Superior Salvage Treatment with Regimen Containing Sorafenib for Relapse of Acute Myeloid Leukemia with FLT3-ITD after Allo-HSCT

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