Here, we report the updated follow-up of the clinical course of our patient, wherein we observed a dynamic evolution of MDS clones that showed different responses to azacitidine and EPO. The response to EPO was likely related to the persistence of RA clones that re-emerged despite azacitidine. After the achievement of the TI and the CR following the second and the sixth azacitidine courses, respectively, the patient continued to receive hypomethylating therapy as maintenance. However, after the fourteenth course, preceded by several weeks in which the patient complained of profound weakness and fatigue [4], progressive anemia (hemoglobin ~7.0 g/dL) requiring red blood cell (RBC) transfusions was noted. Therefore, the patient was reevaluated in the light of the suspicion of a loss of response to azacitidine and evolution to acute myeloid leukemia. However, examination of the bone marrow (BM) showed the disappearance of blast cells and a marked reduction of monocytes in a MDS framework, which was characterized by trilineage dysplasia and erythroid predominance with the features of ineffective erythropoiesis, as observed at the onset of MDS when the patient was diagnosed with RA [1]. According to its disease-modifying effects in MDS, azacitidine had "down-staged" the patient's malignancy from the transformed form of CMML-2 to refractory cytopenia with multilineage dysplasia (RCMD), resulting in a clinical phenotype similar to primary RA. On the basis of these findings, the patient continued to receive azacitidine as maintenance hypomethylating therapy and EPO was reintroduced. A rapid response with the achievement of TI was soon recorded. Therefore, the patient displaying near normal peripheral blood counts, continued to receive azacitidine concomitant with EPO, in order to maintain CR and TI. Our case presents some interesting observations. Initially, our patient was responsive to EPO for many years until the occurrence of an important transfusion requirement corresponding to transformation towards CMML-2. The treatment with azacitidine resulted in the clearance of this transformed, aggressive leukemic component probably by restoring a previous framework consistent with a low MDS risk, such as RCMD, as observed at the onset of primary MDS diagnosis. Therefore, it is likely that the clinical picture of the patient reflected maintained response to azacitidine, with good control of the CMML-2 and re-emergence of ineffective erythropoiesis typically associated with RA/RCMD MDS, which was again responsive to EPO. The patient was 83 years old and had a MDS history for 9 years; he was well after 21 courses of azacitidine and 6 months of TI with EPO. Although both the use of ESA [5] (to reduce the high burden of transfusion requirement in MDS patients [6]) and azacitidine [78] (to contain or reverse the natural progression of disease) are well established, very few studies have explored the therapeutic role exerted by the association of azacitidine with EPO in the setting of higher-risk MDS. A retrospective French study that included 32 higher-risk MDS patients, who concomitantly received ESA and azacitidine found that the addition of ESA to the hypomethylating therapy significantly improved overall survival independent of azacitidine schedule and duration [9]. These findings may reflect synergistic effects exerted by two agents or their separate actions on distinct mechanisms and/or components of MDS. However, no prospective studies have confirmed these findings and there is a need for prospective studies for confirmation [10]. However, we have not been able to thoroughly investigate this case with molecular techniques, owing to which we cannot clarify the biological and pathogenic bases for what we observed. Our case showed that MDS over its course can display different clinical manifestations, combining aspects associated with both high- and low-risk MDS forms. These different manifestations could correspond to underlying biological heterogeneity of different neoplastic clones or their transformation over time in the context of a continuum clonal evolution that may be influenced by the pattern of response to disease-modifying treatments.