Sorafenib As Maintenance Therapy Post Allogeneic Stem Cell Transplantation for FLT3-ITD Positive AML: Results from the Randomized, Double-Blind, Placebo-Controlled Multicentre Sormain Trial

Introduction: Most patients with FLT3-ITD-positive AML, who relapse after allogenic stem cell transplantation (allo-SCT) die from their disease. Whether prophylactic FLT3-ITD inhibition with sorafenib can prevent AML relapse and improve outcome of patients in complete hematological remission (CHR) after allo-SCT is unknown and was tested in the SORMAIN trial.

Methods: This randomized, double blind, placebo-controlled study was done at 14 centers in Germany and Austria. Patients with FLT3-ITD+ AML, aged 18 years or older, who had undergone allogenic stem cell transplantation from a HLA-matched sibling donor, 10/10 or 9/10 HLA-matched unrelated donor, and who were in confirmed CHR at the time of screening between day +30 and day +100 post allo-SCT, were included. Patients were randomly assigned (1:1) to receive either sorafenib (starting dose: 2 x 1 tbl. [2 x 200mg] qd, increasing every 14d to up to 2 x 2 tbl. [2 x 400mg] qd according to tolerability) or placebo (2 x 1 or 2 tbl. qd) for up to 24 months. Randomization was done centrally. In case of drug related adverse events, study medication could be interrupted, stepwise reduced to a minimum of 2 x 1 tbl. qd, temporarily withheld and recommenced at a lower dose level. FLT3-ITD diagnostics was done centrally at baseline and at time of relapse. In relapsing patients, off-label compassionate use of sorafenib was possible. The primary endpoint was relapse-free survival (RFS) as defined by either hematological relapse or death from any cause. The secondary endpoint was overall survival (OS). We here report the final RFS analysis. The OS results will be unblinded only prior to the ASH meeting and will be reported there. The SORMAIN study was terminated prior to full recruitment because of slow accrual. SORMAIN was registered with the European Clinical Trials Database (EudraCT 2010-018539-16) and the German Clinical Trials Register (DRKS00000591).

Results: Between October 29, 2010, and May 17, 2016, 83 patients (41 males, 42 females) were randomized and included in the primary analysis (placebo, n=40; sorafenib, n=43). Median age was 54 years (IQR 47.75 - 61.33) for the entire study population and not significantly different between sorafenib and placebo groups. With a median follow up of 41.8 months after randomization (IQR 24.1 - 42.5), median RFS was 30.9 months (lower bound of 95% CI 5.2 months) in the placebo group versus not reached in the sorafenib group, corresponding to a 2-year RFS of 53,3 % (95% CI 36.5-67.5) in the placebo versus 85.0 % (69.5-93.0) in the sorafenib group (hazard ratio [HR] 0.39, 95% CI; 0.18 -0.85; P=0.0135) (Fig. 1). Overall, sorafenib was well tolerated. The most common grade 3-4 adverse event in both groups was acute GvHD (seven [ 17.5%] in the placebo group vs. nine [20.9%] in the sorafenib group.

Conclusion: Sorafenib maintenance therapy after allo-SCT is feasible and significantly reduces the risk of relapse or death in patients with FLT3-ITD positive AML. OS results will be presented at the meeting.

Figure 1.

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Figure 1.

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