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Internal tandem duplications of the FLT3 gene (FLT3-ITD) with an insertion site (IS) in the beta1-sheet was associated with shorter overall survival (OS) among adults with newly diagnosed acute myeloid leukemia (AML) enrolled in the RATIFY trial, according to results presented at the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress.
“FLT3-ITD mutations are present in approximately 25% of our patients and are associated with poor prognosis, in particular in cases with high mutant to wild-type allelic ratio and/or insertion site in the beta1-sheet in the tyrosine kinase domain 1 (TKD1),” Frank G. Rücker, MD, of the University Hospital of Ulm in Germany, and lead author and presenter, said.
The study used next-generation sequencing to evaluate FLT3-ITD status and its association with outcomes among 452 patients with FLT3-ITD who participated in the RATIFY/Alliance 10603 trial. The RATIFY trial previously demonstrated that midostaurin plus chemotherapy improved survival compared with placebo and chemotherapy in patients with AML and an FLT3 mutation.
Among the 908 FLT3-ITDs identified, 54% of patients harbored ≥2 ITD clones and the median ITD size was 45 nucleotides and all were in-frame with direct head-to-tail orientation. The ITDs were located primarily in the juxtamembrane domain (JMD; 70.8%), followed by the TKD1 (29.2%).
There were 60.6% of patients who achieved a complete response (CR) with treatment in the RATIFY trial. In multivariate analysis, CR was less likely to occur with a higher number of ITDs (odds ratio [OR], 0.82; 95% CI, 0.70-0.97; P=.017), whereas presence of an NPM1 mutation was associated with attaining CR (OR, 1.98; 95% CI, 1.28-3.07; P =.002).
Shorter OS was significantly associated with ITD insertion in the TKD1 alone compared with ITD insertions in the JMD or both the JMD and TKD1 (P =.032). In multivariate analyses, poorer OS was significantly associated with TKD1 insertions vs JMD insertions (hazard ratio [HR], 1.61; 95% CI, 1.10-2.35; P =.014) or JMD and TKD1 insertion (HR, 2.09; 95% CI, 1.24-3.52; P =.004), and age (HR, 1.02; 95% CI, 1.00-1.03; P =.033). Improved OS was associated with NPM1 mutation (HR, 0.57; 95% CI, 0.42-0.78; P <.001) and hematopoietic cell transplant during the first CR (HR, 0.38; 95% CI, 0.24-0.58; P <.001).
The multivariate analyses also found that higher cumulative incidence of relapse (CIR) was significantly associated with FLT3-ITD insertion into the TKD1 vs JMD (HR, 2.20; 95% CI, 1.36-3.56; P =.001) and FLT3-ITD cAR (HR, 1.15; 95% CI, 1.04-1.28; P =.008). In contrast, ITD insertions in JMD vs JMD and TKD1 (HR, 0.58; 95% CI, 0.38-0.88; P =.010) and HCT in the first CR (HR, 0.47; 95% CI, 0.29-0.74; P =.001) were associated with reduced risk of CIR.
Rücker FG, Du L, Blätte TJ, et al.. Molecular landscape and prognostic impact of FLT3 Internal tandem duplication insertion site in acute myeloid Leukemia (AML): results from the RATIFY study (Alliance 10603). Paper Presented at: Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress; June 2020. Abstract S148.
This article originally appeared on Cancer Therapy Advisor