Patient-reported outcomes in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia receiving standard chemotherapy plus quizartinib or placebo (QuANTUM-First): a global, randomised, placebo-controlled, phase 3 trial.
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BACKGROUND: QuANTUM-First is a randomised phase 3 trial in individuals with newly diagnosed acute myeloid leukaemia (AML) that is FLT3 internal tandem duplication (ITD) positive, showing a survival advantage for quizartinib versus placebo plus standard induction and consolidation chemotherapy with or without transplantation, followed by single-agent maintenance therapy. We evaluated the impact of quizartinib on patient-reported outcomes and health-related quality of life using the European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire. METHODS: In this global, multicentre, randomised, placebo-controlled, phase 3 trial, we recruited adults aged 18-75 years, with FLT3-ITD-positive newly diagnosed AML or AML secondary to myelodysplastic syndrome or myeloproliferative neoplasm, and with an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly allocated (1:1) to quizartinib (40 mg/day) or placebo plus standard 7 + 3 induction chemotherapy, and then received standard consolidation chemotherapy with high-dose cytarabine plus quizartinib (40 mg/day) or placebo, allogeneic haematopoietic cell transplantation (allo-HCT), or both, followed by maintenance with single-agent quizartinib (30-60 mg/day) or placebo for up to 36 cycles. Randomisation was managed via an interactive web and voice response system. Patient-reported outcome endpoints, assessed using the European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire, were exploratory and analyses were based on the patient-reported outcome intention-to-treat analysis set. Treatment effects on patient-reported outcomes were assessed using the mixed-effects model for repeated measures, time to sustained improvement, and time until definitive deterioration analyses. A minimal clinically important difference score of 10 or higher for each subscale was defined as clinically meaningful. This trial is registered with ClinicalTrials.gov, NCT02668653, and is completed. FINDINGS: Participants were enrolled between Sept 27, 2016, and Aug 14, 2019. Of 539 randomly allocated participants, 509 (278 [55%] female and 231 [45%] male) were included in the patient-reported outcome analysis set, 254 in the quizartinib group and 255 in the placebo group. The overall median follow-up was 39·2 months (IQR 31·9-45·8). Baseline patient-reported outcome scores were similar between groups. The change in global health status and quality of life score (GHS-QoL) from baseline was above the minimal clinically important difference from consolidation onwards in both groups. The treatment difference (quizartinib minus placebo) in change from baseline for GHS-QoL (by mixed-effects model for repeated measures) was -2·0 (95% CI -4·8 to 0·7, nominal p=0·15), indicating no substantial difference between groups, further confirmed by time to sustained improvement (subdistribution hazard ratio [SHR] 1·126 [95% CI 0·904 to 1·403], nominal p=0·28) and time until definitive deterioration (hazard ratio 0·81 [95% CI 0·51 to 1·28], nominal p=0·37) analyses. Longitudinal analyses of the functional and symptom subscales showed no substantially different patterns between groups. For the functional subscales, the SHR ranged from 0·940 to 1·148 (0·737-1·544, nominal p=0·36-0·90). For the symptom subscales, the SHR ranged from 0·965 to 1·407 (0·720-1·989, nominal p=0·28-0·99). INTERPRETATION: The results indicate that quizartinib plus standard chemotherapy prolongs overall survival without adversely affecting patient-reported outcomes and health-related quality of life, with no substantial differences between groups. Future research in real-world settings is warranted to assess the generalisability of these patient-reported outcome results. FUNDING: Daiichi Sankyo.