In a study reported in the Journal of Clinical Oncology, Grob et al found that next-generation sequencing detection of FLT3-internal tandem duplication (FLT3-ITD) measurable residual disease (MRD) in complete remission was associated with markedly increased risk of relapse and poorer overall survival in newly diagnosed patients with acute myeloid leukemia (AML).
The study included 161 patients with de novo FLT3-ITD AML out of 2,274 patients with AML from the Dutch-Belgian Cooperative Trial Group for Hematology-Oncology or Swiss Group for Clinical Cancer Research clinical trials HO42A AML, HO102 AML, and HO132 AML. Next-generation sequencing was performed at diagnosis and when patients were in complete remission after intensive remission induction treatment. The association of FLT3-ITD MRD status with cumulative incidence of relapse and overall survival was analyzed. Outcomes were also assessed in relation to established prognostic factors, including FLT3-ITD allelic ratio at diagnosis and MRD assessment by next-generation sequencing–based mutant NPM1 detection or multiparameter flow cytometry.
FLT3-ITD MRD was identified in 47 (29%) of 161 (29%) patients with FLT3-ITD AML. The cumulative incidence of relapse at 4 years was 75% among patients with FLT3-ITD MRD vs 33% among those with no FLT3-ITD MRD (hazard ratio [HR] = 3.70, 95% CI = 2.31–5.94, P < .001). Overall survival at 4 years was 31% among patients with FLT3-ITD MRD vs 57% among those with no FLT3-ITD MRD (HR = 2.47, 95% CI = 1.59–3.84, P < .001).
On multivariate analysis for relapse risk, FLT3-ITD MRD vs no FLT3-ITD MRD had independent prognostic significance (HR = 3.55, P < .001). Other factors significantly associated with increased risk of relapse were higher white blood cell count at diagnosis (HR = 2.96, P < .001) and requirement of two cycles vs one cycle of treatment to achieve complete remission (HR = 1.84, P = .020). A borderline association with high vs low FLT3-ITD ratio at diagnosis was observed (HR = 1.76, P = .050), whereas no significant effects of NPM1 mutation vs wild-type at diagnosis (HR = 1.21, P = .522) or increasing age were observed.
On multivariate analysis for overall survival, FLT3-ITD MRD vs no FLT3-ITD MRD had independent prognostic significance for poorer overall survival (HR = 2.51, P = .002). Higher white blood cell count at baseline was also significantly associated with poorer survival (HR = 1.89, P = .035). No significant associations were observed for two cycles vs one cycle to achieve complete remission (HR = 1.73, P = .058), high vs low FLT3-ITD ratio at diagnosis (HR = 1.60, P = .070), NPM1 mutation vs wild-type at diagnosis (HR = 1.30, P = .348), or increasing age.
In an analysis of interaction among FLT3-ITD MRD with next-generation sequencing–based mutant NPM1 MRD measurements in 91 patients and multiparameter flow cytometry MRD measurement in 138 patients, FLT3-ITD MRD was significantly associated with high relapse risk and poorer overall survival, irrespective of mutant NPM1 MRD or multiparameter flow cytometry MRD status. Nonsignificant increased risk of relapse (P = .081) and poorer survival (P = .236) were observed in patients with persistent mutant NPM1 MRD without FLT3-ITD MRD. Multiparameter flow cytometry MRD without FLT3-ITD MRD did not appear to contribute additional prognostic information for relapse or survival.
The investigators concluded, “[Next-generation sequencing]-based detection of FLT3-ITD MRD in complete remission identifies patients with AML with profound risk of relapse and death that outcompetes the significance of most established prognostic factors at diagnosis and during therapy, and furnishes support for FLT3-ITD as a clinically relevant biomarker for dynamic disease risk assessment in AML.”
Peter J.M. Valk, PhD, of the Department of Hematology, Erasmus University Medical Center Rotterdam, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the Queen Wilhelmina Fund Foundation of the Dutch Cancer Society. For full disclosures of the study authors, visit ascopubs.org.
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