Improvement in CNS protective treatment in non-high-risk childhood acute lymphoblastic leukemia: report from the Japanese Children's Cancer and Leukemia Study Group

Abstract

Background Prevention of central nervous system (CNS) leukemia by early introduction of therapy to this sanctuary site is an essential component of modern treatment strategy for acute lymphoblastic leukemia (ALL). However, the optimal form of preventive CNS therapy remains debatable. Procedure To address this issue, we evaluated the efficacy of CNS preventive therapy for 572 children with ALL who achieved complete remission in the Children's Cancer and Leukemia Study Group (CCLSG) ALL874 (1987–1990) and ALL911 (1991–1993) studies. They received risk‐directed therapy based on age and leukocyte count. In the ALL 874 study, the non–high‐risk (low‐risk [LR] + intermediate risk [IR]) patients were randomly assigned to the conventional cranial irradiation (CRT) regimen (L874A and I874A) and the high‐dose methotrexate (HDMTX) regimen without CRT (L874B and I874B). The former patients received 18‐Gy CRT plus 3 doses of intrathecal (IT) MTX and the latter patients received 3 courses of HDMTX at 2 g/m2 plus 13 doses of ITMTX (L874B) or 4 courses of HDMTX at 4.5 g/m2 plus 1 dose of ITMTX (I874B). Results The 7‐year probabilities (± SE) of CNS relapse‐free survival were 97.3% ± 2.6% (L874A, n = 41) vs. 90.3% ± 5.3% (L874B, n = 39) (P = 0.25) in the LR patients, and 100% (I874A, n = 55) vs. 78.5% ± 6.5% (I874B, n = 54) (P = 0.002) in the IR patients. The corresponding disease‐free survival (DFS) rates were 79.4% ± 6.5% vs. 74.4% ± 7.3% (P = 0.62) in the LR group and 63.3% ± 6.8% vs. 58.3% ± 7.2% (P = 0.66) in the IR group. Thus, the HDMTX regimen could not provide better protection of CNS relapse as compared with the CRT regimen, although their overall efficacy was not significantly different. In the ALL 911 study, intensive systemic chemotherapy with extended i,t, injections of MTX plus cytarabine achieved a high CNS relapse‐free survival (98% ± 1.9% at 7 years) and a favorable DFS (85.5% ± 5% at 7 years) in the IR patients. The patients in the high‐risk (HR) group in both ALL874 and ALL911 studies received the 18‐Gy or 24‐Gy CRT with intensive systemic chemotherapy. Their 7‐year probabilities of CNS relapse‐free survival ranged from 88% to 95%, among which the T‐ALL patients had a risk of CNS leukemia, which was 3–4 times higher compared with B‐precursor ALL patients. Conclusions These results indicate that long‐term intrathecal CNS prophylaxis as well as appropriate systemic therapy for the non–high‐risk patients can provide protection against CNS relapse equivalent to that provided by cranial irradiation. Med. Pediatr. Oncol. 32:259–266, 1999. © 1999 Wiley‐Liss, Inc.

Long-term results of the Japanese Childhood Cancer and Leukemia Study Group studies 811, 841, 874 and 911 on childhood acute lymphoblastic leukemia

“…[7][8][9][10] An outline of treatment regimens in the protocols and detailed therapy schedules, including drug dosage, are provided in Tables 2 and 3, respectively. ALL811. The main aim of the S811 protocol was a randomized control study of two different maintenance chemotherapies.…”

“…[5][6][7][8][9][10][11][12] Here, we show longterm outcomes of patients treated from the early 1980s through the mid 1990s (ALL811, ALL841, ALL874 and ALL911), and also discuss late adverse effects.…”

Systematic review and meta‐analysis of randomized trials of central nervous system directed therapy for childhood acute lymphoblastic leukemia

“…Studies were grouped into 11 categories by randomized comparison. Table I gives details of the CNS‐directed treatments 11–56. Steroid use is given in supplementary Table S1.…”

Effect of different doses of prophylactic cranial irradiation in childhood lymphoblastic leukemia on CNS relapse, late cognitive decline and learning disabilities

“…Although the need of prophylactic cranial irradiation in childhood ALL protocols has been limited nowadays to high risk patients [1] still the dose of radiation has been controversial due to its late effect on the cognitive functions and learning abilities of those children. When radiation dose was decreased from 2400cGy to 1800 cGy it reduced the neurotoxicity to an acceptable level without decreased efficacy [2].…”