1. Sorafenib maintenance therapy following allogenic stem cell transplantation in FLT3-ITD acute myeloid leukemia was associated with significantly lower rates of cancer relapse at 1 year post-transplantation.
2. Sorafenib maintenance therapy was well-tolerated and had a similar safety profile to a non-maintenance therapy control.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Patients with the FLT3-ITD mutation in acute myeloid leukemia (AML) have a particular poor prognosis. Several studies have shown maintenance therapy post-transplantation with the multikinase inhibitor sorafenib may reduce risk of relapse and improve survival. In the absence of prior randomized trial evidence, sorafenib was therefore recommended as maintenance therapy post-allogenic stem cell transplantation in this setting (evidence level B-II), yet it lacks data from randomized trials. This phase 3 open-label, randomized trial compared the use of sorafenib maintenance therapy after allogenic hematopoietic stem cell transplantation to a no-maintenance control. Overall, sorafenib maintenance was associated with a significantly lower rate of relapse at 1 year of follow-up post-transplantation. Sorafenib was also well-tolerated, with a similar safety profile to the control arm. Post-hoc multivariate analysis concluded that sorafenib maintenance therapy was the only factor that improved overall survival and leukemia-free survival. This study is important, as it is the first randomized phase 3 trial studying sorafenib maintenance therapy in the post-stem cell transplantation setting. Study limitations include lack of blinding, absence of a placebo arm, and duration of therapy only up to 6 months post-transplantation and not 1 year as is common in clinical practice. Nonetheless, trial results are promising regarding possible benefit with reasonable tolerability, and warrants consideration as a possible therapeutic option in this population.
In-Depth [randomized controlled trial]: This open label randomized multicenter phase 3 trial was conducted in seven hospitals in China, and randomized 202 participants (100 to sorafenib, 102 to control). Patients aged 18 to 60 years with FLT3-ITD acute myeloid leukemia (AML) undergoing a first allogenic stem cell transplantation and achieving composite complete remission before and after transplantation with hematopoietic recovery within 60 days post-procedure were considered eligible. Half of included patients were female, and the average age was 35 years in both arms (interquartile range [IQR] 26 to 42 in sorafenib group, 26 to 43 in control group). The primary outcome was cumulative incidence of relapse 1-year post-transplant; secondary outcomes included overall and leukemia-free survival at 2 years, non-relapse mortality at 2 years, and adverse events until 210 days post-transplant. At 1-year post-transplant, the sorafenib group had significantly lower rates of relapse (7.0%, 95% confidence interval [CI] 3.1 to 13.1 vs. 24.5%, 95% CI 16.6 to 33.2; hazard ratio [HR] 0.25, 95% CI 0.11 to 0.57, p=0.001). Two-year overall survival was 82.1% (95% CI 72·6 to 88·5) and 68.0% (57.8 to 76.2) in sorafenib and control groups, respectively (HR 0.48, 95% CI 0.27 to 0.86; p=0.012). Leukemia-free survival at 2 years was 78.9% (95% CI 69.0 to 85.9) and 56.6% (46.1 to 65.8), respectively (HR 0.37, 95% CI 0.22 to 0.63; p<0·0001). Both sorafenib and control groups had high proportions of patients with at least one type of grade 3 or 4 adverse event (50% vs. 46%, respectively). Common adverse events included infections (25% vs. 24%), acute graft-versus-host disease (23% vs. 21%), chronic graft-versus-host disease (18% vs. 17%) and hematological toxicity (15% vs. 7%). Four patients in the sorafenib group and five in the control group died from adverse events. Based on these findings, sorafenib appears to be a reasonable maintenance therapy with a reduction in relapse rate and a comparable safety profile in patients with FLT3-ITD AML post-allogenic stem-cell transplantation.
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