Adding sorafenib to standard chemotherapy prolongs the event-free survival in patients with acute myeloid leukemia

Data from a randomized phase II study demonstrate that the addition of the tyrosine kinase inhibitor (TKI) sorafenib to standard chemotherapy in patients with acute myeloid leukemia (AML) in a sequential manner is feasible and that this treatment is associated with antileukemic efficacy. In younger AML patients, the addition of sorafenib to standard chemotherapy led to a significantly longer event-free survival (EFS) and relapse-free survival (RFS). However, a higher incidence of infections and bleeding events were seen under sorafenib. As such, this trial produced the first randomized evidence for a clinical benefit of a TKI in this type of leukemia.

Despite the success of TKIs in some types of leukemia, such as chronic myeloid leukemia and a small subset of patients with acute lymphocytic leukemia, until now a TKI had yet to clearly demonstrate improved outcomes in patients with AML. Sorafenib is a multi-kinase inhibitor with activity against several oncogenic kinases that may play a role in the pathogenesis of AML. Moreover, in-vitro data and results from non-randomized clinical trials suggest that sorafenib might be an effective drug in the treatment of AML.

To better determine the safety and efficacy of sorafenib in combination with standard chemotherapy, a total of 267 AML patients aged between 18-60 years were enrolled in a phase II study. In this study, patients were randomized to receive either sorafenib (N= 134) or placebo (N= 133) in addition to a standard treatment protocol consisting of two cycles of induction with DA (daunorubicin 60 mg/m2 on days 3-5 plus cytarabine 100 mg/m2 continuous infusion on days 1-7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 bid on days 1, 3, 5). Patients without response after DA received a second induction therapy with HAM (cytarabine 3 g/m2 bid days 1-3 plus mitoxantrone 10 mg/m2 on days 3-5). Allogeneic stem cell transplantation was scheduled for all intermediate-risk patients in first complete remission with a sibling donor and for all high-risk patients with a matched related or unrelated donor. The primary endpoint of the study was EFS, with an event being defined as either failure to achieve a complete remission (CR) after induction, relapse or death. Secondary objectives included RFS, overall survival (OS), CR rate and the incidence of adverse events.

After three years of follow-up, the median EFS was 9.2 months in the placebo arm and 20.5 months in the sorafenib arm, corresponding to a 3-year EFS rate of 22% vs. 40% (p= 0.013). The median RFS after standard treatment plus placebo was 23 months and was not yet reached in the sorafenib arm. This corresponds to a 3-year RFS of 38% and 56%, respectively (p= 0.017). The median OS had not been reached in either arm and the 3-year OS rates were 56% with placebo as compared to 63% with sorafenib (p= 0.382).

In general, the treatment combination with sorafenib was well tolerated. However, the sorafenib-treated patients did experience higher rates of certain adverse events such as hand-foot syndrome (only in the sorafenib arm, p < 0.001), fever (relative risk [RR] sorafenib/placebo 1.53, p = 0.040), bleeding (RR sorafenib/placebo 3.61, p = 0.008), rash (RR sorafenib/placebo 3.84, p = 0.033) and liver toxicity (RR sorafenib/placebo 3.36, p= 0.038). In summary, the addition of sorafenib to standard chemotherapy in a sequential manner was shown to be feasible in younger AML patients and was associated with a significant prolongation of the EFS and RFS. In addition to validating these results in a larger trial, it will be useful to further evaluate the genetic markers that may predispose some patients to respond better than others to this treatment to fully maximize its potential.


Röllig C, Carsten Müller-Tidow C, Hüttmann A, et al. Sorafenib Versus Placebo in Addition to Standard Therapy in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from 267 Patients Treated in the Randomized Placebo-Controlled SAL-Soraml Trial. Presented at ASH 2014; Abstract #6.

Speaker Christopher Röllig


Christopher Röllig, MD, PhD,
University of Dresden, Dresden, Germany


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