For older patients with treatment-naïve acute myeloid leukemia (AML), research has suggested that a 10-day treatment schedule of the hypomethylating agent decitabine is associated with better responses than a standard, five-day schedule, but a new phase II study published in Lancet Haematology suggested no difference in the safety and efficacy of each schedule.
“Owing to the short half-life of decitabine in vivo, treatment for 10 days rather than five days might be expected to capture a larger proportion of leukemic cells as they asynchronously enter the S phase,” the authors, led by Nicholas J. Short, MD, from the University of Texas MD Anderson Cancer Center, explained. However, based on these results, either schedule can be considered “a reasonable, nonintensive backbone regimen for future investigational combinations with novel agents.”
In this study, the investigators enrolled 71 patients aged 60 years or older who presented with AML at MD Anderson Cancer Center and whose disease was considered unsuitable for intensive chemotherapy with an anthracycline plus cytarabine. Participants were required to have an Eastern Cooperative Oncology Group performance status score of 0 to 3 and adequate renal and hepatic function.
Study participants were randomly assigned to receive intravenous decitabine on one of two schedules, each of which were administered every four to eight weeks for up to three treatment cycles:
- decitabine 20 mg/m2 for 5 consecutive days over a 1-hour period each day (n=28)
- decitabine 20 mg/m2 for 10 consecutive days over a 1-hour period each day (n=43)
The authors noted that patient characteristics were well balanced between each treatment arm and that substantial portions of patients in each group had features associated with poor outcomes, including high-risk cytogenetics.
After a median follow-up of 5.3 months (interquartile range [IQR] = 2-11 months), there was no difference in the proportion of patients who achieved the composite primary endpoint or complete remission (CR), CR with incomplete platelet recovery (CRp), or CR with incomplete hematologic recovery (CRi) between the treatment groups (43% in the 5-day schedule vs. 40% in the 10-day schedule; p=0.78). Response information is presented in the TABLE. Patients who experienced CR, CRi, or CRp then received consolidation therapy with decitabine 20 mg/m2 for five days for up to 24 cycles.
Achievement of the primary endpoint was not significantly different between the five-day and 10-day decitabine regimens when stratified by any of the following variables:
- cytogenetics (50% vs. 30%, respectively; p=0.39)
- adverse-risk cytogenetics (31% vs. 46%; p=0.37)
- de novo leukemia (47% vs. 36%; p=0.50)
- secondary or therapy-related AML (38% vs. 44%; p=0.74)
- TP53-mutated status (29% vs. 47%; p=0.40)
Among the 29 patients who met the primary endpoint, 19 relapsed (8 in the 5-day group and 11 in the 10-day group), for a one-year rate of relapse-free survival of 21 percent and 27 percent, respectively.
The median duration of overall survival (OS), another secondary endpoint, was also comparable with the two schedules: 5.5 months in the five-day group (IQR=2.1-11.7 months) and 6.0 months in the 10-day group (IQR=1.9-11.7 months). In each group, researchers observed a one-year OS rate of 25 percent.
Each treatment schedule had a similar safety profile, the authors reported. Most of the adverse events (AEs) were grade 1 or 2, and the most common grade 3 and 4 AEs in both groups were neutropenic fever (25% in the 5-day group and 33% in the 10-day group) and infection (18% and 37%). Nine patients died during the study – three in the five-day group (sepsis, n=1; hemorrhage, n=1; infection, n=1) and six in the 10-day group (all from infection).
Overall, early mortality (within 30 days) was similar between each group: 4 percent (n=1/28) with the five-day schedule and 9 percent (n=4/43) with the 10-day schedule.
The authors concluded that a five-day schedule should be the optimum duration of decitabine therapy used in future trials of combination regimens for AML, adding that “these results also have implications for the delivery of cost-effective care, as they suggest that additional doses of decitabine could raise treatment costs without providing additional benefit.”
Limitations of the single-center study include the lack of younger patients enrolled in the trial, as well as the exclusion of patients with relapsed or refractory disease, which may limit the generalizability of the findings. The open-label study design also might introduce bias. The study also was not adequately powered to identify differences in subgroups.
The authors report financial relationships with Pfizer, Janssen, Novartis, Abbvie, Seattle Genetics, and others.
Short NJ, Kantarjian HM, Loghavi S, et al. Treatment with a 5-day versus a 10-day schedule of decitabine in older patients with newly diagnosed acute myeloid leukaemia: a randomised phase 2 trial. Lancet Haematol. 2018 December 10. [Epub ahead of print]