NPM1,   FLT3

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

Whether allelic ratio (AR) can be used as a predictive marker for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with FLT3-ITD mutated acute myeloid leukemia (AML) is still unclear. Moreover, according to the recommendation by the European LeukemiaNet (ELN), NPM1 mutated positive AML with FLT3-ITD AR < 0.5 has a favorable prognosis. However, this is still under debate. In Blood Advances, a group of Japanese researchers reported data from their retrospective study, which aimed to evaluate the clinical impact of FLT3-ITD allelic ratio (AR) and also evaluate whether allogeneic HSCT is indicated for FLT3-ITD-positive AML.

One hundred and forty-seven FLT3-ITD positive patients (median age = 56 years, range 18–90) with de novo AML were included in this study who were treated at Nippon Medical School Hospital. Gene mutation analysis was performed on samples obtained from patients at diagnosis.

Key findings:
  • Median FLT3-ITD allelic frequency (AF): 36.98% (range, 3.08%–100%)
  • Survival was analyzed using cutoff values for FLT3-ITD AR set at 0.25 (AF = 20%), 0.5 (AF = 33.3%) and 1.0 (AF = 50%)
  • No significant difference was observed for relapse-free survival (RFS) and overall survival (OS) when the cutoff was set at 0.25 and 1.0
  • Patients were divided into groups; low (AR < 0.5) and high (AR ≥5) AR
  • Relapse-free survival and overall survival were significantly more favorable in the low AR group than high AR group when the cutoff was set at 0.5
    • 5-year RFS: 48.9% vs 23.8%, P = 0.008
    • 5-year OS: 39.1% vs 15.0%, P = 0.015
  • There was no significant difference in the achievement of first complete remission (CR1), second CR (CR2) and relapse rate between patients with low and high AR
  • Patients aged < 70 years with intermediate prognosis
    • Compared to patients in the high AR group, RFS (P = 0.017) and OS (P = 0.049) were significantly better in patients in the low AR group
  • Patients who were NPM1 mutation positive in the low and high AR group, respectively
    • 5-year RFS: 50.5% vs 11.7%, P = 0.026
    • 5-year OS: 41.3% vs 14.7%, P = 0.041
  • FLT3-ITD mutated patients who underwent allogeneic HSCT had a significantly better outcome than patients who did not
    • In patients who underwent HSCT, RFS and OS were significantly better in the low AR group compared with high AR group
    • Among patients with low AR FLT3-ITD, allogeneic HSCT performed in CR1 lead to a significantly better RFS (P < 0.001) and OS (P < 0.001) than in patients who did not receive allogeneic HSCT in CR1

In summary, the results of this study show that FLT3-ITD low AR with NPM1 mutation was not associated with favorable outcome but rather with an intermediate outcome with an OS ≤ 50% (41.3%) which is in contrast with the ELN recommendations. Additionally, the performance of allogeneic HSCT during CR1 irrespective of AR and NPM1 mutation significantly improve outcome.

The researchers concluded by recommending “allogeneic HSCT in CR1 for FLT3-ITD positive AML in cases where a suitable donor is available regardless of whether NPM1 mutation is also present.”

References
  1. Sakaguchi M. et al. Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia. Blood Adv. 2018 Oct 23; 2(20): 2744–2754. DOI: 10.1182/bloodadvances.2018020305.
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