In this single centre retrospective study, treatment results of 227 newly diagnosed consecutive AML patients aged ≥60 years who have been treated with BSC, azacitidine, or intensive chemotherapy, were analysed. This study confirms the dismal prognosis of older AML patients who receive only BSC, which was either related to adverse characteristics at baseline or to the treatment type. To optimise treatment in older patients who are unfit for chemotherapy, new therapies are developed, including azacitidine. A treatment benefit for azacitidine compared to BSC was observed in a post-hoc analysis of the AML patients in the AZA-001 randomized trial . In the same trial, also a limited number of patients treated with intensive chemotherapy was included, but no significant differences in OS were observed between patients treated with azacitidine versus intensive chemotherapy.
In our retrospective study, despite the limitations of the relatively small number of patients and disparities between the treatment groups, we observed no significant differences in OS in patients treated with azacitidine compared to intensive chemotherapy. Also a time-dependent effect could be excluded. When corrected for baseline differences in a multivariate analysis, a HR of 1.07 was found with a 95% CI of 0.58–2.0 when azacitidine and intensive chemotherapy were compared. Despite relatively small numbers resulting in a wide CI, our point estimate (HR = 1.07) does suggest a comparable treatment effect of azacitidine treatment versus intensive chemotherapy in older AML patients with good performance scores and low WBC counts. Comparable results have been reported recently by the MD Andersen Cancer Centre in a cohort study of 671 patients, including 114 patients treated with hypomethylation-based (either azacitidine or decitabine) therapy . In this study they also reported a significant difference in CR rates but similar OS in patients treated with epigenetic therapy versus intensive chemotherapy. These observations, in a larger cohort, are in line with our observations and might suggest that the currently used response criteria are not sufficient for evaluating some (less intensive) treatment strategies. Further, in the perspective of comparing intensive treatment with less intensive treatment, it is also interesting to note that a small prospective randomised trial between chemotherapy and low-dose cytarabine did not result in a survival benefit for intensive treatment .
An important issue, though difficult to analyse, is the reason why some patients received only BSC, others azacitidine and others intensive chemotherapy. The patients receiving azacitidine differed from the intensive chemotherapy patients in terms of older age, and more comorbidities, but also better performance, lower WBC counts, and lower BM blast counts, while the BSC group consisted of older patients with a high cytogenetic risk score, a poor performance score, and a high HCT-comorbidity index. Apparently, although no defined guidelines were used, the treating physicians seem to have integrated these baseline characteristics in their clinical decisions. Azacitidine is currently only registered for the treatment of AML with bone marrow blasts between 20% and 30%. However, we have recently analysed a cohort of 55 AML patients treated in different hospitals with azacitidine, which included 31% patients with ≥30% bone marrow blasts. A comparable OS and response rates were demonstrated in patients with <30% and ≥30% bone marrow blasts (van der Helm, 2013, in publication). These findings are in line with the results of the Italian named patient program and a German trial [20, 21]. An additional advantage of azacitidine is the tolerability [19, 24, 25], which is reflected in our study by a lower number of days in the hospital and a lower number of red blood cell- and platelet transfusions compared to intensive chemotherapy. In addition, only two of 26 azacitidine-treated patients discontinued treatment because of drug toxicity.
The ongoing phase III trial of azacitidine versus BSC versus intensive chemotherapy (AZA-AML-001 trial) is expected to finally provide the decisive answers for the optimal treatment schedule for elderly AML patients. Recently, the results have been reported of a large phase III trial, comparing the efficacy and safety of decitabine (20 mg/m2, days 1–5) (N = 242) with treatment choice (supportive care (N = 28) and low dose cytarabine (N = 215) of older patients with newly diagnosed AML and poor- or intermediate-risk cytogenetics . The authors concluded that there was a significant improvement in median OS with decitabine versus treatment choice.