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The sensitivity of detection of residual disease by two IgH PCR strategies, fluorescent framework 3 (Ffr3) and allele-specific oligonucleotide probing (ASOP), was compared in 57 'remission' BM samples obtained from 19 children with B-lineage acute lymphoblastic leukaemia (ALL). Oligonucleotide probing was more sensitive than FFr3 PCR in 10/16 cases, achieving a sensitivity of 0.01% or greater in 15/16 cases. Comparable sensitivities were obtained in the six remaining cases; the FFr3 PCR achieving a sensitivity of 0.1% or greater in 14/16 cases. 39/57 'remission' BM samples analysed showed no evidence of MRD by either technique although 18 were positive by ASOP and 14 positive by FFr3 PCR. The level of disease was estimated to be 0.01% or less in the four false negative samples.

Approximately one-third of first relapses of childhood ALL occur at an extramedullary site without morphological evidence of bone marrow disease. However, the high incidence of subsequent medullary relapse in these cases strongly suggests that leukaemia is present at submicroscopic levels at the time of 'isolated' relapse. PCR analysis of immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) gene rearrangements now allows detection of leukaemia at levels as low as 0.001%. We have therefore used this technique to reassess bone marrow status at morphologically isolated relapse in 13 children with B-lineage ALL (11 with off-treatment relapses, two on treatment). In 12 of these 13 patients marrow disease was detectable by PCR at the time of this relapse--in all cases at levels below the threshold of light microscopy. Where relapse occurred off-therapy this indicated re-emergence of disease. since MRD has never been detected by PCR at this stage in patients remaining in long-term remission. In both patients who relapsed on-therapy the level of MRD at the time of relapse represented an increase on that seen in their previous marrow sample. We conclude that re-emerging bone marrow disease can be detected in most cases of 'isolated' relapse when investigated by this highly sensitive technique. Our findings at a molecular level confirm a long-held clinical suspicion and indicate that full systemic re-induction as well as local therapy is obligatory for these children.

Focuses on the clinical trials to established to explore the use of minimal residual disease (MRD). Aim of the exercise to stratify patients into different treatment therapies; Use of polymerase chain reaction to quantitate MRD; Likelihood of relapse by half of patients in the lowest treatment regimes; Suggestion for chemotherapy for patients with low MRD; Effectiveness of MRD detection as a prognostic tool.