The Effect of Sorafenib Therapy on the Outcome of Acute Myeloid Leukemia with FLT3-ITD Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background Internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutation has been reported in about 25% patients with acute myeloid leukemia (AML). AML with FLT3-ITD mutations have an inferior survival, primarily due to shorter remission durations and higher relapse rates. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) improves the survival for FLT3-ITD AML, the rate of leukemia relapse remains high. Sorafenib, a multi-kinase inhibitor, has shown promising activity in AML with FLT3-ITD. A growing body of studies have suggested that sorafenib monotherapy or in combination with chemotherapy are effective in attaining complete remission (CR) for untreated and refractory relapsed FLT3-ITD AML. Sorafenib maintenance after allo-HSCT has been proved to be safe for FLT3-ITD AML, but whether it could improve survival remains uncertain. The aim of this study is to evaluate the effect of sorafenib therapy on the outcome of FLT3-ITD AML undergoing allo-HSCT.

Methods A total of 118 AML with FLT3-ITD undergoing allo-HSCT were enrolled in this retrospective study between January 2012 and December 2015 at Nanfang Hospital, Peking University People's Hospital and Zhujiang Hospital. Patients with HLA-matched sibling or unrelated donors received BuCY conditioning (busulfan 3.2 mg/kg/day, on days -7 to -4; cyclophosphamide 60 mg/kg/day, on days -3, -2), and patients with HLA-haploidentical related donors received modified BuCY conditioning (cytarabine4g/m²/day, on days -10, -9; busulfan 3.2 mg/kg/day, on days -8 to -6; cyclophosphamide 1.8g/m²/day, on days -5, -4). Sorafenib therapy pre-HSCT was initiated at the time of induction, post-remission maintenance or relapse, and continued until one week prior to the start of the conditioning regimen. Sorafenib maintenance post-HSCT was started from day 30 to 180 post-transplantation. Either before or after transplantation, the initial dose of sorafenib was 400 mg twice daily and was adjusted on the basis of suspected toxicity or emerging drug resistance (dose range, 200-800 mg daily).

Results Of the 118 patients, 90 were in CR, 8 in partial remission and 20 in non-remission at the time of transplantation. The 118 patients all achieved hematopoietic reconstitution and achieved CR by day +30 post-transplantation. Depending on whether patients received sorafenib pre-HSCT and sorafenib maintenance post-HSCT, the 118 patients were divided into 4 groups. Thirty-two patients only received sorafenib pre-HSCT (Group A), 29 only maintenance post-HSCT (Group B), 23 both pre-HSCT and maintenance post-HSCT (Group C), and 34 did not receive sorafenib pre-HSCT or maintenance post-HSCT (Group D). There were no significant differences in disease status pre-transplantation, donor source or HLA typing among four groups. Thirty-three patients relapsed at a median time of 137 (range, 44 to 589) days post-transplantation. Six abandoned treatment and 27 received salvage therapy of sorafenib combined with chemotherapy and DLI. Thirteen of the 27 patients achieved CR after salvage treatment. The 5-year cumulative incidence of relapse were 20.6%±9.4%, 20.7%±3.4%, 17.4%±4.3% and 50.2%±18.6% in Group A, B, C and D (P=0.006). With a median follow up of 670 (range, 63-1898) days post-transplantation, 85 patients survived and 33 died. The 5-year overall survival (OS) and disease-free survival (DFS) were 75.0%±8.8% and 70.0%±8.6%, 75.9%±8.0% and 75.9%±8.0%, 82.6%±7.9% and 78.3%±8.6%, 51.6%±9.6% and 31.2%±8.9% in Group A, B, C and D (P=0.093, P <0.001). Multivariate analysis revealed that sorafenib therapy pre-HSCT and sorafenib maintenance post-HSCT were the protective factors for lower relapse and longer OS; the nCR (not in CR) status pre-HSCT was the only risk factor for longer OS.

Conclusions Sorafenib therapy pre-HSCT and sorafenib maintenance post-HSCT could reduce relapse and improve survival for AML with FLT3-ITD.