explored in E1905 demonstrated a particularly high rate of complete CyR (22%) with complete clearance of abnormal clone by FISH in 4 tested patients. Further prospective comparison of different AZA schedules will be needed to confirm this higher rate of complete CyR and determine its clinical significance.

Beach:Celgene: Employment. Gore:Celgene: Consultancy, Research Funding, stock options; Syndax: Consultancy.