Combining quizartinib with intensive chemotherapy for older patients with newly diagnosed AML: results of the UK NCRI AML18 trial

We assessed the addition of the tyrosine kinase inhibitor quizartinib, following intensive chemotherapy and as maintenance, for patients aged >60 years with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome, regardless of FLT3 mutation status. Four hundred sixty three patients (median age, 68 years) were randomized (1:1) to receive quizartinib 40 mg or not for 14 days immediately following chemotherapy courses 2 and 3, plus 28 additional days; those allocated quizartinib were further randomized (1:1) to either 12 additional 28-day maintenance courses (“long quizartinib”) or no further treatment (“short quizartinib”). Median follow-up was 76 months. Three hundred fourteen patients were FLT3–wild-type (WT); 116 had FLT3 mutations. The primary end point, overall survival (OS) unselected by FLT3 status, showed no significant benefit, and there was a significant increase in non-relapse mortality with quizartinib. In a pre-planned subgroup analysis, patients with FLT3 mutations who received quizartinib had significantly improved OS (Hazard Ratio, 0.59; 95% Confidence Interval, 0.37-0.93; P =.024) due to reduced relapse risk, with greater benefit in the short quizartinib group. In patients with FLT3-WT, there was no survival benefit and no reduction in relapse risk. No significant differences were observed in time to hematologic count recovery or in length of hospitalization. The most observed grade 3/4 adverse events were febrile neutropenia. In conclusion, the addition of quizartinib to intensive chemotherapy, delayed until chemotherapy course 2, prolonged OS in older patients with FLT3-mutated AML but did not improve OS in non–FLT3-selected patients. This trial was registered at www.isrctn.com as ISRCTN-31682779 and at www.clinicaltrialsregister.eu as EudraCR-2013-002730-21.