Efficacy of Frontline 5-Azacytidine in Older AML Patient Unfit for Chemotherapy

The efficacy of conventional treatment in older patients with acute myeloid leukemia remains unsatisfactory, with low remission rates and poor overall survival. Disappointing results of intensive chemotherapy in patient over 60y are explained by decreased bone marrow reserve and high chemoresistance rate. Novel treatment approaches for this age group are needed. Among these options, 5-azacytidine (AZA) have shown promising results, improving survival in high-risk myelodysplastic syndrome including patient with 20–29% marrow blast now considered WHO AML.

AML patients (marrow blast≥20%) considered not candidates for ICT and treated frontline with only AZA in Toulouse University Hospital were retrospectively analyzed in this study. AZA 75 mg/m2/day was administered subcutaneously for 7 days every 4 weeks, which was defined as 1 cycle.

Ninety eight patients were registered between June 2007 and Dec 2010. In this period of time, a total of 470 AML patients older than 60 years were referred in our center. 234 received ICT, 98 AZA, and 138 LD-ARAC or BSC. Sex ratio M/F was 56/42 and median age was 76 (range 50–89). Eighty eight patients were >65y and 51 were >75y. Forty eight patients (48.9%) had de novo AML, 27 patients (27.5%) had prior history of WHO MDS, 5 patients (5.1%) had prior history of myeloproliferative disorder and 18 patients (18.3%) had therapy related AML. Median white blood cell (WBC) count was 2.2G/L (range 0.76–62) and median bone marrow (BM) blast was 35% (range 20–85). Karyotype (Medical Research Council classification) was intermediate in 48 patients (48.9%) including 36 normal and 6 trisomy 8, adverse in 44 patients (44.8%) including 24 -5/del5q, 28 -7/del7q, 35 complex karyotype and 21 monosomal karyotype, and failed in 6 patients (6.1%). Median follow up in survivors was 12.6 months. Patients received a median of 6 cycles of AZA (range 1–27). All patients received at least 1 cycle of AZA and were considered evaluable for response.

Fifty patients (51%) presented a response to AZA. Overall response rate according to AML IWP criteria was documented in 24 patients (24.5%), including 13 CR, 5CRi (18CR/CRi 18.4%), and 6PR (6.1%). The median duration of remission for patients achieving CR or CRi was 9.5months. Among the 74 patients considered as failure according to AML-IWP criteria, 26 additional patients (26.5%) obtained hematological improvement HI (7 pts on 1 lineage, 13 pts on 2 lineages and 6 pts on the 3 lineages).

Overall, 60 patients required hospitalization during treatment for neutropenic fever. The death rate during the first two months after AZA initiation was 18.3%, due to AML progression in 83% and to infection in 17% of cases.

The unique prognosis factor that impacts the response rate in univariate and multivariate analysis was the cytogenetic risk group. We identified 18 CR/CRi/PR (37.5%) in the intermediate group and 6 CR/CRi/PR (13.6%) in the adverse group (p=0.02). Age, WBC count, BM blast, or secondary status of the AML were not statistically related to the response rate. However, it should be noted that only 14 patients had WBC>10G/L at diagnosis.

In the entire cohort 1y OS was 50% and 2yOS was 28%. In univariate and multivariate analysis, intermediate karyotype was statistically linked to longer survival. Achievement of CR/CRi or PR translated in increased survival, and importantly in patient with no AML-IWP response, achievement of HI, even on 1 lineage only, translated in increased survival. Moreover when comparing patient treated with 1 or 2 courses, with patient receiving 3 or more courses, we noted a significant improve in survival while number of courses increased.

AZA appears to be a valuable option for WHO AML patients considered unfit for chemotherapy and with a low WBC count. In this cohort of very old patients, response rates and more importantly survival rates with AZA are promising. Although, pretreatment prognosis factor such as high risk cytogenetic remains adverse factor, predictive factors of response are needed to guide therapeutic decision.

Off Label Use: Azacytidine is approved by FDA and EMEA in the treatment of high risk MDS and AML up to 30% of bone marrow blast. In our study, Azacytidine use was supported by the published results of the French compasionate Azacytidine program in WHO AML patients with more than 30% blast. Recher:Celgene: Membership on an entity's Board of Directors or advisory committees.