To delay or not to delay, that is the question for patients with acute lymphoblastic leukemia who do not receive prophylactic cranial irradiation

With 5-year survival rates for childhood acute lymphoblastic leukemia (ALL) approaching and even exceeding 90% in many developed countries, current efforts are focused on improving not only the cure rate but also the quality of life of patients by reducing treatment-related toxicities. Because prophylactic cranial irradiation can lead to many serious long-term sequelae, including secondary cancers, neurocognitive impairment, and endocrinopathy, eliminating the use of this treatment modality has been a priority for leukemia therapists worldwide. Two clinical trials in the previous decade achieved excellent 5-year event-free survival rates of 86% and 81% after totally omitting prophylactic cranial irradiation and relying on intensive dexamethasone, vincristine, and asparaginase, high-dose methotrexate, and, for patients with blasts in their cerebrospinal fluid, extra doses of intrathecal therapy. Importantly, isolated and combined central nervous system (CNS) relapse rates in these studies were only 2.7% and 1.2%, respectively, and 2.6% and 0.8%, respectively. Encouraged by these early findings, most study groups now restrict prophylactic cranial irradiation to patients at high-risk for CNS relapse, and some, such as the Taiwan Pediatric Oncology Group (TPOG), as reported in this issue of Cancer, have eliminated this treatment modality altogether. A comparison of contemporary trials of limited use and complete omission of prophylactic cranial irradiation shows similar rates of event-free survival and CNS control (Table 1). The likelihood of 5-year event-free survival and the cumulative risk of an isolated CNS relapse ranged from 72% to 89% and from 1% to 4.1%, respectively, in the 4 studies that omitted irradiation, whereas they ranged from 85% to 87.3% and from 1.4% to 2%, respectively, in the 3 trials in which up to approximately 10% of the patients were irradiated and from 82.5% to 85% and from 0.9% to 1.3%, respectively, when more than 10% were irradiated. Indeed, a 2016 meta-analysis of more than 16,000 patients enrolled in clinical trials of 10 cooperative childhood ALL study groups indicated that prophylactic cranial irradiation had no impact on the overall survival or the cumulative risk of death, any adverse event, isolated CNS relapse, or combined CNS relapse in any subgroup of highrisk patients with the exception of those with overt CNS leukemia (CNS-3 status, 5 or more leukocytes per microliter with blasts). Although cranial irradiation was associated with a reduced risk of isolated CNS relapse in patients with a CNS-3 status, it failed to reduce overall adverse events, hematologic relapses, or mortality rates in these patients. Although intensive systemic and intrathecal therapy can replace prophylactic cranial irradiation even in patients at high risk for CNS relapse, it is associated with acute and late sequelae (although less serious than those induced by irradiation) and could poise difficult challenges for therapists working in developing countries with limited resources. It should also be stressed that even with regimens of intensive systemic and intrathecal chemotherapy, findings of a CNS-3 or CNS-2 status (fewer than 5 leukocytes per microliter with blasts) or traumatic lumbar puncture with blasts (TLP+; 10 or more erythrocytes per microliter with blasts) were still linked to poor event-free survival and overall survival as well as an increased risk of CNS relapse. Recognizing that TLP+ is associated with an inferior treatment outcome and that delaying diagnostic lumbar puncture with intrathecal chemotherapy to day 8 of remission induction, as tested in the Tokyo Children’s Cancer Study Group L89-12 study, can almost completely eliminate the risk of TLP+ (0.6%), investigators at Mackay Memorial Hospital in Taiwan pioneered an innovative study of CNS-directed treatment in which diagnostic lumbar puncture and triple intrathecal therapy were delayed until the clearance of circulating blasts but no later than day 10 of remission induction along with the elimination of prophylactic cranial irradiation. The success of this single-institution pilot