Remission Induction for Newly Diagnosed ALL
Both the proportion of patients receiving radiation and the dose of radiation administered has decreased over the last 2 decades. For example, in a trial conducted between 1990 and1995, the BFM group demonstrated that a reduced dose of prophylactic radiation (12 Gy instead of 18 Gy) provided effective CNS prophylaxis in high-risk patients. In the follow-up trial conducted by that group between 1995 and 2000 (BFM-95), cranial radiation was administered to approximately 20% of patients (compared with 70% on the previous trial), including patients with T-cell phenotype, a slow early response (as measured by peripheral blood blast count after a 1-week steroid prophase), and/or adverse cytogenetic abnormalities. While the rate of isolated CNS relapses was higher in the nonirradiated higher-risk patients compared with historic (irradiated) cohorts, their overall EFS rate was not significantly different.
Two studies, one conducted by the SJCRH and the other by the Dutch Childhood Oncology Group (DCOG), omitted cranial radiation for all patients.[4,43] Each of these studies included four doses of high-dose methotrexate administered every 2 weeks during postinduction consolidation, as well as an increased frequency of IT triple chemotherapy (cytarabine, methotrexate, and hydrocortisone) and frequent vincristine/dexamethasone pulses during the first 1 to 2 years of therapy. The 5-year cumulative incidence of isolated CNS relapse on each trial was between 2% and 3%, although some patient subsets had a significantly higher rate of CNS relapse. On the SJCRH study, clinical features associated with a significantly higher risk of isolated CNS relapse included T-cell phenotype, the t(1;19) translocation, or the presence of blasts in the CSF at diagnosis. The overall EFS for these studies was 85.6% (SJCRH) and 81% (DCOG), in line with outcomes achieved by contemporaneously conducted clinical trials on which some patients received prophylactic radiation. Of note, on the SJCRH study 33 of 498 (6.6%) patients in first remission with high-risk features (including 26 with high MRD, six with Philadelphia chromosome-positive ALL, and one with near haploidy) received an allogeneic stem cell transplant, which included total-body irradiation.
Therapy for ALL patients with clinically evident CNS disease (>5 WBC/hpf with blasts on cytospin; CNS3) at diagnosis typically includes IT chemotherapy and cranial radiation (usual dose is 18 Gy).[23,42] Spinal radiation is no longer used. On the SJCRH Total XV (TOTXV) study, patients with CNS3 status (N = 9) were treated without cranial radiation (observed 5-year EFS, 43% � 23%). On that study, CNS-leukemia at diagnosis (defined as CNS3 status or traumatic LP with blasts) was an independent predictor of inferior EFS. The 5-year EFS of CNS3 patients (N = 21) treated without cranial radiation on the DCOG-9 trial was 67% � 10%. Larger studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.