Remission induction with 7+3 chemotherapy (cytarabine + daunorubicin) should remain the standard of care for younger patients with acute myeloid leukemia (AML), according to results from the phase III SWOG S1203 trial, which evaluated whether adding the histone deacetylase (HDAC) inhibitor vorinostat to a regimen of idarubicin and high-dose cytarabine, or whether idarubicin and high-dose cytarabine alone, could improve event-free survival (EFS; the study's primary endpoint) over 7+3 alone.
"A phase II study of vorinostat plus idarubicin and HDAC induction demonstrated an overall response rate of 85 percent and a 4 percent induction mortality rate," lead author Guillermo Garcia-Manero, MD, from the University of Texas MD Anderson Cancer Center in Houston, said during his presentation of the results. "We hypothesized that the addition of vorinostat to idarubicin plus HDAC is superior to 7+3 in younger patients with AML."
The SWOG S1203 trial enrolled 738 patients with previously untreated AML (age range = 15-60 years) who had preserved cardiac function and no severe comorbidities. Patients with known core-binding factor leukemia or FLT3-mutated leukemia were eligible for inclusion if no other alternative clinical trials existed. Participants' median age was 49 years (range = 18-60), and most patients (75%) were between 40 and 60 years. Patients had median white blood cell and platelet counts of 10.8 (range = 0.3-800) and 4 (range = 3-9,300), respectively. Marrow blast percentage was 60 percent.
Patients were randomly assigned to one of three treatment arms: 7+3 (n=261), idarubicin and high-dose cytarabine (IA; n=261), and IA plus vorinostat (IA+V; n=216).
Most patients had intermediate-risk cytogenetics (63%), while 13 percent had favorable cytogenetics and 22 percent had high-risk cytogenetics. The most common mutation among patients with known mutations was FLT3 (21%), followed by NPM1 (20%).
Induction and consolidation treatment in each arm consisted of:
- 7+3 arm: daunorubicin 90 mg/m2 once daily on days 1-3 plus cytarabine 100 mg/m2 continuous infusion on days 1-7, followed by cytarabine 3 g/m2 every 12 hours on days 1, 3, and 5
- IA arm: idarubicin 12 mg/m2 once daily on days 1-3 plus cytarabine 1.5 g/m2 continuous infusion on days 4-7, followed by idarubicin 8 mg/m2 once daily on days 4-5 plus cytarabine 0.75 g/m2 continuous infusion on days 4-6
- IA+V arm: IA plus vorinostat 500 mg thrice daily on days 1-3 of induction and consolidation
The number of consolidation cycles each patient received depended on transplant indication, Dr. Garcia-Manero explained, because a secondary aim of the study was to transplant all cytogenetically determined high-risk patients (results from this analysis were presented in a separate study).
Contrary to what investigators hypothesized, neither IA nor IA+V was superior to 7+3 on all survival endpoints, including EFS, relapse-free survival, and overall survival.
"The arms were all neutral," Dr. Garcia-Manero reported. "There was no evidence of superiority in the high-dose induction group or the high-dose induction plus vorinostat group." Outcomes with either of the idarubicin arms were similar, the authors noted.
Rates of complete remission (CR) also were similar among all three treatment arms: 75 percent for 7+3, 79 percent for IA, and 77 percent for IA+V (p=0.58).
In a comparison of outcomes among different cytogenetic and molecular groups, the authors found no differences in outcome for any standard-risk group; however, in patients with favorable cytogenetics, outcomes were significantly better with 7+3 than with IA or IA+V), which the authors suggest is related to the use of lower doses of cytarabine during post-remission therapy.
The rates of adverse events (AEs) were similar among all treatment arms, as well, though there was a slightly higher rate of AEs in the vorinostat-treated group, which Dr. Garcia-Manero noted "was to be expected," given the known toxicities of this class of drugs. The most common grade ≥3 AEs were blood/lymphatic, gastrointestinal, and infections, and rates of grade 5 AEs in the 7+3, IA, and IA+V arms were 4 percent, 8 percent, and 9 percent, respectively (p=0.07).
"The good news is that the response rates and the survival rates [in the IA and IA+V arms] were acceptable, but we were not able to demonstrate superiority of these approaches to 7+3," he concluded. "For now, based on this study, a 7+3 approach is still the standard of care for patients with AML."
Future studies, he added, should compare the 7+3 regimen with combination treatments that include nucleoside analogues, monoclonal antibodies, or targeted agents.
Reference
Garcia-Manero G, Othus M, Pagel JM, et al. SWOG S1203: a randomized phase III study of standard cytarabine plus daunorubicin (7+3) therapy versus idarubicin with high dose cytarabine (IA) with or without vorinostat (IA+V) in younger patients with previously untreated acute myeloid leukemia (AML). Abstract #901. Presented at the 2016 ASH Annual Meeting, December 5, 2016; San Diego, CA.