P483: quantum-first trial: flt3-itd–specific measurable residual disease (mrd) clearance is associated with improved overall survival

Topic: 4. Acute myeloid leukemia - Clinical Background: Detection of MRD by flow cytometry or gene fusion transcript quantitation has an established prognostic role in AML and is increasingly used to guide treatment decisions. Routine use of FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) detection in remission as a predictor of relapse risk or overall survival (OS) has been limited by the low sensitivity of both conventional PCR-based assays and broad NGS platforms in clinical practice settings. More recently, FLT3-ITD–specific PCR-NGS assays such as getITD (Blätte, Leukemia 2019) show greater sensitivity and ease of interpretation that point to eventual routine clinical application. However, the clinical value of these measurements has not been evaluated prospectively in the context of FLT3-targeted therapy. The phase 3 QuANTUM-First (NCT02668653) evaluated the novel, potent, and highly selective type II FLT3 inhibitor quizartinib (Quiz) in patients (pts) with newly diagnosed FLT3-ITD+ AML and demonstrated that Quiz added to intensive induction and consolidation followed by single-agent continuation therapy resulted in a significant improvement in OS (Erba, EHA 2022). Aims: We analyzed if FLT3-ITD MRD in QuANTUM-First pts impacted the clinical outcome or the benefits provided by Quiz in pts with newly diagnosed FLT3-ITD+ AML. Methods: Genomic DNA was isolated from bone marrow aspirates or peripheral blood from pts after achievement of remission after 1 or 2 induction courses. The DNA was analyzed with a FLT3-ITD PCR-NGS assay developed for this trial (Levis, Blood 2020). ITD mutations detected after induction were cross-validated against the ITD detected at enrollment. Using a custom bioinformatics program, ITD mutations were identified, and variant mutant allelic frequencies (VAFs) were calculated with a sensitivity of 10−5. MRD was classified as undetectable (using the 0 cutoff) or detectable above or below the 10−4 cutoff. Comparisons of complete response (CR), composite complete response (CRc=CR+CRi), and the % of pts achieving CR during induction with no MRD between treatment arms were made using a stratified Cochran-Mantel-Haenszel test. Comparison of the FLT3-ITD+ VAF during induction between treatment arms was made using Wilcoxon rank sum test. All P values were not adjusted for multiplicity. Results: In QuANTUM-First, 539 FLT3-ITD+ AML pts were randomized to Quiz (n=268) or PBO (n=271). Of the 539 randomized pts, 368 (68.3%) achieved CRc after 1 or 2 courses of induction, and MRD analysis was performed on 321 (87.2%) of those pts (162 pts in Quiz and 159 pts in PBO) using samples collected at the time of response assessment during induction phase, before further therapy. A best response of CRc with MRD of <10−4 correlated with improved OS, with an HR of 0.562 (Fig. 1). The % of pts in CRc with FLT3-ITD MRD of <10−4 was similar across study arms (25.4% Quiz vs 21.8% PBO, P = 0.3430), whereas the % of pts in CRc with undetectable MRD was greater with Quiz vs PBO (12.3% vs 7.0%, P = 0.0403). The median FLT3-ITD+ VAF was 3-fold lower (P = 0.0251) among pts on Quiz vs PBO (Fig. 2). Additional data about MRD impact on pts with or without allogeneic hematopoietic stem cell transplantation in this trial will be presented. Summary/Conclusion: This is the first evidence of the prognostic effect of FLT3-ITD–specific MRD in a prospective trial and demonstrates the potential use of this assay in the management of pts with FLT3-ITD+ AML. Long-term OS benefits conferred by Quiz in QuANTUM-First may in part derive from an early and deep reduction of the FLT3-ITD+ leukemia burden.Keywords: MRD, Flt3-ITD, AML