Post-Remission MRD Kinetics in Children with Acute Lymphoblastic Leukaemia Receiving Augmented BFM Consolidation Compared with Other Regimens: Results of the Medical Research Council Trial UKALL2003.
Authors: Cutting Robert J , Richards Sue , Hancock Jeremy , Goulden Nicholas , Mitchell Christopher D , Vora Ajay J. 
Published: April 2020

The BFM group (Blood Nov 2007; 110a: 585) has reported that monitoring of postconsolidation MRD kinetics identifies a very high risk (MRD VHR) group of children with ALL, who might benefit from novel therapy and first remission allogeneic transplantation. We have compared the effect of consolidation regimen on post-remission MRD kinetics using a standardised quality controlled RQ-PCR assay of Ig and TCR patient specific rearrangements with a reproducible quantitative range of 10−4 in an attempt to identify a MRD VHR group, similar to that reported by the BFM.

MRC UKALL 2003 is a randomised trial testing whether treatment can be stratified by MRD at weeks 4 and 11 in children and young adults (up to age 25 years) with ALL from the UK and Ireland. Initially, patients are stratified by NCI criteria, cytogenetics and early morphological marrow response to receive three (Regimen A) or four (Regimen B, additional daunorubicin) drug induction. Patients with MRD &gt;10−4 at end of induction (EOI) (MRD High Risk) are randomised to continue previously assigned therapy (regimen A or B) or receive the more intensive regimen C. The regimens are of escalating intensity (A→C) and include either CCG modified BFM (A), standard BFM (B) or augmented BFM (C) consolidation, the latter containing pegylated-asparaginase (Peg-ASP; Oncospar, Medac UK, 1000 units/m2 i.m. days 16 and 44) and vincristine (1.5mg/m2 i.v. days 16, 23, 44, 51) in addition to standard BFM consolidation. Only patients with high risk cytogenetics or day 28 BM3 marrow are eligible for CR1 transplant.

Of the134 patients with MRD &gt; 10–4 at EOI, 101 were MRD negative, and 33 had detectable disease post-consolidation therapy (16 low MRD positive; &lt;5×10−4, 17 high MRD positive; &gt;5×10−4). Patients who received augmented BFM consolidation had more rapid clearance of MRD (Neg = 85%, low pos =7%, high pos =8%) than those who received CCG modified or standard BFM consolidation (Neg 65%, low pos =17%, high pos =17%) at week 11 – 15 of treatment (P=0.03 independent of age and white cell count). With median follow-up of 27 months, ten patients have relapsed, 7 in the negative group (3 year relapse Free Survival [RFS] 91.2% se=3.5) 1 in the low positive group (RFS 92.9% se = 6.9) and 2 in the high positive group (RFS 85.7% se = 9.4). The latter two were recipients of the lower intensity Regimens A (isolated CNS relapse) and B (isolated marrow relapse). The small numbers of post-consolidation high-positive patients do not permit us to identify a VHR group with a worse outcome than those patients with lower MRD levels. However, the early relapse risk (&lt;15% at 3 years) for such patients appears to be much lower than that reported by the BFM group (&gt;50% at 3 years). Differences in treatment protocol before and after consolidation may account for this disparity.

In patients treated on the current UK childhood ALL protocol, we are unable to identify a VHR group on the basis of post-consolidation MRD. Augmented BFM consolidation obtains more rapid clearance of MRD than other regimens which, with longer follow-up, might be expected to translate into a better EFS.