In most published studies, adolescent patients with ALL achieve better results when treated with paediatric rather than adult protocols.rrr It is unclear as to the relative contributions of the composition of paediatric protocols, disease differences between children and older patients, the hospital settings in which they are delivered or the effects of selection bias.
A collaborative French studyr retrospectively analysed patients aged between 15 and 20 who had been treated with either an adult ALL protocol (LALA94) or a paediatric protocol (FRALLE-93) showing a 5 year event free survival (EFS) advantage in favour of FRALLE-93 (67% versus 41% 5 year EFS, P<0.001) as well as an advantage for the paediatric protocol in overall survival (78% versus 45% at 5 years, P<0.001). Pui et al 2011 reported an event free survival at 5 years of 86.4% for adolescent patients aged 15 to 18 treated with a paediatric protocol (total therapy study XV, st Jude).
Moricke et al 2008r reported the results of 2169 paediatric and adolescent patients up to age 18 treated for ALL with the ALL-BFM95 protocol. Overall event free survival was estimated to be 79.6% at 6 years. Patients were stratified and treated according to risk (standard, medium and high risk). The 6 year EFS in the MR patients was 79.7% and 49.2% in the HR patients, and 58.3% for all patients aged 15 and older. Minimal residual disease criteria were not used for risk stratification in the ALL-BFM95 regimen. The published results of the ALL-BFM95 study did not demonstrate a benefit from the two randomisations (cytarabine in the intensification phase and pulse during maintenance).r
One retrospective Finnish studyr did not show any improvement in the survival for patients aged 10 to 25 treated on a paediatric rather than an adult protocol, with a 5 year event free survival of 67% for the paediatric and 60% for the adult.
The ALL-BFM95 regimen was used as the standard arm of ALL-BFM 2000 with the incorporation of the minimal residual disease testing in patients with precursor B ALL. With this ALL- BFM 2000 regimen, the 5 year event free survival in this pre-B ALL subpopulation were 92.3%, 77.6% and 50.1% for the standard (42% of patients), intermediate (52% of patients) and high risk patients (6% of patients).r
The ALL- BFM 2000 standard arm has been used as the treatment regimen in this protocol, since it is common to both ALL-BFM95 and ALL- BFM 2000 regimens. If minimal residual disease (MRD) testing is available, then the incorporation of these results appears justified on the published data, at least for the pre-B ALL group.r
The selection of asparaginase preparations is reviewed in the Asparaginase document. Leunase® (colaspase, E. coli preparation) is the most commonly used preparation and the default option as presented in these protocols. Pegasparaginase is given as an alternative preparation and has the advantage of longer half life, lower immunogenicity and more efficient asparaginase depletion than standard preparatations.rr All patients on the ongoing MRC UKALL 14 protocol receive pegylated asparaginase. The doses employed in the current treatment protocol are in line with those employed in the ongoing ANZCHOG, ALLG ALL6 and MRC UKALL 14 studies.
MRD testing has become a standard part of managing children with acute lymphoblastic leukaemia, but is not generally available outside clinical trials. Since many centres are performing MRD testing in AYA patients, the ALL-BFM 2000 risk groups defined on MRD are included. With no standard care approach to ALL in the younger population of patients defined, which risk criteria to utilize is not yet defined. To avoid confusion between groups of patients on studies such as ALLG ALL6 and ANZCHOG, the risk group definitions from these protocols have been adopted.
ALL BFM 2000 is a high intensity regimen with the published results for patients up to the age of 18 years. It is unknown what is the safe upper age limit in tolerability for this regimen.