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Background  Refinement of risk-based treatment stratification by minimal residual disease (MRD) at different time points has improved outcomes of childhood acute lymphoblastic leukemia (ALL). In this prospective study we evaluated effects of such stratification, including intensification of therapy based on response assessment at day-15 and MRD at day-29 of induction to test if treatment intensification would improve outcomes.    Methods  241 patients, 1–14 years old, newly diagnosed with ALL, were recruited and stratified by risk and MRD response into three treatment Arms (A, B, or C). Arm A was modified from COG AALL0331, B from AALL0232, and C from AALL0232 and AALL0434. Assignments were according to NCI risk, phenotype, rapid vs. slow early response (SER), steroid pretreatment, MLL rearrangement ( MLLR ), CNS3, and testicular involvement. Patients on Arm A had treatment intensified early based on day-15 marrow results or late based on end-of-induction MRD.    Results  5-year OS, EFS, and CIR were 89.5% ± 4.0%, 87.6% ± 4.3%, and 7.1% ± 3.5%. No significant difference was found by B- vs. T cell phenotype. 5-year OS, EFS, and CIR for B-cell ALL were 90.5% ± 2.4%, 88.7% ± 2.6%, and 6.4% ± 2.0%. Outcomes for patients with  t (1;19)/ TCF3 - PBX1  and  MLLR  were significantly (p ≤ 0.05) worse than for other patients. MRD level at end-of-induction associated with outcomes, but association with a specific MRD value at end-of-induction varied significantly by NCI-risk group. Late treatment intensification based on end-of-induction MRD significantly improved survival outcomes for NCI-SR patients, however, patients with NCI-HR and positive MRD at end-of-induction had significantly inferior outcomes despite intensification. MRD transitions between day-15 and day-29 of induction associated with differences for OS and EFS.    Conclusions  Arm switching to a more intensive protocol had mixed results. Assigning patients by end-of-induction MRD-risk alone did not reflect response kinetics of the different NCI-risk groups. Although late treatment intensification improved outcomes of NCI-SR patients with positive MRD at end-of-induction, further refinement is needed to improve outcomes of NCI-HR with SER. Integration of NCI-risk group with specific MRD value and time point allows more refined treatment stratification.   Trial Registration  Protocols were approved by King Abdullah International Medical Research Center and Ethics Review Committee RC08053J

experimental hematology and oncology

Early vs. late MRD response- and risk-based treatment intensification of childhood acute lymphoblastic leukemia: a prospective pilot study from Saudi Arabia