Quizartinib Plus Chemotherapy Improved OS in Patients with AML, Little Hindrance to QOL

New research presented at the American Society of Hematology (ASH) 2023 annual meeting happening in San Diego, California, December 9 to December 12, demonstrates that, compared to placebo, quizartinib improved overall survival (OS) in patients with newly diagnosed FLT3-ITD acute myeloid leukemia (AML). According to the authors, QuANTUM-First is the first study to examine the impact of quizartinib, a novel oral fms-like tyrosine kinase 3 inhibitor, on patient-reported outcomes (PROs).

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The multicenter, global, randomized, double-blind phase 3 clinical trial enrolled patients with FLT3-ITD-positive AML aged 18 to 75 years. Patients were randomly assigned to received either chemotherapy plus quizartinib (n = 254) or chemotherapy plus placebo (n = 255). In the first induction cycle, baseline measurement was collected on day 8 and repeated measurements were collected on day 28 of cycles 1 and 2, days 6 and 28 of consolidation cycles 1 through 4, and day 1 of continuation cycles 1 through 34 at 3-cycle intervals.

Further, PRO measures were the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) and EuroQpl EQ-5D-5L, and included the mean score for each domain, as well as mean change from baseline score at each time point. A mixed-effect model for repeated measures (MMRM) and time until definitive deterioration (TUDD)—the time from baseline PRO score to first deterioration of the score beyond the MCID as compared to baseline without further improvement of more than 1 MCID—was used to assess the longitudinal impact of treatment on PROs. In addition, a minimal clinically important difference (MCID) score was equal to or greater than 10 points (≥10) for each domain of the EORTC QLQ-C30 and was considered clinically meaningful.

“In the QuANTUM-First trial, 539 patients with FLT3-positive AML with an ITD mutation were [randomly assigned] to receive intensive induction chemotherapy combined with the selective type 2 FLT3 inhibitor quizartinib, or induction therapy with placebo. Quizartinib or placebo were also combined with post-remission therapy,” said senior author Mikkael A. Sekeres, MD, chief of the division of hematology at Sylvester Comprehensive Cancer Center.

Of the 539 patients enrolled in the study, 509 were included for the PRO analysis. Across both arms, patient compliance to questionnaire completion at the beginning of each phase was high and comparable (Completion rate on induction cycle 1: 99.2%; consolidation cycle 1: 95.3%; and continuation cycle 1: 93.4%). Further, baseline PRO scores were comparable between arms and were lower than the general population norm.

In both arms, there were clinically meaningful improvements from baseline in both Global Health Status (GHS) and fatigue, according to MMRM; however, there was no significant difference between the 2 arms for the change from baseline score, though the placebo arm presented better numerical scores during the maintenance phase (GHS: -2.0 [95% CI: -4.8, 0.7], p = 0.1479; fatigue: 3.0 [95% CI: -0.1, 6.1], p = 0.0600). The quizartinib arm presented slower deterioration by TUDD analysis in several scales—notably GHS, cognitive function, appetite loss, and constipation); however, the differences were not considered statistically significant.

“Patients receiving quizartinib had double the OS compared to those [randomly assigned] to receive placebo…During the continuation phase, quality of life (QOL) in global, physical, social, and role domains—along with symptom scores—were numerically higher, but not statistically different, for patients [who did not receive] quizartinib. This may reflect mild [adverse effects (AEs)] to therapy, which also may remind a patient that [they should continue to] receive therapy for leukemia,” said Sekeres.

Not only did quizartinib demonstrate more success in improving OS when added to standard chemotherapy, but it also did so without significant deterioration to patients’ QOL across multiple domains. Further, AEs were insignificant for a survival-prolonging drug, according to Sekeres.

“[It is important to] develop better, disease-specific instruments as companion studies to registration trials in leukemia,” said Sekeres.

Reference

Oliva, E, Unni, S, Cottone, F, et al. Patient-Reported Outcomes in Acute Myeloid Leukemia Patients with FLT3-ITD Mutation Receiving Quizartinib Vs. Standard Chemotherapy: Results from the Quantum-First Trial. Accessed December 3, 2023. https://ash.confex.com/ash/2023/webprogram/Paper189035.html