Prophylactic Use of Sorafenib in Patients with FLT3-ITD-Positive Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Liu Qifa , Xuan Li , Fan Zhiping , Jiang Qianli , Dai Min , Shi Pengcheng , Yin Changxin , Sun Jing 
Published: October 2019

Abstract
Background Internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutations have been reported in 20%-30% of patients with acute myeloid leukemia (AML). FLT3-ITD-positive AML patients have an inferior survival, primarily due to lower complete remission (CR) rate and higher relapse rate. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) improves the outcomes of some FLT3-ITD-positive AML, a signiﬁcant number will suffer disease recurrence after allo-HSCT. Sorafenib, an inhibitor of multiple kinases including FLT3, has shown promising activity in FLT3-ITD-positive AML. Recent studies have shown that sorafenib monotherapy or in combination with chemotherapy are effective in attaining CR, but they do not have significant improvement in relapse. Currently, prophylactic use of sorafenib after allo-HSCT has been rarely reported, and whether it can improve outcomes of FLT3-ITD-positive AML remains unclear.
Methods A total of 18 patients with FLT3-ITD-positive AML undergoing allo-HSCT from January 2012 to March 2014 at our single institute were enrolled in this retrospective study. Seven patients were in first CR at the time of transplantation and all received standard conditioning: busulfan 4 mg/kg/d P.O. or 3.2 mg/kg/d I.V. (on days -7 to -4), cyclophosphamide 60 mg/kg/d (on days -3, -2). Eleven patients were not in CR (NR) at the time of transplantation and all received intensified conditioning: ﬂudarabine 30 mg/m2/d (on days -10 to -6), cytarabine 2.0 g/m2/d (on days -10 to -6), total body irradiation 4.5 Gy/d (on days -5, -4), cyclophosphamide 60 mg/kg/d (on days -3, -2), etoposide 15 mg/kg/d (on days -3, -2). Sorafenib was used from day 30 to 180 post-transplantation. The initial dose of sorafenib was 400 mg orally twice daily and was adjusted in case of suspected toxicity or resistance (dose range, 200-800 mg daily).
Results Of the 18 patients, 7 received prophylactic sorafenib, including 3 in CR and 4 in NR pre-transplantation; 11 did not receive prophylactic sorafenib, including 4 in CR and 7 in NR pre-transplantation. There were no significant differences in disease status pre-transplantation, HLA-typing and the source of donors between the two groups (all P>0.05). The eleven patients in NR at the time of transplantation all achieved CR and had complete chimerism by day +30 post-transplantation. With a median follow up of 433 (range, 124-765) days post-transplantation, 7 patients with prophylactic sorafenib all had no recurrence and survived. Of the 11 patients without prophylactic sorafenib, 5 experienced leukemia relapse at a median time of 92 (range, 49 to 335) days post-transplantation, including hematologic in 4 and central nervous system (CNS) in 1. The patient with CNS relapse achieved CR after radiotherapy and donor lymphocyte infusion (DLI), and was still alive now. Of the 4 patients with hematologic relapse, one abandoned treatment and 3 received treatment, including sorafenib combined with chemotherapy and DLI. Two of the three patients achieved short CR after treatment and finally all of them died of relapse within half a year. With a median follow up of 343 (range, 135-863) days post-transplantation, 6 patients survived and 5 died in the 11 patients without prophylactic sorafenib. Causes of death included leukemia relapse (n=4) and chronic graft-versus-host disease (n=1). The 1-year cumulative incidence of leukemia relapse was 0.0% and 50.9% in patients with and without prophylactic sorafenib (P=0.046). The 1-year overall and disease-free survival were 100.0% and 100.0% in patients with prophylactic sorafenib, compared with 49.9% and 42.4% in those without prophylactic sorafenib (P=0.066, P=0.028). The main side effect of sorafenib was rash, and none of patients experienced bone marrow suppression. Of the 10 patients with sorafenib treatment, 6 had hand-foot skin reaction and/or rash. Anti-allergy therapy was ineffective, and glucocorticoid was usually required. In 4 of the 6 patients, the skin rash covered gradually after reducing the dose of sorafenib and the use of glucocorticoid. Other two patients even required drug discontinuation, but sorafenib was tolerated after the reuse.
Conclusions Early prophylactic use of sorafenib has an acceptable toxicity profile and could reduce relapse of FLT3-ITD-positive AML.

Disclosures
Liu: It was supported by Natural Science Foundation of Guangdong Province (S2012010009299); the project of health collaborative innovation of Guangzhou city (201400000003-4, 201400000003-1): Research Funding; It was supported by National Natural Science Foundation of China (81270647, 81300445, 81200388); National High Technology Research and Development Program of China (863 Program) (2011AA020105); National Public Health Grand Research Foundation (201202017): Research Funding; It was supported by the Technology Plan of Guangdong Province of China (2012B031800403); the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027): Research Funding. Xuan:It was supported by National Natural Science Foundation of China (81270647, 81300445, 81200388); National High Technology Research and Development Program of China (863 Program) (2011AA020105): Research Funding.