Sorafenib Plus Standard Chemotherapy Associated with Improved Event-Free Survival in Acute Myeloid Leukemia, But Also Toxicity

Adding the multi-kinase inhibitor sorafenib to standard chemotherapy increased event-free survival (EFS) among patients with newly diagnosed acute myeloid leukemia (AML), according to results of a recent randomized, double-blind, placebo-controlled, phase II study conducted by Christoph Röllig, MD, of the Dresden University of Technology in Germany, and colleagues. However, its use was also associated with increased toxicity.

“When this trial began in 2009, standard treatment for AML consisted of a combination of cytarabine plus anthracyclin/anthracenedione. The need for improvement was obvious, with only around 50 percent of patients surviving – even among younger patients,” Dr. Röllig told ASH Clinical News. “To our knowledge, this is the first randomized, controlled trial showing that integrating a kinase inhibitor into standard intensive chemotherapy of younger patients with AML is associated with significant improvement of relapse-free survival, with no increase in treatment-related mortality.”

The trial included 267 patients (age range = 18-60 years) with newly diagnosed de novo or secondary acute AML who were enrolled at 25 sites across Germany between March 27, 2009, and November 28, 2011.

Forty-six (17%) of the patients were positive for FLT3 mutations and 86 (32%) had NPM1 mutations.

Patients were randomized 1:1 to receive standard chemotherapy plus either sorafenib 400 mg twice daily (n=134) or placebo (n=133). Standard chemotherapy consisted of two cycles of induction therapy (daunorubicin 60 mg/m2 on days 3-5 plus cytarabine 100 mg/m2 on days 1-7), followed by three cycles of post-remission therapy (high-dose cytarabine 3 mg/m2 twice daily on days 1, 3, and 5). “Prognostic factors such as age, white blood cell count, and lactate dehydrogenase concentration at initial diagnosis, de novo AML, and cytogenetic and molecular risk factors were similar between both groups,” the authors noted.

After a median follow-up of 36 months, 137 events (primary treatment failure, relapse, or death) had occurred, with an overall median EFS of 13.5 months (95% CI 9-18). Treatment with sorafenib led to greater median EFS than placebo: 21 months in the sorafenib group (95% CI 9-32) compared with nine months in the placebo group (95% CI 4-15). The three-year EFS rate was similarly higher among sorafenib-treated patients: 40 percent (95% CI 29-51) versus 22 percent (95% CI 13-32), for a hazard ratio (HR) of 0.65 (95% CI 0.45-0.91; p=0.013; FIGURE).

The benefits of sorafenib were sustained even after adjusting for established prognostic factors (including lactate dehydrogenase concentration, white blood cell count, and secondary acute myeloid leukemia), with an adjusted HR for EFS of 0.64 (95% CI 0.41-0.99; p=0.0434). “A favorable cytogenetic profile and NPM1 mutation were associated with better event-free survival,” the authors wrote, “whereas FLT3 internal tandem duplication status remained a negative prognostic factor.”

In an explorative analysis, Dr. Röllig and colleagues analyzed the 46 patients with FLT3 mutations, finding no clear pattern for median EFS (5 months [95% CI 0-12] in the sorafenib group and 6 months [95% CI 1-11] in the placebo group), these patients did experience longer relapse-free survival and overall survival with sorafenib:

  • Relapse-free survival: 18 months (95% CI 0-36) with sorafenib versus 6 months (95% CI 0-16) with placebo
  • Overall survival: not reached with sorafenib versus 19 months (95% CI 0-39) with placebo

However, these differences were not statistically significant. “If patients with FLT3 internal tandem duplication mutations were excluded from the study population,” the authors noted, “the increases in event-free survival and relapse-free survival in the sorafenib group remained significant.”

The rates of complete remission (CR) were similar between both groups: 81 (60%) patients in the sorafenib group and 78 (59%) patients in the placebo group. Median relapse-free survival among patients who achieved CR was 32 months, with 47 percent (95% CI 39-56) of patients remaining relapse-free at three years (56% in the sorafenib group, 38% in the placebo group).

The most common treatment-related grade 3 or 4 adverse events included fever, infections, pneumonia, and pain, with grade ≥3 treatment-related adverse events occurring more frequently in the sorafenib cohort.

Fifty-eight adverse events led to withdrawal from study treatment (40 in the sorafenib group and 18 in the placebo group). Adverse events most commonly associated with study withdrawal were:

  • Infections (13 [31%] with sorafenib vs. 7 [37%] with placebo)
  • Skin toxicity (10 [24%] vs. 2 [11%])
  • Hematologic toxicity (4 [10%] vs. 2 [11%])
  • Gastrointestinal toxicity (5 [12%] vs. 1 [5%])
  • Cardiac events (2 [5%] vs. 2 [11%])
  • Pain (4 [10%] vs. 0)
  • Bleeding (1 [2%] vs. 2 [11%])
  • Liver toxicity (1 [2%] vs. 1 [5%])
  • Hypertension (0 vs. 1 [5%])

After accounting for prognostic factors, the HR for relapse or death favored sorafenib over placebo at 0.48 (95% CI 0.27-0.85; p=0.011). And, after three years of follow-up, 63 percent (95% CI 54-72) of patients in the sorafenib group and 56 percent (95% CI 47-65) of patients in placebo group were alive. Three treatment-related deaths were reported in the placebo group (two cases of pneumonia and one case of toxic liver failure) and four were reported in the sorafenib group (two cases of pneumonia and two other infections).

No patients died within two weeks of the first induction cycle, with similar 30-day and 60-day mortality rates between the sorafenib and placebo groups: 2 percent versus 1 percent and 4 percent versus 4 percent, respectively.

“Since early mortality, the proportion of patients who achieved complete remission, and the number of deaths in complete remission were similar in both treatment groups, the longer event-free survival in the sorafenib group is mainly attributable to a reduction in relapses and an increase in the time in complete remission,” the researchers noted. “As there was no improvement in overall survival in the sorafenib group compared with the placebo group, it is unclear whether salvage treatment was equally potent in patients relapsing after placebo or sorafenib treatment.”

“Longer follow-up of this trial and results of other ongoing studies are needed to establish whether the benefit in relapse-free survival translates into improved overall survival,” Dr. Röllig told ASH Clinical News.


Röllig C, Serve H, Huttmann A, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015 November 5. [Epub ahead of print]

FIGURE. Event-Free Survival (A), Relapse-Free Survival (B), and Overall Survival (C)