KEY TAKEAWAYS
- The phase 3 study evaluated if detecting MRD via FLT3-ITD influenced clinical outcomes or the efficacy of quizartinib in newly diagnosed FLT3-ITD+ AML pts.
- This study showed the predictive value of FLT3-ITD-specific MRD, highlighting its potential for managing FLT3-ITD+ AML patients.
This phase 3 study aimed to assess how Minimal Residual Disease (MRD) detection via FLT3-ITD influenced both the clinical results and the effectiveness of the FLT3 inhibitor quizartinib in newly diagnosed patients (pts) with FLT3-ITD positive acute myeloid leukemia (AML).
DNA was extracted from either bone marrow or peripheral blood samples of pts who entered remission post-induction and analyzed using next-generation sequencing for FLT3-ITD through polymerase chain reaction. ITD mutations identified post-induction were verified against mutations detected during initial enrollment.
A specialized bioinformatics software was utilized to identify ITD mutations and compute variant mutant allelic frequencies (VAFs) at a 10-5 sensitivity level. MRD status was categorized as either undetectable (with a 0 cutoff) or detectable, either above or below a 10^-4 cutoff. Complete response (CR) rates, composite complete response rates (CRc, which includes CR and CR with incomplete count recovery [CRi]), and the proportion of pts reaching CR with no MRD during induction across different treatment groups were compared using a stratified Cochran-Mantel-Haenszel test. FLT3-ITD+ VAF comparisons during induction between treatment groups were conducted using the Wilcoxon rank sum test. P-values remained unadjusted for multiple comparisons.
Of 539 randomized participants, 368 (68.3%) attained CRc post-induction. MRD evaluations were carried out on 321 individuals (87.2%), with samples taken during the response assessment phase of induction. A CRc best response correlated with MRD levels below 10-4 resulted in enhanced overall survival (HR=0.562). Comparable percentages of pts reaching CRc with FLT3-ITD MRD levels below 10-4 were observed across both treatment groups (quizartinib, 25.4%; placebo, 21.8%; P=0.3430).
A larger percentage of pts achieving CRc with undetectable MRD was noted in the quizartinib group compared to the placebo group (12.3% vs 7.0%; P=0.0403). Patients on quizartinib exhibited a 3-fold lower median FLT3-ITD+ VAF (P=0.0251). Further information regarding the impact of MRD with or without allogeneic hematopoietic stem cell transplantation will be discussed.
This initial proof of FLT3-ITD-specific MRD’s predictive value in a forward-looking trial underscored its potential role in managing pts with FLT3-ITD positive AML. The prolonged overall survival benefits observed with quizartinib in the QuANTUM-First study may be partially attributed to an early and substantial decrease in the FLT3-ITD+ leukemia load.
Source: https://clml-soho2023.elsevierdigitaledition.com/272/index.html
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT02668653
Levis, M.J., Erba, H.P., Montesinos, P., Vrhovac, R., Patkowska, E., Kim, H-J., Zak, P., Wang, P-N., Rohrbach, J.E.C., Chang, K.C.N., Hanyok, J., Liu, L., Kamel, Y.M., Lesegretain, A., Cortes, J., Sekeres, M.A., Dombret, H., Amadori, S., Wang, J., Schlenk, R.F., Perl, A.E. QuANTUM‑First Trial: FLT3–Internal Tandem Duplication (FLT3‑ITD)– Specific Measurable Residual Disease (MRD) Clearance Is Associated With Improved Overall Survival (OS).
