Genetic risk groups defined by the 2017 European LeukemiaNet (ELN) recommendations may reliably predict prognosis in patients with acute myeloid leukemia (AML) and internal tandem duplications (ITD) of FLT3, according to study findings published in Blood. The study, which analyzed patients enrolled in the randomized RATIFY trial, also verifies the survival benefit associated with protein kinase inhibitor midostaurin in these patients and across all three risk groups included in the 2017 ELN.
In the 2017 ELN recommendations, an international expert panel identified and defined four distinct FLT3-ITD genotypes that are based on ITD allelic ratio (AR) and NPM1 mutational status. Konstanze Döhner, MD, and colleagues from the University of Ulm in Germany performed a retrospective analysis of the prognostic and predictive value of the 2017 ELN’s NPM1/FLT3-ITD genotypes in 717 patients with AML and activating FLT3 mutations who were enrolled in the RATIFY trial, which compared midostaurin plus chemotherapy with placebo in patients with FLT3-mutated AML.
The retrospective exploratory analysis by Dr. Döhner and colleagues focused only on RATIFY patients with FLT3-ITD and available data for the four NPM1/FLT3-ITD genotypes in the 2017 ELN (n=427). In 358 of these patients, the following 2017 ELN high-risk markers were assessed: RUNX1, ASXL1, and TP53.
Of the original 427 patients who had mutational status data on FLT3-ITD AR and NPM1, the researchers categorized each patient into one of the four NPM1/FLT3-ITD genotypes:
- NPM1mut/FLT3-ITDlow (n=85)
- NPM1mut/FLT3-ITDhigh (n=159)
- NPM1wt/FLT3-ITDlow (n=74)
- NPM1wt/FLT3-ITDhigh (n=109)
The investigators then were able to categorize 318 patients into the following 2017 ELN risk groups:
- favorable risk: NPM1mut/FLT3-ITDlow AML (n=85)
- intermediate risk: NPM1mut/FLT3-ITDhigh AML (n=93) and NPM1wt/FLT3-ITDlow AML (n=18)
- adverse risk: NPM1wt/FLT3-ITDhigh AML (n=92); NPM1mut/FLT3-ITDhigh AML (n=8) exhibiting high-risk molecular markers; and NPM1wt/FLT3-ITDlow AML (n=22) with high-risk molecular markers and/or adverse-risk cytogenetics
Next, when the authors assessed response to therapy in RATIFY participants by ELN risk, they found that, among those randomized to placebo, responses within the favorable-, intermediate-, and adverse-risk groups were 68.1%, 59.6%, and 44.4%, respectively (p=0.05). In the midostaurin-treated patients, however, the proportions of patients who responded to therapy were 71.1%, 66.7%, and 57.4%, respectively (p=0.34).
Factors significantly associated with lower complete remission rates in a multivariable logistic regression analysis were:
- ELN adverse-risk vs. favorable-risk categorization (odds ratio [OR] = 0.54; 95% CI 0.29-0.99; p=0.052)
- higher white blood cell (WBC) count (OR=0.62; 95% CI 0.39-0.97; p=0.039)
In the 318 patients who were risk-categorized according to 2017 ELN, the estimated median follow-up was 57.5 months, and the median overall survival (OS) was 26.3 months in the entire group, while the 5-year OS rate was 44%. The median event-free survival (EFS) in these patients was 4.7 months, and the median 5-year EFS rate was 24%. In the midostaurin arm, however, the median OS has not been reached (range = 29.8 months to not reached).
Patients categorized with favorable-risk AML according to the 2017 ELN had the greatest 5-year OS probability (0.62; 95% CI 0.53-0.74). Next were patients with intermediate-risk AML (0.43; 95% CI 0.34-0.53), followed by patients with adverse-risk AML (0.33; 95% CI 0.25-0.42; difference between survival curves, p<0.001).
The investigators also observed that midostaurin treatment was associated with greater survival, compared with placebo, across all risk groups. For example, the 5-year OS rates were 0.73 for favorable-risk, 0.53 for intermediate-risk, and 0.52 for adverse-risk midostaurin-treated patients. In the placebo group, however, the 5-year OS rates were 0.34, 0.43, and 0.20, respectively.
Among all patients, a multivariate Cox model for OS identified the following factors as significant predictors of prognosis:
- 2017 ELN risk classification (hazard ratio [HR] = 2.64; 95% CI 1.69-4.13; p<0.001)
- treatment of midostaurin vs. placebo (HR=0.55; 95% CI 0.43-0.83; p<0.002)
- allogeneic hematopoietic cell transplantation (alloHCT; HR=0.57; 95% CI 0.42-0.94; p=0.021)
- WBC count (log10) (HR=1.51; 95% CI 1.11-2.00; p=0.009)
Midostaurin was found to be effective across all ELN risk groups independent of alloHCT.
“A complete work-up according to 2017 ELN recommendations, including assessment of the ITD allelic burden, should be mandatory for all newly diagnosed FLT3-ITD patients eligible for intensive therapy,” the authors said.
Study authors report relationships with Novartis, which sponsored the RATIFY trial.
Döhner K, Thiede C, Jahn N, et al. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia. Blood. 2020;135:371-380.