FLT3-ITD-specific MRD assessment useful for clinical management of AML

Minimal residual disease (MRD) measurements demonstrated utility in the clinical management of participants with FLT3-ITD-positive acute myeloid leukaemia (AML) in a sub-study of the QuANTUM-First trial. FLT3-ITD MRD elimination was associated with longer overall survival (OS). Also, participants with multiple ITDs or long ITD inserts responded well to quizartinib therapy.

The previously published phase 3 QuANTUM-First study (NCT02668653) showed that quizartinib added to standard chemotherapy results in improved OS in participants with FLT3-ITD-positive AML, as compared with a regimen of chemotherapy and placebo [1]. The current study analysed FLT3-ITD MRD in participants who were enrolled in QuANTUM-First to evaluate features of therapy efficacy. “321 participants achieved the composite complete remission endpoint by the end of induction and had available MRD data,” introduced Prof. Alexander Perl (University of Pennsylvania, PA, USA) [2].

FLT3-ITD MRD negativity was associated with OS improvements across various therapy timepoints. After induction, the median OS in MRD-negative participants was not reached, whereas the median OS was 29.4 months in MRD-positive participants (HR 0.56; 95% CI 0.39–0.79). Similarly, after the last consolidation cycle, the median OS was not reached and 14.8 months in MRD-negative and MRD-positive participants, respectively (HR 0.46; 95% CI 0.33–0.63). “We observed that quizartinib evoked deeper responses and more frequently eliminated detectable MRD than placebo,” added Prof. Perl. After induction, the median FLT3-ITD MRD variant allele frequency was 0.01% in participants on quizartinib and 0.03% in participants on placebo. After the last consolidation cycle, the corresponding rates were 0.0% and 0.0017%. Further, it was shown that long ITD insertions were associated with worse OS outcomes: participants with ITD lengths below the median of 54 bp had a median OS of 40.7 months, whereas participants with longer ITD lengths showed a median OS of 17.0 months. Finally, multiple ITDs were associated with worse survival outcomes: the median OS decreased from 17.2 months for participants with 1 ITD mutation to 14.2 months for participants with more than 1 ITD mutation (HR 0.84; 95% CI 0.58–1.21). Compared with placebo, quizartinib appeared to be particularly efficacious in participants with more than 1 ITD mutation (median OS 14.2 months vs ‘not reached’; HR 0.57; 95% CI 0.35–0.91).

“These findings indicate that some of the long-term OS benefits conferred by quizartinib derive from an early, deep, and sustained reduction of the FLT3-ITD-positive leukaemia burden,” concluded Prof. Perl.

1. Erba HP, et al. Lancet. 2023;401(10388):1571-1583.
2. Perl AE, et al. QuANTUM-First Trial: FMS-Like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-specific measurable residual disease (MRD) clearance assessed through induction and consolidation is associated with improved overall survival in newly diagnosed FLT3-ITD+ AML Patients. Abstract 832, 65^th ASH Annual Meeting, 9–12 December 2023, San Diego, CA, USA.

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Posted on 7 February, 20247 February, 2024