Superior Salvage Treatment with Regimen Containing Sorafenib for Relapse of Acute Myeloid Leukemia with FLT3-ITD after Allo-HSCT
Authors: Xuan Li , Wang Yu , Chen Jia , Jiang Erlie , Gao Li , Wu Bingyi , Deng Lan , Liang Xinquan , Huang Fen , Fan Zhiping , Tang Xiaowen , Sun Jing , Zhang Xi , Han Ming-Zhe , Wu De-Pei , Huang Xiao Jun , Liu Qifa 
Published: October 2019

Abstract
Background Internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutation has been reported in about 25% of patients with acute myeloid leukemia (AML). In contrast to patients with FLT3-ITD wild-type, AML with FLT3-ITD mutations have an inferior survival, primarily due to shorter remission duration and higher relapse rate. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) improves the survival for FLT3-ITD AML, the rate of leukemia relapse remains high. Patients experiencing leukemia relapse post-transplants have a dismal prognosis. Recent studies have demonstrated that sorafenib monotherapy or in combination with other therapeutic strategies could induce sustained responses for patients with FLT3-ITD relapsed post-transplants. The aim of this study is to evaluate the efficacy of sorafenib combined with other therapeutic strategies for AML with FLT3-ITD relapsed after allo-HSCT.
MethodsA total of 76 AML with FLT3-ITD relapsed after allo-HSCT from January 2012 to May 2017 were enrolled in this study. Depending on whether receiving salvage therapy containing sorafenib, patients were divided into 2 groups: sorafenib group (n=49) and non-sorafenib group (n=27). On the basis of the differences of therapeutic regimens, patients were divided into 4 subgroups, including sorafenib+ chemotherapy+donor lymphocyte infusion (DLI) (Group A, n=39), sorafenib+ chemotherapy (Group B, n=10), chemotherapy +DLI (Group C, n=15), and monochemotherapy (Group D, n=12). Outcomes of different therapeutic regimens were compared.
Results Forty patients obtained complete remission (CR) and 12 partial remission after salvage therapies, with the CR and overall response (OR) rates of 52.6% and 68.4%. The CR and OR rates were 65.3% and 81.6% in the sorafenib group, compared with 29.6% and 44.4% in the non-sorafenib group (P=0.003, P=0.001). Subgroup analysis showed that the CR and OR rates in Group A were higher than that in Group D (P=0.006, P=0.001), and they were similar to that in Groups B and C (all P values >0.008). There were also no significant differences in the CR and OR rates among Groups B, C, and D (all P values >0.008). With a median follow-up of 245 (range 30-1992) days after relapse, 26 patients remained alive and 50 died. The 3-year overall survival (OS) was 33.8% (95% CI, 23.3%-44.5%). The 3-year OS in the sorafenib group was superior to that in the non-sorafenib group (42.0% vs 18.5%, P=0.002). Subgroup analysis revealed that sorafenib combined with chemotherapy followed by DLI was superior to other regimens, with 3-year OS of 47.8%, 20.0%, 20.0%, and 16.7% in Groups A, B, C, and D, respectively (P=0.007). The incidences of acute and chronic GVHD as well as the mortality of GVHD after salvage therapies were similar among the four groups (P=0.304, P=0.429, P=0.601, respectively). Multivariate analysis revealed that salvage therapy containing sorafenib was the only protective factor for OS (P=0.022, hazard ratios= 0.479).
ConclusionsSalvage therapy containing sorafenib was superior to that not containing sorafenib, and sorafenib combined with chemotherapy followed by DLI revealed optimal efficacy for relapse of AML with FLT3-ITD after allo-HSCT.

Disclosures
Fan: National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding.