The use of flow cytometry alone to determine measurable residual disease (MRD) status did not sufficiently identify children with acute myeloid leukemia (AML) and Down syndrome (DS) who were eligible for reduced treatment intensity, according to study findings published in Blood.
While high-dose cytarabine (HD-AraC) is used in most treatments for children with AML and DS (ML-DS), previous research has associated HD-AraC with treatment-related morbidity in this patient population.
A team of researchers led by Johann Hitzler, MD, of the University of Toronto in Canada, investigated whether the elimination of HD-AraC was a feasible strategy in 140 patients with ML-DS who had negative MRD following their first treatment course. Multidimensional flow cytometry was used to assess MRD status in these patients.
Patients with a negative MRD status were assigned to the standard-risk group that did not receive HD-AraC (n=114), while those with positive MRD status were assigned to the high-risk group that received HD-AraC (n=26).
Patients were between the ages of 3 months and 4 years. The cohort included patients with AML, myelodysplastic syndromes, or greater than 5% blasts in the peripheral blood or increasing blast count (>5%) in serial bone marrow aspirate.
The two-year overall survival (OS) rate was 91.0%. In addition, the two-year event-free survival (EFS) for patients in the high-risk group treated with HD-AraC was 85.6% compared with 93.5% for patients in the standard-risk group not treated with HD-AraC (p=0.0002).
Twelve relapses occurred in standard-risk patients, including 11 in the bone marrow and one in the central nervous system. Aside from one relapse, all other relapse events occurred within a one-year period from study entry (median time-to-relapse = 208 days). For standard-risk patients, the cumulative two-year incidence of relapse was 10.8% (95% CI 5.9%-17.4%). The one-year OS was 16.7% for standard-risk patients with relapse.
In a post hoc re-analysis of MRD levels in end of induction-1 (EOI-1) bone marrow samples of 12 standard-risk patients who relapsed, the researchers confirmed a negative MRD result (undetectable). A single standard-risk patient had an EOI-1 MRD of 0.03%, and this patient has not yet relapsed.
According to the researchers, HD-AraC represents a crucial treatment component capable of maintaining excellent EFS outcomes "when using solely MRD by flow cytometry for therapy stratification." The authors added that the assessment of MRD via flow cytometry alone did not adequately identify patients who may safely derive benefit from a reduction in the intensity of treatment, calling for improvements to risk stratification.
"We found that the prognostic value of flow cytometric MRD in patients with ML-DS needs to be assessed with caution and that MRD via flow cytometry alone is insufficient to identify patients for whom treatment intensity can be reduced," the researchers added.
Additionally, the researchers concluded that improvements to risk stratification of patients with ML-DS could be made with the incorporation of cytogenetic findings as well as more sensitive MRD methods. In turn, these strategies may also "guide the integration of molecularly-targeted small molecules or immunotherapy into future trials to reduce the number of patients who relapse and to improve overall outcomes."
Reference
Hitzler J, Alonzo T, Gerbing R, et al. High-dose AraC is essential for the treatment of ML-DS independent of post-induction MRD–Results of COG AAML1531 [published online ahead of print, 2021 Jul 30]. Blood. doi: 10.1182/blood.2021012206
