Introduction
The central nervous system (CNS) is involved in 30% of relapses (isolated or in combination with bone marrow or other site) of pediatric Acute Lymphoblastic Leukemia (ALL) and remains a major obstacle to improving survival.1-4 Isolated CNS relapse (iCNS-R) occurs in 2-5% of patients in recent clinical trials, predominantly in patients without prior overt CNS disease.5-20
Improved outcomes following iCNS-R are the result of intensified systemic therapy with drugs that effectively treat CNS leukemia (high-dose (HD) methotrexate, HD cytarabine, dexamethasone, and pegaspargase), in addition to CNS-directed treatment including intrathecal chemotherapy and cranial (CRT) or craniospinal radiotherapy (CSI). These strategies have been successfully applied to front-line protocols seeking to reduce and/or eliminate CNS radiation in at risk patients (CNS3 and those with traumatic taps and presumed introduction of circulating blasts into the cerebrospinal fluid [CSF]) without compromising survival.9-11,14,21-24 However, patients receiving cranial radiotherapy (CRT) have an increased prevalence of acute and long-term neurotoxicity, endocrinopathies, second cancers, neurocognitive deficits, late mortality, and impaired quality of life.13,25-33
Pediatric Oncology Group (POG) trials for children with CNS-R conducted in the 1990s (9061 and 9412) aimed to limit the use of CSI and delayed radiotherapy to enable a longer period of time to deliver effective systemic chemotherapy without inducing excessive marrow toxicity.19,34 These strategies yielded impressive long-term second remissions with 4-year event-free survival (EFS) rates of 70-80%.19,20,34 Compared to POG 9061, 9412 reduced CRT dose from 2400 to 1800 cGy, eliminated spinal radiation (1500 cGy), and delayed radiation to 12 months.20 The 4-year EFS for POG 9412 B-ALL iCNS-R patients with CR1 > 18 months was 78%+ 6%. Both studies identified length of first remission as a major prognostic indicator, and on POG 9412, National Cancer Institute (NCI) risk group 35 at time of their initial diagnosis was an independent prognostic variable.
Based on these encouraging results, Children’s Oncology Group (COG) AALL02P2 aimed to further decrease CRT dose to 1200 cGy and delay its delivery until completion of 12 months of further intensified systemic chemotherapy in patients with late iCNS-R (≥18 months after initial diagnosis). It was hypothesized that this decreased exposure to radiation would decrease adverse events of CRT, while preserving POG 9412 outcomes.