Importance of effective central nervous system therapy in isolated bone marrow relapse of childhood acute lymphoblastic leukemia. BFM (Berlin- Frankfurt-Munster) Relapse Study Group

Abstract

Presymptomatic central nervous system (CNS) treatment in children with a late isolated first bone marrow (BM) relapse of acute lymphoblastic leukemia (ALL) was based on intermediate-dose systemic and intrathecal (IT) methotrexate (MTX) in the multicenter trial, ALL-REZ BFM 85. Because this was associated with an excess of overt second CNS relapses, cranial radiotherapy (cRT) plus prolonged triple IT therapy with MTX, cytarabine, and prednisone was instituted during the course of the subsequent trial, ALL-REZ BFM 87. Results of children with or without cRT, but otherwise identical chemotherapy, are presented here. Between April 1985 and March 1990, 93 children with their first late isolated BM relapse of ALL were entered on protocols ALL-REZ BFM 85M and ALL-REZ BFM 87. An intensive 6-month phase of multiagent chemotherapy that included 8 courses of systemic MTX (1 g/m2) plus IT MTX was followed by 2 years of conventional maintenance therapy with daily 6-thioguanine and biweekly MTX. Children with bone marrow transplantation excluded, 73 were in complete remission at the end of intensive polychemotherapy, 40 of whom received fractionated cRT plus triple IT therapy during the following 6 months; 11 did not receive cRT but prolonged triple IT; 22 received neither cRT nor prolonged triple IT. Except for a higher percentage of children who had received cRT in front-line protocols (29 of 33 v 20 of 40), the patient groups without or with salvage cRT were comparable. Of 33 children without salvage cRT, 26 relapsed, compared with 21 of 40 who had received cRT (P < .05). The difference was solely attributable to second relapses with CNS involvement (10 of 33 v 1 of 40; P < .01). Estimated 6-year event- free survival rates were .18 for children without cRT and .46 for children with cRT (P < .01). In patients without cRT, no impact of prolonged IT therapy could be shown. The data suggest that second CNS prophylaxis with cRT and prolonged triple IT therapy in children with late isolated BM relapse of ALL is effective in preventing CNS relapses, in reducing the overall relapse rate, and in increasing the overall survival rate.

Relapsed Childhood Acute Lymphoblastic Leukemia: Experience from a Single Tertiary Center in Thailand

“…The chemotherapy protocols used to treat patients with relapsed ALL were divided into 2 periods as follows. Between 2000 and 2013, relapsed patients treated according to the ALL-REZ Berlin-Frankfurt-Münster (BFM) 87 regimen (Bührer et al, 1994). In the period from 2014-2019, they treated according to UKALL R3 chemotherapy regimen (Parker et al, 2010).…”

ALL-REZ BFM - The Consecutive Trials for Children with Relapsed Acute Lymphoblastic Leukemia

“…Preventive cranial irradiation was introduced for all children with isolated BM relapse because in trial ALL-REZ BFM 87 an excess of CNS relapses following isolated BM relapse was observed. This resulted in a signifi cant reduction of CNS relapses and an improved overall outcome [ 9 ] . During the course of the trials it became evident, however, that maintenance therapy was never suffi cient to maintain 2 nd CR in children with early BM and systemic relapses of T-cell ALL.…”

Relapsed Lymphoblastic Leukaemia in Children: A Continuing Challenge

“…Early protocols for relapsed ALL were complicated by a high incidence of CNS relapse, and the need for CNS‐directed therapy became apparent in these cases, as in newly diagnosed lymphoblastic leukaemia ( Chessells et al , 1984 ; Buhrer et al , 1994 ). Most protocols have incorporated regular intrathecal methotrexate, with or without hydrocortisone and cytarabine and some, in addition, moderate or high dose intravenous methotrexate.…”

“…The BFM study group randomized patients with relapsed ALL to receive either intravenous methotrexate 12 g/m 2 as a 4 h infusion or 1 g/m 2 as a 36 h infusion; the randomization was stopped after it became apparent that the 37 patients receiving high‐dose MTX did not achieve better systemic control or CNS protection than intermediate‐dose methotrexate ( Henze et al , 1991 ). The group have subsequently introduced cranial irradiation and triple intrathecal chemotherapy in children with late isolated BM relapse because of their concerns about the risk of CNS relapse, but this has been done empirically and not in a randomized fashion ( Buhrer et al , 1994 ).…”