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Summary: The regimen of 5‐azacytidine for patients with myelodysplastic syndrome (MDS) has remained unchanged since its first approval. Although several modifications have since been made and delays and dose reductions are common especially during the first treatment cycles, there are minimal data on the prognostic effect of these modifications. In this study, based on data from 897 patients with MDS treated with 5‐azacytidine recorded in a national registry, the effect of treatment delays and dose reductions on response, transformation to acute myeloid leukaemia, and survival (after 5‐azacytidine initiation, OST) were analysed. Delays during the first two cycles were noted in 150 patients (16·7%) and were found to adversely affect OST independently of the International Prognostic Scoring System score [hazard ratio (HR), 1·368; P = 0·033] or pre‐existing neutropenia (HR, 1·42; P = 0·015). In patients achieving a response, delays before response achievement were correlated with its type (complete remission, 2·8 days/cycle; partial remission, 3·3 days/cycle; haematologic improvement, 5·6 days/cycle; P = 0·041), while delays after response achievement did not have any effect on retention of response or survival. Dose reductions were found to have no prognostic impact. Based on our results, treatment delays especially during the first cycles should be avoided, even in neutropenic patients. This strict strategy may be loosened after achieving a favourable response. [ABSTRACT FROM AUTHOR]

Ribonucleotide Reductase (RNR) is a two-subunit (RRM1, RRM2) enzyme, responsible for the conversion of ribonucleotides to deoxyribonucleotides required for DNA replication. To evaluate RNR as a biomarker of response to 5-azacytidine, we measured RNR mRNA levels by a quantitative real-time PCR in bone marrow samples of 98 patients with myelodysplastic syndrome (MDS) treated with 5-azacytidine with parallel quantification of the gene promoter's methylation. Patients with low RRM1 levels had a high RRM1 methylation status (p = 0.005) and a better response to treatment with 5-azacytidine (p = 0.019). A next-generation sequencing for genes of interest in MDS was also carried out in a subset of 61 samples. Splicing factor mutations were correlated with lower RRM1 mRNA levels (p = 0.044). Our results suggest that the expression of RNR is correlated with clinical outcomes, thus its expression could be used as a prognostic factor for response to 5-azacytidine and a possible therapeutic target in MDS. [ABSTRACT FROM AUTHOR]

Objectives: The demethylating factor 5-Azacytidine (5-AZA) improves survival of patients with myelodysplastic syndromes (MDS) in randomized control trials but the results in 'real life' are controversial. Methods: In this retrospective study, we evaluated the outcome of 56 high-risk MDS patients who were treated with 5-AZA between 2005 and 2013. 5-AZA was administered in an outpatient basis at a dose 75 mg/m2 s.c. with the following schedule: 5 days on/weekend off/2 days on (5/2/2). Results: The overall response rate (ORR) was 50%; 21.2% patients achieved complete response (CR), 3.8% partial response (PR), and 25% hematologic improvement (HI); 34.6% had stable disease (SD) and 15.4% showed progressive disease (PD). The estimated median event free survival (EFS) and overall survival (OS) were 11 and 17 months, respectively. Interestingly, the estimated time to acute myeloid leukemia transformation was 30 months, which refers to patients who responded to AZA treatment or remained stable. Patients who responded to the 5-AZA achieving CR, PR, and HI had better EFS and OS compared to the patients who had SD or PD. In addition, Δ WHO Classification-based Prognostic Score System (ΔWPSS), which represents the improvement of WPSS risk group before and after treatment, was associated with significantly improved OS and better EFS. Finally, the response to treatment was not associated with the expression of p53. Conclusions: In conclusion, 5-AZA is an effective treatment for high-risk MDS. Improved OS and EFS were found mainly in patients who responded to the treatment while ΔWPSS seems to represent a promising future prognostic tool. [ABSTRACT FROM AUTHOR]