Optimal Number of Treatment Courses Explored in Younger Patients with AML

A study of the optimal number of treatment courses of high-dose daunorubicin and cytarabine (Ara-C) for younger patients with acute myeloid leukemia (AML) published in the Journal of Clinical Oncology revealed that although a fourth course reduced cumulative incidence of relapse (CIR) and improved relapse-free survival (RFS), it did not result in a significant overall survival (OS) benefit.¹

However, even with this knowledge, the investigators suggested that if Ara-C is the selected consolidation treatment, a fourth course of overall treatment would likely be beneficial.

“In general, patients with more favorable characteristics appear to benefit from a fourth course, but only when high-dose Ara-C consolidation is used, whereas those with intermediate-risk characteristics do not, although these were only trends for benefit,” explained the study authors, who were led by Alan K. Burnett, MD.

The United Kingdom National Cancer Research Institute AML17 trial (ISRCTN55675535) randomly assigned patients who were not considered high risk to a total of either 3 or 4 courses of Ara-C. Patients included in the study received 2 induction courses of Ara-C, usually with gemtuzumab ozogamicin (Mylotarg). Following remission, a total of 1017 patients were randomly assigned to a third course of amsacrine, etoposide, and Ara-C—also known as the MACE regimen—plus a fourth course of mitoxantrone and Ara-C, or MidAc. Following the reporting of clinical trial results showing comparable outcomes between MACE/MidAc and Ara-C, the protocol was amended so that patients would receive 1 or 2 courses of Ara-C after consolidation.²

The coprimary end points of the study were CIR, RFS, and OS. The outcomes were then correlated with patient characteristics, mutations, cytogenetics, induction treatments, and measurable residual disease (MRD) postinduction.

At 5 years, rates of CIR (50% vs 58%; HR, 0.81; 95% CI, 0.69-0.97; P = .02) and RFS (43% vs 36%; HR, 0.83; 95% CI, 0.71-0.98; P = .03) were improved in recipients of 4 compared with 3 courses, respectively, by logrank analyses. Moreover, though OS was not found to have improved significantly, at 63% with 4 course and 57% with 3 courses (HR, 0.84; 95% CI, 0.69-1.03; P = .09), the noninferiority of 3 courses to 4 courses was not established.

Regarding relapse, the benefit of a fourth course on relapse was significant only when the fourth course was Ara-C (HR, 0.81; 95% CI, 0.68-0.98). Further, the effect size was comparable but not significant when MidAC was the fourth course (HR, 0.82; 95% CI, 0.49-1.38).

In exploratory analyses, though MRD had an impact on survival, a fourth course did not have an effect in patients who were MRD positive (HR, 0.89; 95% CI, 0.60-1.29) or MRD negative (HR, 0.77; 95% CI, 0.45-1.31) after the first course of induction. Corresponding effects were observed in the MRD-positive (HR, 1.02; 95% CI, 0.62-1.68) and MRD-negative (HR, 0.78; 95% CI, 0.50-1.24) groups after the second course of induction.

However, a fourth course of treatment was found to be beneficial in patients who lacked a mutation of FLT3 or NPM1, had less than 3 mutations in other genes, or had a presenting white blood cell count of less than 10 × 10⁹/L^-1.

“It could be speculated that the most useful interaction will eventually be the initial discrimination based on the MRD status after the first or second induction course, where there may be little benefit in a fourth course for those who are MRD positive, but benefit for those who are negative, or vice versa,” the authors wrote.

Of note, patients who received 2 courses of FLAG-Ida (fludarabine, Ara-C, granulocyte colony-stimulating factor, and idarubicin) as induction without consolidation in a retrospective analysis in the AML15 trial experienced survival results similar to that observed in control patients who received 2 induction courses of DA (daunorubicin and Ara-C) treatment followed by 2 courses of consolidation. However, these were nonrandomized data and are currently being tested in the ongoing AML19 trial (ISRCTN78449203).

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, 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):3360-8. doi: 10.1200/JCO.2012.47.4874