Investigators from the phase III US Intergroup SWOG-led S1203 trial reported that remission induction with 7+3 chemotherapy (cytarabine plus daunorubicin) should remain the standard of care for younger patients with acute myeloid leukemia (AML). In addition, the researchers were able to increase the proportion of patients with high risk acute myeloid leukemia (AML) who proceeded to allogeneic hematopoietic cell transplantation (alloHCT) in first remission, which may significantly increase the likelihood of relapse-free survival (RFS).
7+3 Still Standard of Care
In the first analysis, Guillermo Garcia-Manero, MD, from the University of Texas MD Anderson Cancer Center in Houston, and cooperative group clinical investigators evaluated whether adding the histone deacetylase (HDAC) inhibitor vorinostat to a regimen of idarubicin and high-dose cytarabine, or using high-dose cytarabine during induction instead of standard-dose cytarabine, could improve event-free survival (EFS; the study’s primary endpoint) over standard 7+3.1
“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,” Dr. Garcia-Manero 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 who had preserved cardiac function and no severe comorbidities. Participants’ median age was 49 years (range = 18-60 years), and most (75%) were between 40 and 60 years of age.
Patients were randomly assigned to one of three treatment arms: 7+3 (n=261), idarubicin and high-dose cytarabine (IA; n=261), or 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. Among patients with known mutations, the most common 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 consolidation with 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 during induction, followed by consolidation with 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
Contrary to what investigators hypothesized, neither IA nor IA+V was superior to 7+3 on all survival endpoints, including EFS, RFS, and overall survival (OS). “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.”
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).
There were no differences in outcomes 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, though there was a slightly higher rate of AEs in the vorinostat-treated group, which Dr. Garcia-Manero noted “was to be expected,” given its known toxicities.
“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.
Earlier AlloHCT Should Be a New Standard
As a secondary aim of the SWOG S1203 trial, researchers sought to transplant all cytogenetically determined high-risk patients during first CR (CR1), to determine if proceeding to transplant before a relapse could improve patients’ survival.2
“Although prior studies suggest a better outcome in high-risk AML patients in CR1 who undergo alloHCT, compared with consolidation chemotherapy, only 40 percent of such patients actually proceed to transplant,” lead author John M. Pagel, MD, PhD, of the Swedish Medical Center in Seattle, Washington, said during his presentation of the results. “This study showed we can get significantly more high-risk AML patients to a stem cell transplant before their cancer recurs by simply working hard to identify an appropriate donor and proceeding to transplantation as soon as possible. … This process may establish a new standard of care.”
Using the same SWOG S1203 population analyzed in the study by Dr. Garcia-Manero and colleagues, Dr. Pagel and researchers conducted expedited human leukocyte antigen-typing in the 159 patients with high-risk cytogenetics (22% of the total population). Patients were also encouraged to be referred for consultation with a transplant team with the goal of conducting an alloHCT during CR1.
Overall, 107 high-risk patients achieved CR/CR with incomplete blood count recovery (CRi) (67%). AlloHCT was performed in 43 percent of the entire SWOG S1203 population, and 68 (64%) of the high-risk patients (significantly higher than the historical rate of 40%; p<0.001). Of the high-risk population:
- 25 patients had a matched related donor (37%)
- 31 had a matched unrelated donor (45%)
- 3 had a mismatched related donor (4%)
- 8 had a mismatched unrelated donor (12%)
- 1 received an umbilical cord blood transplant (1%)
Of the 66 high-risk patients transplanted in CR/CRi with detailed data available, the median time to alloHCT from CR1 was 76 days (range = 20-365 days). Fifty-seven patients (86%) received a myeloablative regimen and nine (14%) received reduced-intensity conditioning. The reasons for not proceeding to alloHCT were varied: Relapse (n=6), death (n=6), physician decision (n=3), patient decision (n=3), co-morbidities (n=1), no insurance (n=1), no donor (n=1), other (n=10), or unknown (n=8).
AlloHCT during CR1 appeared to increase the median OS by 6 months, compared with high-risk patients who did not receive alloHCT: 18 (range = 3-33 months) versus. 12 months (range = 3-33 months).
The 2-year RFS estimate in the entire high-risk cohort is 32 percent, which the authors found was significantly higher than the 22 percent historical rate (p=0.05). Median RFS in the high-risk CR1 cohort (n=107) was 10 months (range = 1-32 months), and 1-year estimates of RFS and OS were similar regardless of type of donor (matched related = 40% and 56%, respectively; matched unrelated = 52% and 56%, respectively).
“Cytogenetic testing with an organized effort to identify a suitable donor led to a high CR1 transplant rate, which in turn led to a significant improvement in RFS over historical controls,” the authors concluded. “Better outcomes in poor prognosis AML patients may be achieved simply by rapidly finding unrelated donors and performing alloHCT in CR1 as soon as possible.”
- 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, California.
- Pagel JM, Othus M, Garcia-Manero G, et al. Feasibility of allogeneic hematopoietic cell transplantation among high-risk AML patients in first complete remission: results of the transplant objective from the SWOG (S1203) randomized phase III study of induction therapy using standard 7+3 therapy or idarubicin with high-dose cytarabine (IA) versus IA plus vorinostat. Abstract #1166. Presented at the 2016 ASH Annual Meeting, December 5, 2016; San Diego, California.