Treatment options for elderly AML must be based on four

Treatment options for elderly AML must be based on four main factors: patient\'s clinical condition, disease characteristics, patient wishes and social support. Thus, the most frail and oldest among the oldest will have the least net benefit from chemotherapy or hematopoietic transplantation, even if they receive the best available treatment, while the fittest and youngest patients will benefit most. Having said that, it is obvious that the “relative prognosis” of an elderly AML patient will depend on our capability to administer an effective treatment, and that the risk-benefit of subjecting a patient to intensive chemotherapy must be carefully weighed and based not only on the predicted toxicity of the regimen, but also on the likelihood of response, where cytogenetics play a continine role. Indeed, the relation between adverse cytogenetics and poor and short-lived responses to intensive chemotherapy have been consistently demonstrated [37,38]. The most favorable situation would be a patient harboring acute promyelocytic leukemia, who can be treated conventionally in most cases with rather optimistic expectations, followed by core-binding-factor leukemias, where the benefit of conventional chemotherapy is also important. In the remainder of the elderly AML patients, intensive chemotherapy has not consistently shown to improve overall survival within controlled clinical trials (Table 3), and the information that supports its potential benefit comes from registry data. This is the consequence not only of a high early mortality, but also of a short duration of the responses [38]. Thus, the proportion of AML patients aged 65 years and over that nowadays receive intensive chemotherapy in daily practice is much lower than in the young [36]. The role of HCT in the treatment of elderly AML will be discussed later on in this review, but the proportion of older adults that are finally transplanted is also small. The comparisons of intensive vs. attenuated/supportive therapy are scarce and of low quality. By contrast, higher-level evidence supports the fact that patients treated with low-intensity regimens live longer than those that received only supportive therapy (Table 3). In practice, the physician should aim to proceed to conventional intensive chemotherapy followed by hematopoietic transplantation whenever this is feasible (taking into account disease-related, patient-related and transplantation-related prognostic factors), since this is the best option for curing the leukemia, whereas supportive therapy alone should be avoided as much as possible, and every effort should be made to administer at least low-intensity chemotherapy. Recently, a predictive scoring system for response and survival in elderly patients treated in real world by azacitidine, based exclusively on clinical features, has been developed and validated in Europe [39] (Table 4 and Fig. 1). Furthermore, some data suggest that this drug might even result in superior OS, as compared to intensive chemotherapy or low-dose cytarabine, in patients harboring high-risk cytogenetics, MDS-related AML, or erythroleukemia [40–42]. This might be improved in the near future by including some molecular predictors such as mutations in TET2 [43] and IDH1/2 [44]. Despite promising response rates, none of the various other agents tested, other than azacitidine in low-blast count leukemia, have been able to overcome the 12 months landmark for median overall survival (Table 5) and there is great need for novel agents in this group of patients. Currently, there are numerous novel agents being tested in clinical trials, many of which target recently described molecular defects. These include modified cytotoxics, epigenetic regulators, cell cycle kinase inhibitors, etc. Many are currently being tested in monotherapy or in combination with already established regimens. According to very preliminary results from Phase I/II trials, several agents hold promise, such as a) The FLT3 inhibitors gilteritinib (ASP2215) [45] and sorafenib [46], which have been tested in monotherapy, and in combination with chemotherapy in the case of sorafenib. Remission rates obtained with monotherapy are as high as 50% in patients with FLT3 mutations. Combination of sorafenib with chemotherapy in adults with mutated FLT3 improved 1yr survival from 30% to 62% [46]. As regards the multi-kinase inhibitor midostaurin, its efficacy in combination with standard chemotherapy (RATIFY trial) in patients under 60 [47] is yet to be proved in patients over 60, b) The Inhibitors of IDH1 and IDH2, which have obtained overall response rates of about 40% in heavily pre-treated older AML patients harboring IDH-1 or IDH-2 mutations [48], c) The addition of the HDAC inhibitor pracinostat to azacitidine, that achieved 1-year survival rates of 60% with 54% overall response rate [49], d) Monoclonal antibodies, such as vadastuximab talirine (SGN-CD33A), an anti-CD33 antibody conjugated with a pyrrolobenzodiazepine dimer, as well as Durvalumab, an anti-PD-L1 antibody, that have shown promising preliminary response rates and are currently being tested further [50,51].