Prognostic Significance of Central Nervous System (CNS) Status of Children with Acute Lymphoblastic Leukemia (ALL) Treated without Cranial Irradiation: Results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group Study 58951
Authors: Sirvent Nicolas , Suciu Stefan , Benoit Yves , Bertrand Yves , Nelken Brigitte , Robert Alain , Uyttebroeck Anne , Lutz Patrick , Ferster Alina , Yacouben Karima , Norton Lucilia , Margueritte Geneviève , Munzer Martine , Plantaz Dominique , Millot Frédéric , Boutard Patrick , Philippet Pierre , Hoyoux Claire , Baila Liliana , Otten Jacques 
Published: April 2020

Abstract
Background: Cranial irradiation (XRT) in combination with intrathecal chemotherapy has markedly reduced the incidence of meningeal relapse in childhood acute lymphoblastic leukemia (ALL), and is still recommended for patients (pts) at high risk of relapse within the CNS. Because of late adverse effects of XRT, the previous CLG trial (EORTC 58881, 1989–1996) deleted XRT from the treatment regimen of all ALL patients. Nevertheless, the results (5-year event-free survival (EFS) rates) of 58881 trial were good in CNS-1 (72.1%), dubious CNS-2 (62.2%), surreptitious CNS-2 (64.6%) and particularly good in pts with CNS leukemia involvement (70.3%, SE 6.2%), emphasizing the importance of systemic chemotherapy in such pts, of whom, 50% were treated according to a very high risk group protocol (ASH, 2006). In order to validate this therapeutic strategy, we evaluate the prognostic significance of CNS status at diagnosis in ALL children enrolled from 12/1998 to 2/2008 in the EORTC CLG 58951 randomized phase III trial.
Methods: Treatment design was according to BFM. Three randomizations were programmed:
R1) the value of Dexamethasone (DEX) vs Prednisolone (PRED) during induction (all pts); R2) the value of prolonged (24 injections) vs conventional (12 injections) duration of L-asparaginase courses during consolidation and late intensification (all except very high risk pts); R3) the value of 6 (DEX or PRED + vincristine) pulses every 10 weeks in maintenance therapy (average risk pts).
CNS-directed therapy consisted in i.v. methotrexate (MTX) (5 g/sqm over 24 hours) in 4 to 10 courses, according to the degree of initial CNS involvement, and intrathecal MTX. No radiotherapy was used. According to CNS status, pts were classified in 4 groups:
CNS-1: no blasts and WBC&lt;6/μl, RBC&lt;100/μl; dubious CNS-2: presence of blasts, RBC □100/μl; surreptitious CNS-2: presence of blasts, WBC&lt;6/μl, RBC&lt;100/μl; CNS-3: presence of blasts, WBC&gt;5/μl, RBC&lt;100/μl.
Only CNS-3 pts were to receive 10 courses of i.v. MTX, but some of dubious (n=21) and surreptitious CNS-2 pts (n=38) did eventually receive 10 courses as well.
Results: Between 12/1998 and 2/2008, a total of 1853 ALL pts were registered in 58951 trial. On 2/2008 a total of 1686 were evaluable for EFS; the distribution according to initial CNS status was: CNS-1 (n=1494, 88.6%), dubious CNS- 2 (n=100, 5.9%), surreptitious CNS-2 (n=59, 3.5%) and CNS-3 (n=33, 2%). The higher the degree of CNS involvement, the higher the incidence of unfavourable features: initial WBC□100000/μl, T-lineage, NCI high risk; very high risk (VHR) initial features (peripheral blasts ≥1000/μl post prephase, high-risk cytogenetics). In CNS-3 group, 10/33 (30%) pts were treated according to VHR protocol. Median follow-up was 4 years.
CNS-1 Dubious CNS-2 Surrept. CNS-2 CNS-3 No CR 17 (1.1%) 0 (0%) 0 (0%) 1 (3.0%) CCR 1286 (86.1%) 84 (84.0%) 50 (84.7%) 22 (66.7%) Isolated CNS rel. 17 (1.1%) 3 (3.0%) 1 (1.7%) 2 (6.1%) Combined CNS r. 23 (1.5%) 1 (1.0%) 2 (3.4%) 2 (6.1%) Non-CNS relapse 20 (13.4%) 2 (2.0%) 1 (1.7%) 5 (15.2%) Death in CR 31 (2.1%) 2 (2.0%) 1 (1.7%) 1 (3.0%) 4-yr EFS (%, SE) 84.0% (1.1%) 88.2% (3.5%) 82.4% (5.4%) 55.1% (10.8%) 4-yr OS (%, SE) 90.7% (0.9%) 92.0% (2.9%) 88.0% (4.6%) 63.4% (12.8%)
Conclusion: In comparison with previous EORTC 58881 trial, and according to CNS status, EFS, OS, and isolated and combined CNS relapses rates improved in 58951 trial, except for CNS-3 pts. These “disappointing” results in CNS-3 pts (representing 2% of the entire population), less heavily treated in 58951 than in 58881, confirm the importance of systemic chemotherapy in such pts.