Negative flow cytometric measurable residual disease (MRD) after a single course of induction therapy did not identify a favorable risk group of pediatric patients with myeloid leukemia and Down syndrome (ML-DS) for whom a high-dose cytarabine course (HD-AraC) could be eliminated, according to results of the Children’s Oncology Group (COG) AAML1531 trial (ClinicalTrials.gov Identifier: NCT02521493). Complex cytogenetics were associated with increased risk of relapse in patients who achieved MRD (defined as <0.05% leukemic cells in bone marrow) after the first course of induction therapy and not treated with HD-AraC. The findings were recently published in Blood.
In AAML1531, the investigators used therapeutic risk stratification based on flow cytometric MRD status, which had been previously identified as a prognostic factor at the end of the first course of induction therapy. Patients were classified as standard risk or high risk if they achieved or did not achieve negative MRD, respectively. After induction (thioguanine/cytarabine/daunorubicin [TAD] and AraC), patients in the standard-risk arm did not receive HD AraC but received 2 more courses of TAD followed by 2 identical courses of intensification therapy with cytarabine/etoposide; whereas, those with high risk received mitoxantrone/AraC followed by HD AraC/etoposide then HD AraC and L-asparaginase
The interim analysis (data cutoff: March 31, 2020) included 114 patients with standard risk (median age, 1.68 years; range, 0.66-3.55), with a median follow-up duration of 2.1 years (range, 0.48-3.6). Patients with standard risk had a 2-year event-free survival (EFS) of 85.6% (95% CI, 75.7-95.5), which was significantly lower than the EFS of patients treated with HD-AraC who achieved MRD on AAML0431, a previous COG trial (ClinicalTrials.gov Identifier: NCT00369317; P =.0002).
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The 2-year overall survival (OS) in patients with standard risk was 91.0% (95% CI, 83.8-95.0). A total of 12 patients with standard risk relapsed, usually within 1 year of study entry; these patients had a 1-year OS of 16.7% (95% CI, 2.7-41.3).
Complex karyotypes were more frequent in patients with standard risk who relapsed than in those who did not relapse (36% vs 9%; P =.0248). MRD by error-corrected sequencing of GATA1 mutations was evaluated in 18 patients with standard risk. Among these patients, MRD was detected in 60% of those who relapsed and 23% of those who did not relapse (P =.2682).
“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 authors concluded in their report.
The team suggests the use of cytogenetics and more sensitive MRD methodologies and a better understanding of molecular disease mechanisms are required to improve risk stratification in ML-DS.
Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Reference
Hitzler J, Alonzo T, Gerbing R, et al. High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial. Blood. 2021;138(23):2337-2346. doi:10.1182/blood.2021012206
