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.