Treatment and Assessments
The AALL02P2 chemotherapy backbone for this study has been previously reported36 with some minor differences based on site of relapse. Induction included 4 weeks of systemic therapy plus weekly intrathecal triple (ITT) chemotherapy (Supplementary Table 1 ). CNS remission was defined as two consecutive lumbar punctures with no morphologic blasts evident on CSF analysis. Induction failure was defined as failure to achieve CNS remission following six weekly ITT. Following Induction, patients received Consolidation, Intensification I, Reinduction, and Intensification II, with concomitant ITT chemotherapy. These phases were designed to last 50 weeks, following which patients with iCNS-R received a 3-week block of chemotherapy with 1200 cGy cranial radiation given as 8 daily fractions of 150 cGy. AALL02P2 was designed to allow radiation to be delayed up to 2 months to allow completion of the intensive chemotherapy phases. Following irradiation, patients received five 10-week cycles of intensified maintenance, each including 4 doses of cyclophosphamide 300 mg/m2 given weekly. Cyclophosphamide doses were omitted if the absolute neutrophil count was <500/microliter or platelet count was <75,000/microliter. No further intrathecal therapy was given during maintenance, but diagnostic lumbar punctures were performed on day 1 of each maintenance cycle.
Bone marrow samples taken prior to treatment initiation were assessed for MRD via flow cytometry,37 at a single central reference laboratory at the University of Washington.