Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: randomized phase 3 ASTRAL-2 trial.

Guadecitabine is a novel hypomethylating agent (HMA) resistant to deamination by cytidine deaminase. Patients with relapsed/refractory acute myeloid leukemia (AML) were randomized to guadecitabine or a preselected treatment choice (TC) of high-intensity chemotherapy; low-intensity treatment with HMAs, or low-dose cytarabine; or best supportive care (BSC). The primary endpoint was overall survival (OS). 302 patients were randomized to guadecitabine (n=148) or TC (n=154). Preselected TCs were low intensity treatment (n=233 [77%; mainly HMAs]), high intensity chemotherapy (n=63 [21%]), and BSC (n=6 [2%]). The median OS were 6.4 and 5.4 months for guadecitabine and TC, respectively (hazard ratio 0.88 [95% confidence interval 0.67, 1.14]; log-rank P=0.33). Survival benefit for guadecitabine was suggested in several prospective subgroups, including age <65 years, Eastern Cooperative Oncology Group performance status 0-1, refractory AML, and lower peripheral blood blasts ≤30%. Complete response (CR) + CR with partial hematologic recovery rates were 17% for guadecitabine vs 8% for TC (P<0.01); CR+CR with incomplete count recovery rates were 27% for guadecitabine vs 14% for TC (P<0.01). Safety was comparable for the two arms, but guadecitabine had a higher rate of grade ≥3 neutropenia (32% vs 17%; P<0.01). This study did not demonstrate an OS benefit for guadecitabine. Clinical response rates were higher for guadecitabine, with comparable safety to TC. There was an OS benefit for guadecitabine in several prespecified subgroups. This study was registered as ClinicalTrials.gov as NCT02920008.