Group B: Randomized trial with factorial design. The 4 treatment arms are standard LMB89 therapy B, reduction of cyclophosphamide (CPM) in COPADM2, deletion of COPADM3, both reduction and deletion. Randomization occurs following COPADM1 and is stratified for national group, histology (large cell; small non cleaved cell) and stage (Murphy I orII; Murphy III+LDH\<2N; Murphy III+LDH\>2N or Murphy IV).
The primary analysis questions are whether reducing CPM dose in COPADM2 results in a smaller long-term EFS whether omitting COPADM3 results in a smaller long-term EFS
Group C: Randomized trial. The 2 treatment arms are standard LMB89 therapy C versus reduction of CYVE + deletion of the last 3 maintenance courses. Randomization occurs following COPADM2 and is stratified for national group, histology (large cell; small non cleaved cell) and CNS disease.
The primary analysis question is whether reducing CYVE and omitting the last 3 maintenance courses result in a smaller long-term EFS than standard LMB 89 treatment C
