Evaluating Post-Transplant Sorafenib Maintenance in FLT3-Mutated AML

For patients with acute myeloid leukemia (AML) and an FLT3-ITD mutation, maintenance treatment with the multitargeted tyrosine kinase inhibitor (TKI) sorafenib significantly prolonged relapse-free survival (RFS) after allogeneic hematopoietic cell transplantation (HCT), compared with placebo, according to results of the German-Austrian phase II SORMAIN trial published in the Journal of Clinical Oncology.

“Considering that approximately half of the patients with FLT3-ITD–positive AML experience relapse after HCT and eventually die as a result of AML, relapse prevention after HCT represents an unmet clinical need,” wrote lead author Andreas Burchert, MD, from Philipps University of Marburg in Germany, and colleagues. “SORMAIN establishes targeted maintenance therapy as a novel efficacious treatment paradigm with the potential to meaningfully improve outcome after HCT.”

The randomized, placebo-controlled, double-blind phase II SORMAIN trial enrolled adults with FLT3-ITD–positive AML who were in complete hematologic remission (CHR) after HCT, including those in second or subsequent CHR.

A total of 142 patients were screened, and 83 were randomized to receive either sorafenib (n=43) or placebo (n=40). Median age was 54 years, and treatment arms were well balanced in terms of potential prognostic factors, such as cytogenetic risk category and time of transplantation, the authors noted. The median duration of sorafenib treatment was 54.4 weeks, compared with 34.6 weeks in the placebo group.

After a median follow-up of 41.8 months, median RFS was not reached in the sorafenib group and was 30.9 months in the placebo group. Compared with placebo, treatment with sorafenib was associated with a 61% lower risk of relapse or death, the researchers reported. Sorafenib also significantly improved rates of RFS at 24 months (85.0% vs. 53.3%; hazard ratio [HR] = 0.256; p=0.002).

The median overall survival (OS) was not reached in either treatment group, with estimated 24-month OS rates of 90.5% and 66.2% (HR=0.241; p=0.007).

Twenty-five patients experienced disease relapse during study follow-up. Most of these participants received sorafenib (n=18; 72%), while 17 (68%) were treated with chemotherapy, and 6 (24%) underwent second HCT, with no significant differences in the frequency and types of relapse therapies between the two treatment arms.

In an exploratory analysis, the investigators found that the RFS benefit of sorafenib was even greater in patients who achieved undetectable measurable residual disease levels before and after undergoing HCT (p=0.028 and p=0.015).

“SORMAIN establishes targeted maintenance therapy as a novel efficacious [post-HCT] treatment paradigm.”

——Andreas Burchert, MD

Sorafenib was “generally well tolerated,” the researchers wrote. More patients in the sorafenib than the placebo group required dose reductions (48.8% vs.0%) and discontinued treatment due to toxicity (22.0% vs. 5.0%). The most common grade ≥3 adverse events in both treatment arms were graft-versus-host disease (76.8% for sorafenib and 59.8% for placebo), followed by infections (26.2% and 23.1%) and gastrointestinal toxicity (14.3% and 15.4%). Sixteen patients died during study follow-
up; only two of the deaths were deemed unrelated to AML and both occurred in the placebo arm.

Although the trial was terminated early because of inadequate enrollment, the investigators noted that, with more than 4.5 years of median follow-up, SORMAIN provides the first placebo-controlled evidence supporting maintenance therapy’s RFS benefit. The finding that 4 of 10 RFS events occurred after sorafenib treatment ended suggests that longer maintenance duration could further prevent relapse and death.

“Ongoing post-HCT maintenance therapy studies use more FLT3-specific TKIs, such as quizartinib or gilteritinib,” they added. “They could help to better understand to which extent FLT3 selectivity versus immune-stimulatory off-target activities govern the overall efficacy of sorafenib.”

Study authors report relationships with Bayer, the manufacturer of sorafenib.


Burchert A, Bug G, Fritz LV, et al. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3–internal tandem duplication mutation (SORMAIN). J Clin Oncol. 2020;38:2993-3002.