Sorafenib Maintenance May Prevent Recurrence After Transplant in FLT3-ITD+ AML

The risk of relapse or death was reduced by 61% with sorafenib maintenance compared with placebo following allogeneic hematopoietic stem cell transplantation in patients with FLT3-ITD–positive acute myeloid leukemia.

The risk of relapse or death was reduced by 61% with the use of sorafenib (Nexavar) maintenance therapy compared with placebo following allogeneic hematopoietic stem cell transplantation (HSCT) in patients with FLT3-ITD–positive acute myeloid leukemia (AML), according to the results of the phase 2 SORMAIN trial recently published in the Journal of Clinical Oncology.

“SORMAIN provides evidence that an inhibition of FLT3 and potentially additional kinases through sorafenib significantly reduces the risk of relapse and death after allogeneic hematopoietic stem cell transplantation for FLT3-ITD–positive AML. Molecularly detectable minimal residual disease (MRD) level prior and post-transplantation could be important predictors of relapse risk,” the study authors, led by Andreas Burchert, MD, of the University of Marburg in Germany, explained in their published report. “A 2-year sorafenib maintenance therapy should be considered as a new treatment standard for [patients with] FLT3-ITD–positive AML in complete remission (CR) after allogeneic hematopoietic stem cell transplantation.”

The multicenter, randomized, double-blind, placebo-controlled SORMAIN trial sought to investigate if sorafenib monotherapy could inhibit FLT3-ITD–positive AML recurrence following HSCT. Adult patients with FLT3-ITD–positive AML who were in CHR (CHR) following HSCT were eligible for enrollment in the study. Treatment with FLT3-targeted therapies prior to enrollment in the study was allowed, with the exception of sorafenib.

Patients were randomized 1:1 to receive either sorafenib (n = 43) or placebo (n = 40) administered between 60 and 100 days after HSCT. Treatment started at 2 tablets of 200 mg sorafenib daily for 2 weeks and was then escalated to 600 mg per day for 4 weeks followed by a total of 800 mg per day, which was given continuously for up to 24 months or until relapse or unacceptable toxicity.

The primary end point was relapse-free survival (RFS) and secondary end points included overall survival (OS), FLT3-ITD ratio, NPM1 mutational status, graft-versus-host disease (GVHD) incidence, and safety.

An independent Data and Safety Monitoring Committee and the Trial Steering Committee decided to end trial recruitment early due to inadequate and slow patient recruitment.

Of the 83 patients in the intention-to-treat (ITT) population, baseline characteristics were well balanced between the 2 treatment arms. The median age in both groups was 54 years (range, 18.58-75.58) and about half of the patients (50.6%) were female. The majority of patients had an ECOG performance status of 1 (61.4%), intermediate cytogenetic risk (91.56%), no detectable FLT3-ITD at baseline (81.93%), and no detectable NPM1 (59.62%). Additionally, while the majority of patients were in their first remission (71.08%), the remainder of patients were in their second or subsequent remission and were considered high risk.

Prior to HSCT, the majority of patients had received 2 or more cycles of intensive chemotherapy, with 14.46% having received more than 3 cycles. Most patients were in CHR at the time of transplant without a molecular CR (55.42%), but 25.3% had a molecular CR, and 19.28% had no CHR. About half of the patients (55.42%) required reduced intensity conditioning therapy prior to transplantation.

The median duration of treatment was 34.57 weeks in the sorafenib arm (range, 1.29-106.86) and 54.36 weeks in the placebo arm (range, 1.71-128.29). Patients discontinued treatment most frequently due to adverse events (AEs) in the sorafenib group (20.93%) and due to relapse in the placebo group (42.50%).

After a median follow-up of 41.8 months (range, 24.1-42.5), the median RFS was not reached in the sorafenib arm compared with 30.9 months in the placebo arm (HR, 0.39; 95% CI, 0.18-0.85; log-rank P = .013). At 2 years, the estimated RFS rate was 85.0% (95% CI, 70%-93%) with sorafenib treatment compared with 53.3% (95% CI, 36%-68%) with placebo (HR, 0.256; 95% CI, 0.10-0.65; log-rank P = .002).

Deaths due to relapse occurred at a higher rate in the placebo arm compared with the sorafenib maintenance arm (14 vs 4 patients, respectively; P = .01).

The median OS was not reached in either arm after a median follow-up duration of 55.1 months, but the hazard ratio favored the sorafenib arm (HR, 0.52; 95% CI, 0.24-1.11; log-rank P = .086). At 24 months, the estimated OS rate was 90.5% (95% CI, 77%-96%) with sorafenib treatment and 66.2% (95% CI, 49%-79%) with placebo treatment (HR, 0.241; 95% CI, 0.08-0.74; log-rank P = .007).

“In spite of recruiting fewer patients than intended and the phase 2 design, to our knowledge, SORMAIN—with its more than 4.5 years of median follow-up—provides the first placebo-controlled evidence that post-[HSCT] maintenance therapy can reduce the risk of relapse and death,” Burchert et al wrote.

According to an analysis of minimal residual disease (MRD) levels, patients with no detectable MRD before HSCT derived more benefit from sorafenib than from placebo (P = .028) and patients with positive MRD had more benefit from sorafenib than placebo after HSCT (P = .015). 

Twenty-five patients relapsed and received subsequent treatment of sorafenib in 72%, chemotherapy in 68%, and second HSCT in 24%.

The multikinase inhibitor was considered to be well tolerated. Dose reductions were required in 48.8% of patients, but only 22.0% of patients discontinued sorafenib due to toxicity.

The most common AEs reported in the sorafenib arm were acute and/or chronic GVHD (76.8%); the most common grade ≥3 AEs included infections (26.2%), gastrointestinal toxicity (14.3%), electrolyte alterations (14.3%), and skin toxicity (11.9%). No deaths occurred during the treatment period in the sorafenib arm that were due to AML.

“SORMAIN establishes targeted maintenance therapy as a novel efficacious treatment paradigm with the potential to meaningfully improve outcome after HCT,” the study authors concluded. “Ongoing post-HCT maintenance therapy studies use more FLT3-specific TKIs, such as quizartinib or gilteritinib. They could help to better understand to which extent FLT3 selectivity versus immune-stimulatory off-target activities govern the overall efficacy 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. Published online July 16, 2020. doi:10.1200/JCO.19.03345