Prognostic Significance of Blasts with/without Pleiocytosis in the Cerebro-Spinal Fluid (CSF) 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 58881.
Authors: Sirvent Nicolas , Suciu Stefan , Rialland Xavier , Robert Alain , Mazingue Francoise , Millot Frederic , De Moerloose Barbara , Ferster Alice , Rohrlich Pierre , Norton Lucilia , Lescoeur Brigitte , Dresse Marie-Francoiseçoise , Lutz Patrick , Baila Liliana , Behar Catherine , Bertrand Yves , Otten Jacques 
Published: October 2019

Abstract
To evaluate the prognostic significance of blasts in the CSF at diagnosis in children with ALL, 2049 patients (pts) enrolled from 1989 to 1996 in EORTC 58881 trial were retrospectively studied. Treatment design was according to BFM. Central nervous system (CNS)-directed therapy consisted in i.v. methotrexate (MTX) (5 g/sqm over 4 hours) in 4 to 10 courses, according to grade of initial CNS involvement, and intrathecal MTX. No radiotherapy was used. Three randomizations were programmed: Erwinia vs Medac E.coli asparaginase (all pts); addition or not of i.v. Ara-C to i.v. MTX (for increased-risk pts); addition of monthly courses of i.v. 6-MP in maintenance therapy (all pts). According to CNS status, pts were classified in 4 groups: 1) CNS-1: <6 WBC/μl, RBC<100/μl, no blasts; 2) dubious CNS-2: presence of blasts, RBC>100/μl; 3) surreptitious CNS-2: presence of blasts, <6 WBC/μl, RBC<100/μl; 4) CNS-3: presence of blasts, >5 WBC/μl, RBC<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=19) did eventually receive 10 courses as well. Dubious CNS-2 (n=53), surreptitious CNS-2 (n=52), and CNS-3 (n=54) contained a higher rate of pts with unfavourable features than CNS-1 pts: WBC > 100000/μl; T-lineage; NCI high risk; very high risk (VHR) features (≥1000 peripheral blasts/μl post prephase, high-risk cytogenetics). Median follow-up was 7.5 years. The 5-yr overall event-free survival (EFS) and overall survival (OS) rates (SE%) were 71.6 % (1.0 %) and 82.6 % (0.8%) respectively. The 5-yr EFS rate (SE%) was 72.1 % (1.0%) for CNS-1, 62.2 % (6.6%) for dubious CNS-2, 64.7 % (6.7%) for surreptitious CNS-2, and 70.3 % (6.2%) for CNS-3 group. Overall, pts with blasts in the CSF (dubious CNS-2, surreptitious CNS-2 or CNS-3) had a significantly (p=0.02) shorter EFS than those in the CNS-1 group: 5-yr EFS rate 65.6% (3.8%) vs 72.1%. Multivariate analysis indicated that low WBC, Medac E-Coli asparaginase, absence of VHR features, middle age group were, together, predictive for longer EFS, whereas CNS involvement (CNS-2/-3 vs CNS-1) lost its prognostic value (p=0.87). Out of 2018 pts who reached CR, a total of 71 isolated and 78 combined CNS relapses were reported. The 5-yr isolated CNS relapse rate was 3.8%: 3.5% in CNS-1, 6.7% in dubious CNS-2, 10.5% in surreptitious CNS-2 and 7.1% in CNS-3 group. The 5-yr isolated or combined CNS relapse rate was 7.9%; in the 4 CNS-groups it was 7.6%, 11.1%, 14.7% and 9.2% respectively. The 5-yr OS rate (SE%) was 83.5% (0.9%) in CNS-1 vs 72.4% (3.9%) in CNS-2/-3: p=0.0003. Prognostic importance was lost (p=0.23) in multivariate analysis. Conclusion: the presence of blasts in the CSF, with or without pleiocytosis, is associated with unfavorable prognostic features and with worse outcome. Intensification of CNS-directed chemotherapy, without CNS radiation, is an effective treatment of initial meningeal leukemic involvement.