Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-Münster-based intensive chemotherapy. The Associazione Italiana di Ematologia ed Oncologia Pediatrica.
OBJECTIVE
To assess the effect of treatment intensification and that of extended intrathecal methotrexate substitution for cranial irradiation in intermediate-risk acute lymphoblastic leukemia (ALL) children treated with a Berlin-Frankfurt-Münster (BFM)-based intensive chemotherapy.


METHODS
Three hundred ninety-six children with non-B-ALL were enrolled onto the Associazione Italiana di Ematologia ed Oncologic Pediatrica (AIEOP) ALL 88 study. Standard risk (SR) included patients with low tumor burden (BFM risk index [RI], < 0.8); intermediate risk (IR) were patients with an RI > or = 0.8 but less than 1.2; and high risk (HR) were those with an RI > or = 1.2 or CNS involvement at diagnosis. The treatment schedule was a modified version of the ALL-BFM 86 study. CNS-directed treatment consisted of high-dose methotrexate (HD-MTX; 5 g/m2 for four courses) plus intrathecal methotrexate (IT-MTX; nine doses); IR patients additionally received extended IT-MTX (nine doses during continuation therapy); cranial irradiation was given only to HR patients.


RESULTS
Of the 375 (94.7%) children who achieved remission, 1.3% had an adverse event other than relapse. The estimated event-free survival (EFS) at 6 years was 66.6% (SE 2.4) overall; 80.7% (4.5) in the SR patients, 77.5% (3.9) in the IR patients, and 54.5% (3.7) in the HR patients. Relapse occurred in 107 children (27.0%). Isolated CNS relapse occurred in 20 children (5.0%): 5 (6.3%) in the SR group, 1 (0.8%) in the IR group, and 14 (7.1%) in the HR group. The estimated 6-year CNS leukemia-free survival was 94.6% (1.2) overall: 93.5% (2.8) in the SR group, 99.1% (0.9) in the IR group, and 92.3% (2.0) in the HR group.


CONCLUSIONS
Cranial irradiation may be omitted safely in IR ALL patients treated with BFM-based intensive chemotherapy when extended intrathecal chemotherapy is given. Because the CNS disease control was less complete in the SR group, these data challenge the effectiveness of HD-MTX for protection from CNS disease and support the protective role of extended intrathecal chemotherapy.
Conter
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Department of Pediatrics, University of Milano, Italy.
Aricò
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M
Valsecchi
M G
MG
Rizzari
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C
Testi
A M
AM
Messina
C
C
Mori
P G
PG
Miniero
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R
Colella
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R
Basso
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G
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000517:prevention & control*; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D003520:Cyclophosphamide / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007223:Infant; D007278:Injections, Spinal; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy*; D011241:Prednisone / Q000008:administration & dosage; D012008:Recurrence; D012044:Regression Analysis; D012074:Remission Induction; D016019:Survival Analysis; D014750:Vincristine / Q000008:administration & dosage
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D014750:Vincristine; D003520:Cyclophosphamide; D015122:Mercaptopurine; D001215:Asparaginase; D011241:Prednisone; D008727:Methotrexate; D003630:Daunorubicin