Flow-cytometric vs. -morphologic assessment of remission in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group (COG)

Minimal residual disease (MRD) after initial therapy is integral to risk stratification in B-precursor and T-precursor acute lymphoblastic leukemia (B-ALL, T-ALL). Although MRD determines depth of remission, remission remains defined by morphology. We determined the outcomes of children with discordant assessments of remission by morphology vs. flow cytometry using patients age 1-30.99 years enrolled on Children's Oncology Group ALL trials who underwent bone marrow assessment at the end of induction (N = 9350). Morphologic response was assessed locally as M1 (<5% lymphoblasts; remission), M2 (5-25%), or M3 (>25%). MRD was centrally measured by flow cytometry. Overall, 19.8% of patients with M2/M3 morphology had MRD < 5%. M1 with MRD >= 5% was less common in B-ALL (0.9%) than T-ALL (6.9%; p < 0.0001). In B-ALL, M1/MRD >= 5% was associated with superior 5-year event-free survival (EFS) than M2/MRD >= 5% (59.1% +/- 6.5% vs. 39.1% +/- 7.9%; p = 0.009), but was inferior to M1/MRD < 5% (87.1% +/- 0.4%; p < 0.0001). MRD levels were higher in M2/MRD = 5% than M1/MRD >= 5% patients. In T-ALL, EFS was not significantly different between M1/MRD >= 5% and M2/MRD >= 5%. Patients with morphologic remission but MRD >= 5% have outcomes similar to those who fail to achieve morphological remission, and significantly inferior to those with M1 marrows and concordant MRD, suggesting that flow cytometry should augment the definition of remission in ALL.