Choosing a hypomethylating agent in MDS: does gender matter?

Hypomethylating agents (HMA) are the first line treatment of higher-risk myelodysplastic syndromes (MDS) ineligible for bone marrow transplant. Azacitidine (5azacytine, AZA) improves overall survival (OS), acute myeloid leukemia transformation-free survival (AMLFS) and quality of life [1], whereas decitabine (5-azadeoxycytine, DAC) only improves progression-free survival (PFS) [2]. This discrepancy may reflect differences in trial design, and may also be the consequence of the different pharmacodynamics of these closely related compounds. Responses to HMA are difficult to predict with clinical parameters, and the impact of gene mutations may depend on the type and schedule of HMA [3]. Furthermore, there has been no prospective comparison of AZA and DAC. In countries such as the US where both drugs are licensed in overlapping indications, clinicians lack tools to allocate either drug on a rational basis in a specific patient. The large retrospective multicentric study carried by the US MDS Clinical Research Consortium reported by DeZern et al. in this issue [4] reports the outcome of 642 higher-risk MDS patients treated in first line by HMA. They show that female patients treated with DAC have superior response rates (53.3% vs 40%, p<.001) and longer OS (18.9 vs 11.4 months, p1⁄4.0031) than those treated by AZA. This difference in survival seems to persist in multivariate analysis. Such superiority of DAC over AZA is not seen in males. Retrospective studies have inherent methodological limitations and the authors have made all possible attempts to limit biases by inferring missing data and by matching DAC and AZA patients with the help of propensity scores. As for other retrospective studies with HMA, responses can be difficult to assess, and timing of evaluation may vary. For instance, in this study, DAC-treated women had longer time on treatment than AZA-treated ones and it is difficult to know retrospectively if it is a cause or a consequence of higher response rates and longer OS. Bone marrow transplantation may also have influenced these results. Leaving aside those limitations, what could possibly explain the differences between AZA and DAC seen in women alone? Three types of explanations may contribute to this gender-specific difference between HMAs. First, differences in compliance between males and females may theoretically have affected the comparison as AZA, but not DAC, is often administered at home. Second, the biology of MDS may differ between males and females. In particular, TET2 and ASXL1 mutations are more frequent in males [5], and affect response to HMAs [6,7]. Finally, an intriguing possibility raised by the authors point to different pharmacokinetics of those drugs between males and females. The pharmacokinetics and mechanisms of action of azanucleotides have been reviewed recently [8]. Briefly, both molecules enter the cell by human equilibrative (hENT/SLC29A) or concentrative nucleoside transporters (hCNT/SLC28A), and SLC15/SLC22 transporter families. Both drugs are then activated by three successive ATP-dependent phosphorylations to generate 5-aza-dCTP, which can be incorporated into DNA during S-phase. The first phosphorylation step is limiting, and is catalyzed by uridine-cytidine kinase (UCK) for AZA, and by deoxycytidine kinase (DCK) for DAC. The metabolism of AZA is more complex, as >80% of its activated form is incorporated in RNA during transcription, while <20% is converted from 5-aza-CTP to 5-aza-dCTP by ribonucleotide reductases before incorporation in DNA. Both azanucleotides are instable,