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Guadecitabine in selected MDS and AML after azacitidine failure
ic mutations, associated with a better response to treat- ment, while no response was observed in 11 TP53 mutat- ed patients. Thus, TP53 mutated MDS/AML patients may have high response rates (although of short duration) with early use of HMA (especially a 10-day regimen of decitabine),5 but after HMA failure, those patients may be particularly resistant to further HMA therapy, even with a different agent.
Regarding OS, our multivariate analysis showed that primary AZA failure (vs. secondary failure), low to high R-IPSS and higher demethylation in blood (on day 8 of cycle1) were associated with better OS, factors that could help select patients more likely to benefit from second-line treatment with guadecitabine. The survival impact of guadecitabine did not seem to differ between “low-risk”
and “high-risk” patients, based on Nazha et al.’s scoring system for HMA failure patients.
Altogether, our study suggests that some selected patients [primary AZA failure and low to high IPSS-R, patients with no or few somatic mutations (especially no TP53 mutations), patients with higher demethylation rate in blood during the first cycle of treatment] may benefit from guadecitabine treatment after AZA failure. Our results also suggest that primary AZA failures may be better can- didates than secondary AZA failures to receive guadecitabine. An international phase III study (clinicaltri- als.gov identifier: 02907359) is underway to compare guadecitabine treatment with best investigator’s choice in high-risk MDS patients relapsing or failing after first-line AZA or decitabine.
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