Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in acute myeloid leukemia

Abstract

In the opinion of the European LeukemiaNet (ELN), nucleophosmin member 1 gene mutation (NPM1 mut)-positive acute myeloid leukemia (AML) with an fms-like kinase 3-internal tandem duplication (FLT3-ITD) allele ratio (AR) <0.5 (low AR) has a favorable prognosis, and allogeneic hematopoietic stem cell transplant (allo-HSCT) in the first complete remission (CR1) period is not actively recommended. We studied 147 patients with FLT3-ITD gene mutation-positive AML, dividing them into those with low AR and those with AR of ≥0.5 (high AR), and examined the prognostic impact according to allo-HSCT in CR1. Although FLT3-ITD AR and NPM1 mut are used in the prognostic stratification, we found that NPM1 mut-positive AML with FLT3-ITD low AR was not associated with favorable outcome (overall survival [OS], 41.3%). Moreover, patients in this group who underwent allo-HSCT in CR1 had a significantly more favorable outcome than those who did not (relapse-free survival [RFS] P = .013; OS P = .003). Multivariate analysis identified allo-HSCT in CR1 as the sole favorable prognostic factor (RFS P < .001; OS P < .001). The present study found that prognosis was unfavorable in NPM1 mut-positive AML with FLT3-ITD low AR when allo-HSCT was not carried out in CR1.

Graphical abstract

Figure 1.

Impact on RFS and OS of FLT3-ITD AR with cutoff value set at 0.5. (A) RFS. (B) OS. RFS and OS were found to be significantly more favorable in the low-AR group than in the high-AR group (RFS at 5 years: low-AR group 48.9% vs high-AR group 23.8%, P = .008; OS at 5 years: low-AR group 39.1% vs high-AR group 15.0%, P = .015).

Figure 2.

Impact on RFS and OS of FLT3-ITD AR focus on patients younger than 70 years with intermediate prognosis based on karyotype and NPM1 mut. (A) RFS (left) and OS (right) of patients <70 years with intermediate prognosis based on karyotype stratified for FLT3-ITD AR. The low-AR group was found to have significantly better outcomes in both RFS and OS than the high-AR group (RFS at 5 years: low-AR group 51.9% vs high-AR group 22.8%, P = .017; OS at 5 years: low-AR group 41.9% vs high-AR group 17.1%, P = .049). (B) RFS (left) and OS (right) of NPM1 mut–positive cases stratified for FLT3-ITD AR. When analysis was restricted to NPM1 mut–positive cases, RFS and OS were again found to be significantly more favorable in the low-AR group than the high-AR group (RFS at 5 years: low-AR group 50.5% vs high-AR group 11.7%, P = .026; OS at 5 years: low-AR group 41.3% vs high-AR group 14.7%, P = .041). However, in contrast to the classification of the ELN guidelines, the low-AR group, with a 5-year survival rate of 41.3%, was found to have not a good but an intermediate prognosis, and the high-AR group, with a 5-year survival rate of 14.7%, was found to have not an intermediate but an unfavorable prognosis.

Figure 3.

Impact on RFS and OS of FLT3-ITD AR and allo-HSCT. (A) Comparison of RFS (left) and OS (right) with and without allo-HSCT. The group in which transplant was carried out had significantly better OS than the nontransplant group. Additionally, although the difference was not significant, RFS showed a superior tendency in the transplant group compared with the nontransplant group (RFS at 3 years: allo-HSCT [+] 47.4% vs allo-HSCT [−] 9.9%, P = .165; OS at 3 years: allo-HSCT [+] 46.1% vs allo-HSCT [−] 10.1%, P < .001). (B) RFS (left) and OS (right) with and without allo-HSCT and stratified for AR. When analysis was restricted to FLT3-ITD low-AR cases, RFS and OS were again found to be significantly more favorable in the allo-HSCT (+) group than the allo-HSCT (−) group (RFS at 2 years: allo-HSCT [+] group 72.6% vs allo-HSCT [−] group 0.0%, P = .012; OS at 2 years: allo-HSCT [+] group 76.5% vs allo-HSCT [−] group 17.4%, P < .001). Among FLT3-ITD high-AR cases, the transplant group had significantly better OS than the nontransplant group. Additionally, although the difference was not significant, RFS showed a superior tendency in the transplant group compared with the nontransplant group (RFS at 5 years: allo-HSCT [+] group 32.4% vs allo-HSCT [−] group 12.7%, P = .784; OS at 2 years: allo-HSCT [+] group 33.7% vs allo-HSCT [−] group 6.4%, P = .002).

Figure 4.

Impact on RFS and OS of allo-HSCT in CR1 and FLT3-ITD AR. (A) RFS (left) and OS (right) with and without allo-HSCT in CR1 and stratified for FLT3-ITD AR. Among FLT3-ITD low-AR cases, the group in which transplant was carried out in CR1 had significantly more favorable RFS and OS than the group in which transplant was not carried out in CR1 (RFS at 3 years: allo-HSCT in CR1 [+] group 92.9% vs allo-HSCT in CR1 [−] group 12.8%, P < .001; OS at 4 years: allo-HSCT in CR1 [+] group 66.7% vs allo-HSCT in CR1 [−] group 20.4%, P < .001). Similarly, among FLT3-ITD high-AR cases, RFS and OS were significantly more favorable in the group with transplant in CR1 than in the group without transplant in CR1 (RFS at 3 years: allo-HSCT in CR1 [+] group 85.6% vs allo-HSCT in CR1 [−] group 4.1%, P < .001; OS at 4 years: allo-HSCT in CR1 [+] group 59.3% vs allo-HSCT in CR1 [−] group 9.2%, P < .001). (B) RFS (left) and OS (right) in patients positive for both FLT3-ITD and NPM1 mut, showing results with and without allo-HSCT in CR1 and stratified for FLT3-ITD AR. Among FLT3-ITD low-AR cases, RFS and OS were significantly more favorable in the group with transplant in CR1 than in the group without transplant in CR1 (RFS at 3 years: allo-HSCT in CR1 [+] group 85.7% vs allo-HSCT in CR1 [−] group 15.2%, P = .013; OS at 4 years: allo-HSCT in CR1 [+] group 66.7% vs allo-HSCT in CR1 [−] group 15.6%, P = .003). Among FLT3-ITD high-AR cases similarly, RFS and OS were significantly more favorable in the group with transplant in CR1 than in the group without transplant in CR1 (RFS at 3 years: allo-HSCT in CR1 [+] group 66.7% vs allo-HSCT in CR1 [−] group 0.0%, P = .036; OS at 4 years: allo-HSCT in CR1 [+] group 75.0% vs allo-HSCT in CR1 [−] group 9.9%, P = .030). The group without allo-HSCT in CR1 includes cases that did not receive allo-HSCT.