High Dose Methotrexate (HD MTX at 2 gr/sqm x 4) Associated to Extended Intrathecal (IT) Chemotherapy Is Effective for Prevention of Central Nervous System (CNS) Relapse in Childhood ALL Treated with BFM Systemic Therapy.
Authors: Conter Valentino , Rizari Carmelo , Valsecchi Maria Grazia , Silvestri Daniela , Aricò Maurizio , Barisone Elena , Casale Fiorina , De Rossi Giulio , Locatelli Franco , Lo Nigro Luca , Messina Chiara , Micalizzi Concetta , Pession Andrea , Parasole Rosanna , Rondelli Roberto , Santoro Nicola , Testi Anna Maria , Jankovic Momcilo , Basso Giuseppe , Biondi Andrea , Masera Giuseppe 
Published: April 2020

Abstract
Introduction: In the last two decades, treatment to prevent CNS relapses in childhood ALL has been characterized by a progressive replacement of cranial radiotherapy (CRT) with HD-MTX and/or protracted IT chemotherapy. AIEOP has already reported that HD-MTX (5 g/sqm x 4), associated with protracted use of IT MTX led to a 6-year isolated CNS relapse rate of 0.8% in a relatively small fraction of intermediate risk (IR) ALL children (30% of the total) treated in the BFM-oriented AIEOP ALL 88 study (J Clin Oncol, 13; 10: 2497–2502, 1995).
Aim: To evaluate if adequate CNS relapse prevention is obtained also by using HD-MTX at lower doses (2 gr/sqm x 4 instead of 5 gr/sqm x 4) and in a larger proportion of patients (up to 80% of the overall population) when associated to protracted IT chemotherapy.
Patients and methods: Eligibility: children with newly diagnosed non-T ALL with no HR features [i.e. no poor-prednisone response and/or no t(9;22) or t(4;11) clonal translocations and/or no CR after protocol IA] and no CNS or testicular involvement at the onset. Chemotherapy was based on a traditional BFM back-bone (protocols IA+B, M, II, continuation phase). CNS relapse preventive therapy consisted of one IT MTX at diagnosis; TIT x 4 in protocol IA+IB; HD-MTX (2 g/sqm x 4) + TIT x 4 in protocol M; TIT x 2 in protocol II; during the continuation phase, TIT x 6 in the IR group and TIT x 8 in the standard risk (SR) group.
Results: From 4/95 to 8/2000 1745 patients were recruited in the study AIEOP ALL 95; of these, 1441 (82.6 % of the overall ALL population) were SR (n=115) or IR (n=1326) and fulfilled the eligibility criteria for the present study. Among these 1441 patients, the following events have been observed: 264 relapses, 8 deaths in induction, 13 deaths in complete remission and 3 secondary neoplasms. Among relapses, 198 were isolated in the bone marrow, 15 isolated in the CNS, 15 isolated in the testes, 12 in the CNS+bone marrow, 10 in the testis+bone marrow, 9 in other sites +bone marrow, 5 in other isolated extramedullary sites. With a median follow-up of 5.5 years, the 6-year event-free survival (EFS) of the 1441 patients was 78.6% (SE 1.2) with an isolated CNS relapse rate of 1% (SE 0.3); when also the combined relapses involving the CNS were counted, the CNS relapse rate was 2%.
Conclusions: These data confirm and extend our previous findings, suggesting that, in the context of an intensive chemotherapy program, prevention of CNS relapse may be effectively obtained in non-HR ALL children using HD-MTX at 2 gr/sqm x 4, associated with protracted IT chemotherapy, thus permitting to avoid the use of CRT.