Outcomes of Adding a Fourth Chemotherapy Course in AML

Administering 2 additional courses of chemotherapy with high-dose cytarabine (Ara-C) after 2 courses of induction therapy improved relapse rates but did not improve overall survival for patients with acute myeloid leukemia (AML), according to research in the Journal of Clinical Oncology.¹ 

For patients with AML who are younger than age 60 years, the optimal number of chemotherapy courses has been unclear. Previous studies found that 5 total courses offered no additional benefit over 4 courses of treatment.^2,3 Therefore, a team of investigators conducted an analysis to determine whether 3 or 4 courses of treatment improved patient outcomes for patients with AML. The primary outcome of the study measured overall survival at 5 years, as well as cumulative incidence of relapse and relapse-free survival (RFS). 

The study included 1017 patients who had received 2 courses of induction therapy, were in remission, were aged 60 years or younger, and were not considered high risk. Participants were randomly assigned to receive the third course (n=510; amsacrine, Ara-C, and etoposide) and fourth courses (n=517; mitoxantrone and Ara-C). Results from the MRC AML15 trial led the researchers to amend the protocol to randomly assign patients to either 1 or 2 additional courses of high-dose Ara-C; 885 patients received Ara-C exclusively per the amended protocol.

Compared with patients who received 3 courses, patients who received 4 courses had a reduced cumulative incidence of relapse (50% vs 58%, respectively; P =.02) and improved RFS (43% vs 36%, respectively; P =.03).

The overall survival did not significantly differ between 3 and 4 courses (63% vs 56%, respectively), and noninferiority was not established (P ­=.09). Although measurable residual disease (MRD) is often predictive of relapse, a fourth treatment course did not improve overall survival for MRD-positive or MRD-negative patients.

The investigators noted that some patients with favorable cytogenetics may benefit from 2 additional courses with high-dose Ara-C. Patients without an FLT3 or NPM1 mutations, or patients with less than 3 mutations, may have the greatest survival benefit.

Patients who received 4 courses of therapy had more days in hospital, more days on antibiotics, and needed more blood products compared with patients who were treated with 3 courses; however, patients with 3 total courses, had higher rates of relapse, leading to higher rates of salvage transplants.

“Overall, this experience suggests that if Ara-C is the chosen consolidation treatment, a fourth course of overall treatment is probably beneficial,” the authors noted.

Disclosure: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

References

1. Burnett AK, Russell NH, Hills RK, et al. Defining the optimal total number of chemotherapy courses in younger patients with acute myeloid leukemia: a comparison of three versus four courses. J Clin Oncol. Published online December 23, 2020. doi:10.1200/JCO.20.01170
2. Burnett AK, Hills RK, Milligan DW, et al. Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol. 2010;28(4):586-595. doi: 10.1200/JCO.2009.22.9088
3. Burnett AK, Russell NH, Hills RK, et al. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the Medical Research Council AML15 trial. J Clin Oncol. 2013;31(27):3360-3368. doi: 10.1200/JCO.2012.47.4874