Impact of Concomitant Genetic Abnormalities on Sorafenib Therapy in FLT3-ITD Positive Acute Myeloid Leukemia Undergoing Allo-HSCT
Authors: Shao Ruoyang , Liu Qifa 
Published: November 2021

Abstract
Aim
In this study, we investigated the co-occurring mutation landscape in acute myeloid leukemia (AML) patients with FLT3 internal tandem duplication (FLT3-ITD), and explored whether post-allogenic hematopoietic stem cell transplantation (allo-HSCT) sorafenib maintenance therapy could improve the outcomes of FLT3-ITD AML patients combined with other co-occurring genetic abnormalities.
Methods
A total of 456 FLT3-ITD AML patients receiving first allo-HSCT were included in this study. Gene mutations were detected using direct sequencing or next generation sequencing. Fusion genes were detected using a 53-gene polymerase chain reaction panel. The frequency of each genetic abnormality was investigated, and the mutation landscape was investigated. The primary outcome of this study was 3-year cumulative incidence of relapse. The secondary outcomes were 3-year overall survival (OS), disease-free survival (DFS) and non-relapse mortality (NRM). The outcomes were compared between patients who received post-HSCT sorafenib maintenance and those who did not in the whole population and in subgroups referring to co-occurring mutations.
Results
A total of 190 patients received post transplantation sorafenib maintenance therapy (sorafenib group) and 266 patients did not (control group). Of the patients receiving sorafenib pre-transplantation, the median duration of sorafenib therapy was 106 days (IQR 68 - 132) in the sorafenib group, and 99 days (IQR 71 - 142) in the control group (p = 0.883). Of the patients receiving post-transplantation sorafenib maintenance therapy, sorafenib was initiated at a median of 30 days (IQR, 30 - 52 days) after allo-HSCT, and continued for a median of 148 days (IQR, 112 - 150).
Median follow-up time was 38.7 months (IQR, 28.1 - 47.9). Thirty-four patients in the sorafenib group and 93 patients in the control group relapsed. The 3-year cumulative incidence of relapse was 18.0% (95% CI 13.1% - 24.3%) in the sorafenib group and 36.1% (95% CI 30.5% - 42.3%) in the control group (HR 0.43, 95% CI 0.29 - 0.64; p &lt; 0.001). A total of 126 patients died, including 39 in the sorafenib group and 87 in the control group. Three-year DFS was 75.8% in the sorafenib group and 57.5% in the control group (HR 0.47, 95% CI 0.34 - 0.66; p &lt; 0.001). Three-year OS was 79.5% for patients in the sorafenib group and 68.4% for patients in the control group (HR 0.57, 95% CI 0.39 - 0.83, p = 0.004).
Gene mutations were detected using a 12-mutation panel direct sequencing including FLT3-ITD, FLT3-TKD, NPM1, KIT, DNMT3A, CEBPA, ASXL1, TP53, TET2, IDH1, IDH2 and RUNX1 in all patients, and a 127-gene panel new generation sequencing in 188 patients.
Except FLT3, a total of 920 co-occurring gene mutations and 147 cytogenetic abnormalties were detected. The co-occurring mutations that presented in at least 10% the cases were NPM1 (31.6%), DNMT3A (15.4%), TET2 (11.4%), and CEBPA (10.5%). There were 10.5% patients presented with both NPM1 and DNMT3A mutations (Triple-mutated AML patients), and 13.8% patients combined with at least one additional genetic abnormality classified as adverse according to the 2017 ELN risk stratification other than FLT3-ITD. Cytogenetic abnormalities presented in more than 1% the patients were RUNX1-RUNX1T1, which occurred in 23 patients (5.0%), followed by +8 (2.9%), complex karyotype (2.6%), CBFB-MYH11 (2.4%), DEK-NUP214 (1.3%) and -y (1.3%).
Patients combined with NPM1(p = 0.009 and 0.009), DNMT3A (p = 0.036 and 0.086), triple-mutated AML patients (p = 0.030 and 0.027), and patients with at least one additional adverse abnormality (p = 0.014 and 0.005) benefit significantly in DFS and OS from post-transplantation sorafenib maintenance, but not those with CEBPA (p = 0.669 and 0.576) or TET2 (p = 0.375 and 0.178) mutations.
Conclusion
Post transplantation sorafenib maintenance therapy can improve the prognosis of FLT3-ITD AML patients combined with DNMT3A or NPM1, patients with triple-mutated AML, and patients combined with at least one additional adverse abnormalities, but not of those combined with CEBPA or TET2 mutations.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.