CNS therapy for standard-risk patients
Intrathecal chemotherapy without cranial radiation, given in the context of appropriate systemic chemotherapy, results in CNS relapse rates of less than 5% for children with standard-risk ALL.[4,25,40,41,42,43] The use of cranial radiation does not appear to be a necessary component of CNS-directed therapy for these patients.[23,44]
The CCG-1952 study for NCI standard-risk patients compared the relative efficacy and toxicity of triple IT chemotherapy (methotrexate, prednisone, and cytarabine) with methotrexate as the sole IT agent in nonirradiated patients. There was no significant difference in either CNS or non-CNS toxicities. Triple IT chemotherapy was associated with a lower rate of isolated CNS relapse (3.4% � 1.0% compared with 5.9% � 1.2% for IT methotrexate; P = .004). This effect was especially notable in patients with CNS2 status at diagnosis (lymphoblasts seen in cerebrospinal fluid [CSF] cytospin, but with <5 WBC/hpf on CSF cell count); the isolated CNS relapse rate was 7.7% � 5.3% for CNS2 patients who received triple IT chemotherapy compared with 23.0% � 9.5% for those who received IT methotrexate alone (P = .04). There were, however, more bone marrow relapses in the group that received the triple IT therapy, leading to a worse overall survival (OS) (90.3% � 1.5%) compared with the IT methotrexate group (94.4% � 1.1%; P = .01). When the analysis was restricted to patients with precursor B-cell ALL and rapid early response (M1 marrow on day 14), there was no difference between triple and single IT therapy in terms of rates of CNS relapse rate, OS, or EFS. In a follow-up study of neurocognitive functioning in the two groups, there were no clinically significant differences.[Level of evidence: 1iiC]
Patients with blasts in the CSF but fewer than 5 WBC/�L (CNS2) are at increased risk of CNS relapse, although this risk appears to be nearly fully abrogated if they receive more intensive IT chemotherapy, especially during the induction phase. Data also suggest that patients who have a traumatic lumbar puncture showing blasts at the time of diagnosis have an increased risk of CNS relapse, and these patients receive more intensive CNS-directed therapy on some treatment protocols.[48,49]
CNS therapy for high-risk patients
Controversy exists as to which, if any, high-risk patients should be treated with cranial radiation. Depending on the protocol, up to 20% of children with ALL receive cranial radiation as part of their CNS-directed therapy, even if they present without CNS involvement at diagnosis. Patients receiving cranial radiation on many treatment regimens include those with T-cell phenotype and high initial WBC count and certain patients with high-risk precursor B-cell ALL (e.g., those with extremely high presenting leukocyte counts and/or adverse cytogenetic abnormalities).