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M. Sebert et al.
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Figure 3. Response to guadecitabine of patients treated after azacitidine failure. (A) Cumulative incidence of response. (B) Duration of response.
Figure 4. Overall survival of patients treated with guadecitabine after azacitidine failure. (A) Overall survival. (B) Survival according to Nazha score.
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only four patients in this study had received first-line treatment with HMA (more than 1 cycle), and predictive factors of response and survival were not analyzed.
In the present series, we observed significant demethy- lation in blood and bone marrow samples after one cycle of treatment, even if there was no significant correlation between the demethylation rate and the hematologic response, possibly because of the small number of respon- ders. Similar results were reported using decitabine after AZA failure.16 However, a higher demethylation rate in blood on day 8 of cycle 1 was significantly associated with longer OS and remained a significant prognostic factor in multivariate analysis, suggesting that demethylation achieved with guadecitabine after AZA failure is a mech- anism implicated in response. This could possibly also explain the relatively good response rate of patients with
primary AZA failure, who might have experienced AZA resistance due to low level and duration of HMA expo- sure, but subsequently responded to guadecitabine, which induced greater demethylation.
To our knowledge, this is the first study analyzing the prognostic factors of response and OS in high-risk MDS/AML receiving a HMA after failure of a first HMA. Previous studies reported that TET2 mutations,19-21 partic- ularly at a VAF >10% and in the absence of co-occurring ASXL1 mutations,20 were associated with higher response rates, whereas a higher number of detectable mutations predicted for lower likelihood of response and complete response, as well as shorter response duration to HMA; however, those studies involved HMA naïve patients.21 In the present study, the only predictive factor of response to guadecitabine was the absence or small number of somat-
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haematologica | 2019; 104(8)