Study Explores Molecular Landscape, Prognostic Impact of FLT3-ITD Insertion Site in Patients With AML

In an analysis of the phase III RATIFY trial published in Leukemia, researchers examined the molecular landscape of FLT3 internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML), confirming this subtype’s distinct heterogeneity and the negative prognostic impact of the tyrosine kinase domain-1 (TKD1) insertion site (IS).

The retrospective study, led by Frank Rücker, MD, of the University Hospital of Ulm in Germany, looked at the prognostic impact of FLT3-ITD IS in 452 patients with AML who participated in the randomized, placebo-controlled RATIFY trial, which evaluated the effects of midostaurin plus intensive chemotherapy in 717 patients with AML and activating FLT3 mutations.

In the current analysis, patients assigned to placebo more often had a normal karyotype, compared to those who received midostaurin (80.1% vs. 62.2%; p<0.001). Placebo-treated patients also more often had an NPM1 mutation (NPM1mut; 64.3% vs. 50.0%; p=0.008), and favorable genotype NPM1mut/FLT3-ITDlow (23.9% vs. 14.7%; p=0.031).

A total of 908 ITDs were identified with next-generation sequencing (NGS), including 643 insertions in the juxtamembrane domain (JMD), as well as 265 insertions in the TKD1. Based on IS, patients were classified as:

  • JMDsole (n=251; 55%)
  • JMD and TKD1 (JMD/TKD1; n=117; 26%)
  • TKD1sole (n=84; 19%)

Overall, there were no significant differences between the three groups in regard to clinical variables.

Approximately 55% of FLT3-ITD+ patients with AML (n=452) died during a median follow-up of 60.6 months. The median overall survival (OS) rate was 24.4 months, and the estimated four-year OS probability was 0.43. The estimated four-year OS probabilities were significantly greater among patients in the JMD/TKD1 group (0.50) compared with the JMDsole (0.44) and TKD1sole (0.30) groups (p=0.032).

Cox regression analyses revealed the following unfavorable factors for OS:

  • FLT3-ITD IS in TKD1sole vs. JMDsole (hazard ratio [HR] = 1.61; 95% CI 1.10-2.34; p=0.014)
  • JMD/TKD1 (HR=2.17; 95% CI 1.29-3.67; p=0.004)
  • higher white blood cell (WBC) count (HR=1.12; 95% CI 1.03-1.23; p=0.010)
  • advancing age (HR=1.17; 95% CI 1.02-1.43; p=0.029)

In contrast, favorable factors for OS were NPM1mut (HR=0.58; 95% CI 0.43-0.78; p<0.001) and hematopoietic cell transplantation (HCT) in first complete remission (HR=0.46; 95% CI 0.30-0.70; p<0.001). The use of multikinase inhibitor midostaurin demonstrated no beneficial effect on OS, the researchers noted.

Looking at the risk for relapse, the researchers found that FLT3-ITD IS in TKD1sole (vs. JMDsole), higher WBC count, and higher NGS-based calculated FLT3-ITD allelic ratio per patient were associated with a greater cumulative incidence of relapse. In contrast, NPM1mut and HCT in first complete remission were associated with a reduced risk of relapse. Again, midostaurin showed no impact on relapse risk.

The authors also observed superior outcomes among patients with the JMDsole/NPM1mut genotype who received additional treatment with midostaurin. In this genotype, the four-year rates for OS and relapse with either midostaurin or placebo were 65% versus 44% (p=0.016) and 30% versus 53% (p=0.018), respectively. The JMDsole/NPM1wt genotype was the only other genotype that benefited from additional treatment with midostaurin, they added.

“The results from this retrospective analysis of the RATIFY trial further classify the molecular landscape of FLT3-ITD,” the authors wrote. The data also show that the negative impact of TKD1 insertions might not be overcome by treatment with the multikinase inhibitor midostaurin. This clinical observation “does not only confirm the known resistance to chemotherapy of patients with TKD1 insertions, but also to tyrosine kinase inhibitor (TKI) treatment, which is in line with preclinical data,” they added.

“Furthermore, the significantly higher [relapse] rate for patients with TKD1 insertions compared to patients with JMDsole insertions might reflect different patterns of clonal evolution and acquired co-mutations mediating secondary resistance to TKIs between these groups.”

The authors report no relevant conflicts of interest.

Reference

Rücker FG, Du L, Luck TJ, et al. Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results [published online ahead of print, 2021 Jul 28]. Leukemia. doi: 10.1038/s41375-021-01323-0.