乌鸦传媒

ORLANDO -- A drug once thought to be ineffective in acute myeloid leukemia (AML) might make a comeback as an agent targeted at a subset of patients, a researcher said here.

In an international phase III randomized trial involving patients with a specific AML mutation, midostaurin combined with standard chemotherapy strikingly outperformed chemotherapy alone, said , of the Dana-Farber Cancer Institute in Boston.

The 5-year survival rate for patients taking the drug was 50.9% compared with 43.9% for those on standard chemotherapy alone -- a 23% improvement -- and a similar benefit was seen for event-free survival (EFS), Stone said during a press conference at the American Society of Hematology (ASH) meeting.

If the drug is approved, it will be the first new medication in several years in AML, commented of the University of Florida in Gainesville, who was not involved in the study but who moderated the ASH press conference.

"There have been very few drugs for AML since I trained 30 years ago," he told 乌鸦传媒. "It's very exciting."

He noted that early studies of the drugs, treating all comers, seemed to show it was ineffective in AML, but that was because, as a kinase inhibitor, it works best against the mutated FLT3 kinase, which drives some forms of the disease but not others.

Hromas likened the mutated FLT3 to a "gas pedal" that drives cells to divide. "It makes the engine go faster for (FLT3) AML but other AMLs have other drivers," he said.

The mutated FLT3 mutation is only found in about 35% of AML patients, but their prognosis is very poor, Hromas said. "It's a population that has done very poorly -- they suffer and they die," he said.

The only treatment option has been an allogeneic stem cell transplant, he added.

The trial, dubbed RATIFY, took a decade to organize and run, Stone said, partly because FLT3 patients are a minority of those newly diagnosed with AML and partly because of the challenges of setting up and running a trial in 17 countries.

Starting in May 2008, organizers screened 3,279 patients, ages 18 through 60, and had found 887 with the FLT3 mutation when patient accrual ended in October 2011.

Of those, 717 were randomized to get induction therapy with midostaurin or placebo, in combination with daunorubicin (Cerubidine) and cytarabine (Depocyt), followed by high-dose cytarabine plus or minus midostaurin in consolidation therapy.

Patients with a complete response after consolidation had a year of maintenance therapy with either midostaurin or placebo, Stone reported. All patients are now off treatment and the median follow-up for surviving patients is 57 months.

The primary endpoint was overall survival, but the investigators also looked at a range of secondary endpoints including complete response rates, EFS, and adverse events.

The key finding was that the midostaurin treatment extended life. The hazard ratio for death was 0.77, favoring midostaurin, and was significant (P=0.0076).

Also, median survival in the midostaurin arm was 74.7 months compared with 25.6 months in the placebo arm.

The rate of complete responses after consolidation was similar between the arms at 59% for midostaurin and 54% for placebo.

On the other hand, EFS -- defined as no complete response within 61 days or relapse or death from any cause -- favored midostaurin (HR 0.79, P=0.0032).

The investigators reported they saw no statistically significant differences in the overall rate of grade three or higher hematologic or nonhematologic adverse events between midostaurin and placebo.

All told, there were 37 grade five adverse events with no significant differences between the arms, they found.

"The RATIFY study...reflects our relentless pursuit to develop targeted therapies that can improve and extend people's lives," said , of midostaurin developer Novartis Oncology, in a press release. "Based on the results of this trial, we plan to move forward with global regulatory submissions for [midostaurin] in the first half of 2016."

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