Trial Test of Sorafenib Alone or in Combination with Chemotherapy for Treating Refractory and Relapsed Acute Myeloid Leukemia with FLT3 Mutation
Authors: Miao Miao , Depei Wu , Sun Aining , Xu Ting , Jin Song , Yan Lingzhi , Bao Haiyan 
Published: October 2019

Abstract
Introduction The prognosis was poor and the rate of refractory and relapsed was high for FLT3-mutated AML. The remission durations are shorter. Once relapsed, the disease is rapidly fatal. Some patients were often refractory to induction. While there was some success with immediate allogenic transplantation, it was shown that patients without FLT3 mutations were still prone to high rates of relapsed, posing a tremendous clinical challenge. At the moment there are no clear guidelines for treating these special patients in both the preliminary and induction phase.
Method Six of refractory and relapsed AML with FLT3-ITD mutation were evaluated, with a medium age of 43 (33-61 years old) and a male/female ratio of 3/3. Four of the cases were refractory (1 case at M2, 1 case at M4, and 2 cases at M5), while 2 were relapsed (1 case at M1, 1 case at M5). Two cases had FLT3-ITD mutation only, one patient had FLT3-TKD mutation only, 2 cases was coexisted NPM1 mutation, and one patient was combined DNMT3A mutation. Two cases were treated with sorafenib 200 mg bid or 400 mg bid, five days per week, while four cases were treated with sorafenib (same dosage) with combined half-course IAG or AAG chemotherapy (7 days) during induction. Results Four cases with combined therapies resulted in CR, while the symptoms in 2 relapsed patients with sorafenib-only treatment were unable to be alleviated. After the treatment was terminated, these two patients expired as the disease progressed for 6 months. The time range of sorafenib use was between 9 - 260 days, with a medium of 34 days. The 4 cases of CR included 2 cases with only FLT3-ITD mutation, 1 case with only FLT3-TKD mutation, and 1 case of combined NPM1 mutation. Three of the four cases received hematopoietic stem cell transplantation after the symptoms were reduced. The survival periods were 62, 90, and 117 days respectively. The last case exhibited a recurrence after consolidation chemotherapy was applied in place of sorafenib. FLT3-ITD was negative during the relapsed, and the symptoms were controlled after cladribine treatment with large doses of cytarabine. The major toxicities observed during the induction phase were neutropenia, thrombocytopenia and infections. All patients experienced grade IV WHO neutropenia and thrombocytopenia. The medium days of agranulocytosis was 18 days (4 - 27 days), platelets<20*109/L, medium 17 days (0 - 24 day). All four cases exhibited post-treatment infection: 2 were pulmonary infections, and the other two were infections of the upper respiratory tracts. All the infection was successfully treated. One patient showed a side effect of diarrhea, which was promptly alleviated with berberine, and another patient exhibited signs of a skin rash. The other patients were free of side effects.
Conclusion The preliminary results of our trial using sorafenib alone or combined chemotherapy for treating refractory and relapsed acute myeloid leukemia with FLT3 mutation showed positive results and was well tolerated. Therefore, this method of treatment is considered to be suitable for establishing better condition for patients to undergo allogenic hematopoietic stem cell transplantation. Whether sorafenib combined with chemotherapy can become a standard theray for newly diagnosed FLT3-mutated AML still needs further investigation, and more samples and controlled trials are required.

Disclosures
No relevant conflicts of interest to declare.