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. 2011 Sep;96(9):1310-7.
doi: 10.3324/haematol.2011.040592. Epub 2011 May 23.

Prognostic impact of white blood cell count in intermediate risk acute myeloid leukemia: relevance of mutated NPM1 and FLT3-ITD

Hendrik J M de Jonge  1 , Peter J M Valk, Eveline S J M de Bont, Jan Jacob Schuringa, Gert Ossenkoppele, Edo Vellenga, Gerwin Huls
Affiliations

Prognostic impact of white blood cell count in intermediate risk acute myeloid leukemia: relevance of mutated NPM1 and FLT3-ITD

Hendrik J M de Jonge et al. Haematologica. 2011 Sep.

Abstract

Background: High white blood cell count at presentation is an unfavorable prognostic factor for treatment outcome in intermediate cytogenetic risk acute myeloid leukemia. Since the impact of white blood cell count on outcome of subgroups defined by the molecular markers NPMc(+) and FLT3-internal tandem duplication (ITD) is unknown, we addressed this issue.

Design and methods: We studied the effect of white blood cell count on outcome in a clinically and molecularly well-defined cohort of 525 patients with acute myeloid leukemia using these molecular markers. In addition, since an increased white blood cell count has been associated with an increased FLT3-ITD/FLT3 (wild-type) ratio, we investigated whether the effect of white blood cell count on outcome could be explained by the FLT3-ITD/FLT3 ratio.

Results: This analysis revealed that white blood cell count had no impact on outcome in patients with the genotypic combinations 'NPMc(+) without FLT3-ITD' and 'NPM1 wild-type with or without FLT3-ITD'. In contrast, white blood cell count had a significant impact on complete remission rate (P=0.034), event-free survival (P=0.009) and overall survival (P<0.001) in patients with the genotypic combination 'NPMc(+) with FLT3-ITD'. A FLT3-ITD/FLT3 ratio greater than 1 was also associated with a reduced complete remission rate (P=0.066) and significantly reduced event-free survival (P= 0.001) and overall survival (P=0.001) in patients with the genotypic combination 'NPMc(+) with FLT3-ITD'. Multivariable analysis revealed that white blood cell count and FLT3-ITD/FLT3 ratio were independent prognostic indicators for outcome in the subgroup with the genotypic combination 'NPMc(+) with FLT3-ITD'.

Conclusions: Our results demonstrate that both high white blood cell count and FLT3-ITD/FLT3 ratio are prognostic factors in patients with acute myeloid leukemia with the genotypic combination 'NPMc(+) with FLT3-ITD'.

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Figures

Figure 1.
Figure 1.
Impact of WBC count on event-free survival (EFS) and overall survival (OS) in cases with cytogenetically intermediate risk AML defined by the molecular markers NPMc+ and FLT3-ITD. (A) EFS according to WBC levels in 70 cytogenetically intermediate risk AML cases with NPMc+ without FLT3-ITD mutation. (B) OS for this group. (C) EFS according to WBC levels in 75 cytogenetically intermediate risk AML cases with NPMc+ and FLT3-ITD. (D) OS for this group. (E) EFS according to WBC levels in 40 cytogenetically intermediate risk AML cases with wild type NPM1 and FLT3-ITD. (F) OS for this group. (G) EFS according to WBC levels in 146 cytogenetically intermediate risk AML cases with wild-type NPM1 without FLT3-ITD. (H) OS for this group. The P value is given for the overall comparison across all three groups.
Figure 2.
Figure 2.
Impact of FLT3-ITD/FLT3 ratio on event-free survival (EFS) and overall survival (OS) in cases with cytogenetically intermediate risk AML with the genotypic combination ‘NPMc+ with FLT3-ITD’. (A) EFS and (B) OS according to FLT3-ITD/FLT3 ratio within 75 cytogenetically intermediate cytogenetic risk AML cases with the genotypic combination NPMc+ with FLT3-ITD. Ratio <1: n=9; ratio 1: n=28; ratio >1: n = 38. The P value is given for the overall comparison across all three groups.
Figure 3.
Figure 3.
Combined effect of WBC count and FLT3-ITD/FLT3 ratio on event-free survival (EFS) and overall survival (OS) in cases with cytogenetically intermediate risk AML with the genotypic combination ‘NPMc+ with FLT3-ITD’. (A) EFS in patients with WBC count <100x109/L and FLT3-ITD/FLT3 ratio ≤1 (n=24) compared to those with WBC count >100x109/L or FLT3-ITD/FLT3 ratio >1 (n=51) (B) OS in these cases.
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