Patients with acute myeloid leukemia (AML) often face limited treatment options, as standard chemotherapy does not result in positive outcomes for all. Recent clinical trials led by Eunice Wang, MD, Chief of Leukemia at Roswell Park Comprehensive Cancer Center, indicate that combining targeted inhibitors with chemotherapy may lead to better results for patients with aggressive forms of the disease.
The findings from two studies will be presented at the 67th annual meeting of the American Society of Hematology (ASH) in Orlando, Florida. This conference attracts over 30,000 professionals globally each year.
A phase 3 clinical trial led by Dr. Wang was conducted in the U.S. and Europe between 2018 and 2024. The trial tested whether adding the FLT3 inhibitor crenolanib to salvage chemotherapy would improve outcomes for patients with relapsed or treatment-resistant AML carrying an FLT3 mutation. Patients who received crenolanib had a higher overall response rate (60% compared to 39%) and lower treatment resistance (24% versus 59%) than those receiving chemotherapy alone. At a median follow-up of just over three years, event-free survival was longer in the crenolanib group (3.4 months versus zero), as was overall survival (10.4 months compared to 8.7 months).
For participants whose AML had both FLT3 and NPM1 mutations, those treated with crenolanib plus chemotherapy saw statistically superior event-free survival (6.1 months versus zero), a higher complete response rate (70% versus 46%), and a trend toward longer overall survival (12.4 months compared to 6.3 months) relative to those on chemotherapy alone.
Dr Wang stated: "This trial validates the importance of testing for FLT3 and NPM1 mutations in patients with relapsed acute myeloid leukemia and adding a targeted oral inhibitor to standard chemotherapy of FLT3 mutant AML to significantly improve clinically meaningful responses and prolong survival."
The study received support from Arog Pharmaceuticals.
In another study presented at ASH, updated results from the KOMET-007 phase 1a/b trial examined adults with relapsed or refractory AML who had either an NPM1 mutation or KMT2A gene rearrangement—genetic abnormalities that account for up to 40% of AML cases. Participants were treated with ziftomenib—a menin inhibitor recently approved by the FDA—combined with low-intensity venetoclax and azacitidine chemotherapy.
Among evaluable patients at about four months' follow-up, those with NPM1-mutant AML had an overall response rate of 65% and a complete response rate of 49%. Patients with KMT2A-rearranged AML had rates of 33% and 22%, respectively. Expected response rates after previous therapy are typically below 20%.
For patients who had not previously received venetoclax treatment, composite complete response rates were even higher: 71% for NPM1-mutation cases and 33% for KMT2A-r cases; overall response rates reached up to 81% in some groups.
Dr Wang commented: "To have 50 percent to 80 percent of patients with relapsed or refractory AML obtain clinical responses following this triple drug therapy, two components of which are oral medications, is remarkable. The results of these and other studies of menin inhibitors being presented at his meeting supports further trials of adding menin inhibitors to standard therapy of all AML patients with these genetic abnormalities to further improve outcomes."
Roswell Park leukemia patients were among the first worldwide treated with ziftomenib through clinical trials supported by the Roswell Park Alliance Foundation.
The KOMET-007 trial was funded by Kura Oncology/Kirin Kyowa.
Both studies highlight how new combinations using targeted therapies may increase treatment effectiveness for certain aggressive subtypes of AML.
