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To investigate monitoring minimal residual disease (MRD) using cerebral spinal fluid for predicting central nervous system leukemia (CNSL) and treatment.There is no survival difference between enhanced triple intrathecal therapy (ETIT) and cranial radiation for CNSL patients with positive morphology and MRD. Positive MRD correlated with CNSL, whereas negative MRD indicated a lower chance of CNSL recurrence. Altogether 79 cerebral spinal fluid specimens indicating negative morphology but positive MRD were given either ETIT or conventional triple intrathecal therapy. The ETIT group indicated lower relapse.Flow cytometry is sensitive to predict CNSL and ETIT is a potent intervention.