NEW ORLEANS – Adding dasatinib to standard first-line chemotherapy and continuing the KIT inhibitor as maintenance therapy are tolerable in core binding factor acute myeloid leukemia, even for older patients, a phase II study shows.
There were no unexpected toxicities, and clinical outcomes were at least comparable to those historically achieved in this population, Dr. Guido Marcucci said at the annual meeting of the American Society of Hematology.
Core binding factor (CBL) acute myeloid leukemia (AML) has a relatively favorable prognosis, though about 40% of patients will eventually relapse.
Dr. Guido Marcucci
The Cancer and Leukemia Group B (CALGB) 10801 study investigators hypothesized that adding dasatinib (Sprycel) to chemotherapy would improve patient outcomes, because KIT mutations are present in about 25%-30% of CBL AML patients and are associated with a higher frequency of relapse, said Dr. Marcucci, professor of hematology at the Ohio State University, Columbus.
Molecular screening confirmed CBF AML in 69 patients, with 61 starting induction therapy with daunorubicin 60 mg/m2 per day on days 1-3, cytarabine 200 mg/m2 per day on days 1-7, and oral dasatinib 100 mg/day on days 8-21. Patients with residual disease on day 21 underwent reinduction chemotherapy, while those achieving complete remission received consolidation therapy with high-dose cytarabine and dasatinib for four cycles. Patients remaining in remission were maintained on dasatinib at 100 mg/day for 12 months.
The median age in the study was 51 years (range, 20-85 years), 65% were positive for the CBFB-MYH11 gene fusion, and 35% were positive for the RUNX1-RUNX1T1 gene fusion.
After a median follow-up of 14 months, 30-day survival was 97%. The complete remission rate was 89% overall – 91% for patients younger than 60 years, and 80% for those older than 60 years – Dr. Marcucci said.
To date, 20 patients remain on treatment and only 2 have relapsed. Four patients died during induction/consolidation therapy, and four died during follow-up (two after relapse).
Among 58 patients evaluable for toxicity, the most common grade 4 toxicities were sepsis (6 cases), increased alanine aminotransferase (3 cases), and 2 events each of pleural effusion, lung infection, elevated aspartate aminotransferase, hypocalcemia, and dyspnea. Grade 5 toxicities included sepsis in two patients and one respiratory failure. Nine patients discontinued treatment due to adverse events.
"We did not really see any adverse events that have not been seen before with chemotherapy or dasatinib," Dr. Marcucci said.
By 12 months, event-free survival was 85% and overall survival was 89%. So far, no survival difference has been seen between patients with chromosome 21 translocations and those with chromosome 16 inversions; however, younger patients seem to have better outcomes than older patients, he said.
The KIT inhibition strategy makes sense scientifically, but the follow-up is too short to enable investigators to draw conclusions, since the bulk of AML patients will relapse within 2 years, said Dr. Peter D. Emanuel, director of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas, Little Rock.
"At least so far, in early follow-up, it looks like they haven’t done any damage and time will tell if they’ve done good or not," he said in an interview.
Dr. Marcucci concluded that rapid screening for CBF AML is feasible within a cooperative group, noting that patients entered the trial at a median of just 4 days from diagnosis. This may not be feasible, just yet, in clinical practice.
"Most private practice hem/oncs send off the chromosomes from the bone marrow, and you’ll be way into induction chemo by the time you get those results back," Dr. Emanuel observed. "It’s got to be ramped up so it’s in a real-world setting beyond the university setting. I think we’ll get there because there are more and more labs capable of doing this."
The National Cancer Institute sponsored CALGB 10801. Dr. Marcucci reported research funding from Boehringer Ingelheim.