Impact of FLT3-ITD Molecular Characteristics on the Prognosis of Patients with De Novo Acute Myeloid Leukemia
Authors: Zhang Kainan , Ma Xiaohang , Lu Xiaoxuan , Ruan Guo-rui , Wei Fangfang , Jiang Hao , Huang Xiao Jun , Zhao Xiaosu 
Published: December 2024

Objective To investigate the relationship between molecular features of FLT3-ITD such as allelic ratio (AR), variant allele frequency (VAF), insertion length, insertion number in patients with de novo acute myeloid leukemia (AML) and their overall survival (OS) and event-free survival (EFS), and to explore the prognostic value of FLT3-ITD molecular features in AML patients.

Methods Next-generation sequencing (NGS) was used to detect FLT3-ITD mutations in 170 patients with newly diagnosed AML (except acute promyelocytic leukemia). The relationships among FLT3-ITD molecular characteristics, clinical features, treatment methods, and prognosis were analyzed. Prognostic scores were assigned based on FLT3-ITD molecular and clinical features.

Results Patients at diagnosis with AR &gt; 0.5 and VAF &gt; 30% had significantly higher white blood cell (WBC) counts (AR&lt;0.5 vs. AR&gt;0.5: 16.2×109/L vs. 55.3×109/L, p&lt;0.0001; VAF&lt;30% vs. VAF&gt;30%: 24.5×109/L vs. 53.0×109/L, p=0.0316) and bone marrow blast percents (AR&lt;0.5 vs. AR&gt;0.5: 54.5% vs. 67.5%, p=0.0029; VAF&lt;30% vs. VAF&gt;30%: 53.0% vs. 74.3%, p&lt;0.0001). Although molecular features of FLT3-ITD did not statistically impact OS and EFS, patients with longer insertion length (&gt;54bp, median), higher AR (&gt;0.7, median), and more mutation numbers (&gt;1) had relatively shorter OS. Patients who underwent early transplantation had longer OS compared to those transplanted after relapse (early transplantation vs. post-relapse transplantation: not reached vs. 18.1 months, p = 0.0066). Similarly, patients who received FLT3 inhibitors as initial treatment had longer OS than those who received them after relapse (early FLT3 inhibitor use vs. post-relapse FLT3 inhibitor use: not reached vs. 18.1 months, p = 0.0099). Then patients were grouped based on age, WBC counts, bone marrow blast percents and 2022 ELN risk classification. A scoring system was established, with 1 point assigned for each of the following: age &gt; 60 years, WBC count &gt; 30 × 109/L, bone marrow blast percent &gt; 65%, and adverse classification. No significant difference in OS was found between the 0-2 and 3-4 score group (two-year survival rate: 69.0% vs. 53.0%, p = 0.2059). However, when FLT3-ITD characteristics (AR, insertion number of FLT3-ITD) were included in the score (AR &gt; 0.7 and FLT3-ITD mutation number &gt;1 each counted as 1 point), a significant difference in OS was observed between the 0-2 and 3-5 score group (two-year survival rate: 72.4% vs. 55.1%, p = 0.0469). When WBC, bone marrow blast count, and age (with more significant impact on OS) were weighted at 2 points and used in the scoring system, a statistically significant difference in OS was found between the 0-3 and 4-7 score group (two-year survival rate: 75.3% vs. 56.1%, p = 0.0323). By integrating AR&gt;0.7 and insertion number of FLT3-ITD &gt;1 (each contributing 1 point) to our weighted scoring system, we were able to more distinctly differentiate the OS between the 0-4 and 5-8 score group (two-year survival rate: 73.7% vs. 50.7%, p = 0.0162). Additionally, this weighted scoring system including molecular features of FLT3-ITD has also proven to be an effective tool in predicting the recurrence of patients. Those who got &gt;4 points are considered to have a significantly higher probability of relapse (p=0.0005).

Conclusion Early transplantation and FLT3 inhibitor administration significantly improve prognosis in AML patients. Incorporating FLT3-ITD molecular features into prognostic analysis helps identify patients with worse outcomes in time.

Keywords Acute myeloid leukemia; Prognosis; FLT3-ITD