Does the early intensification of intrathecal therapy improve outcomes in pediatric acute lymphoblastic leukemia patients with CNS2/TLP+ status at diagnosis?

Objectives: We aimed to determine whether the addition of two extra intrathecal methotrexate (ITM) doses during induction in acute lymphoblastic leukemia (ALL) patients eliminate the prognostic significance of CNS2/TLP+ status. Methods: We retrospectively analyzed 224 patients according to the central nervous system (CNS) involvement at diagnosis: CNS1, CNS2, or CNS3. Patients with CNS2/TLP+ received two additional ITM doses during induction. Patients were treated according to the Children's Cancer Group (CCG)-1991/1961 protocols between January 2001 and December 2007. Results: The 5-year relapse-free survival (RFS) rates for the ALL patients in the CNS1, CNS2, and CNS3 groups were 80.4 +/- 3.0, 100, and 73.5 +/- 11.3%, respectively; a non-significant difference was observed between the groups (P = 0.063). However, the patients with CNS2 had significantly better survival compared with the CNS3 patients (P = 0.03). The 5-year cumulative incidence of relapse (CIR) rates for the three groups were 17 (95% confidence interval (CI): 11.9-22.9), 0, and 18.8% (95% CI: 4.3-41.1), respectively; (P = 0.214) and those of isolated or combined CNS relapse were 9.6 (95% CI: 5.8-14.5), 0 and 6.3% (95% CI: 0.3-25.8), respectively (P = 0.424). Conclusions: This study shows that the intensification of ITM therapy during induction improves outcomes in patients with CNS2/TLP+ status and eliminates its prognostic significance. This suggests that early intensification using CNS-directed therapy is beneficial in controlling minimal CNS disease.