RISK-DIRECTED THERAPY FOR CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA - RESULTS OF THE OCIAZIONE-ITALIANA-EMATOLOGIA-ONCOLOGIA-PEDIATRICA 82 STUDIES

Background. In 1982, the Associazione Italiana Ematologia Oncologia Pe diatrica (AIEOP) started its third-generation study, aiming to improve previous results obtained by AIEOP '79 study and to deliver a standar dized treatment to most Italian children with acute lymphoblastic leuk emia (ALL). Methods. We treated 902 children (older than 1 year and yo unger than 15 years of age) with newly diagnosed ALL in multicenter st udies of risk-directed therapy (111 low risk [LR] from Study 8201; 570 average risk [AR] from Study 8202; and 117 and 104 high risk [HR] fro m Studies 8303 and 8503, respectively). Induction therapy was composed of vincristine, prednisone, and asparaginase for LR or AR patients an d these agents plus daunorubicin, (Study 8503) or vincristine, prednis one, cytarabine, and intermediate-dose methotrexate (Study 8303) for H R patients. Central nervous system (CNS) preventive therapy consisted of intrathecal methotrexate only (LR), intrathecal methotrexate plus 1 8 Gy cranial irradiation (AR and HR Study 8503), or high-dose (HD) cyt arabine (HR Study 8303). Reinduction therapy was vincristine/prednison e/daunorubicin for AR patients with cyclophosphamide added for HR pati ents in Study 8303 and HD asparaginase in Study 8503. LR patients did not receive intensification therapy. Continuation therapy comprised 6- mercaptopurine plus methotrexate and monthly pulses with vincristine p lus prednisone for all patients, except for HR patients in Study 8303 who also received teniposide plus cytarabine. Weekly HD asparaginase w as also given in Study 8503. Duration of treatment was 24 months for S tudies 8201 and 8202, 15 months for Study 8303, and 22 months for Stud y 8503. The overall complete remission (CR) rate was 94.7% (97.3% for LR, 94.9% for AR, and 93.2% for HR). Results. Overall 7-year event-fre e survival (EFS) was 53.6% (standard error [SE], 1.8). EFS was 60.8% i n LR (SE, 4.7), 60.6% in AR at 7 years (SE, 4.7), and 18.5% in Study 8 303 (HR) at 5 years (SE, 3.8). Because of the poor result in HR patien ts, a successor study (8503) was developed that yielded a 5-year EFS o f 46.1% (SE, 5.1). Site-specific relapse rates were 18.5% (LR), 13.4% (AR), 35.1% (HR on 8303), and 18.3% (HR in Study 8503) for bone marrow and 9.2%, 7.9%, 17.5%, and 19.3%, respectively, for the CNS (isolated ). Isolated testicular relapse was observed in 3.9% of male patients. Conclusions. This risk-directed therapy cured at least 50% of patients with ALL with relatively nonintensive therapy. The 80% overall surviv al rate for LR and AR patients at 7 years suggested that the total cur e rate may be higher than 50% because of the significant salvage rate for patients who received antimetabolite-based therapy initially.