Relapse following initial chemotherapy remains a barrier to survival in approximately 20% of children suffering from acute lymphoblastic leukemia (ALL). Recently, to investigate the mechanism of relapse, we analysed clonal populations in 27 pairs of matched diagnosis and relapse ALL samples using PCR-based detection of multiple antigen receptor gene rearrangements. These clonal markers revealed the emergence of apparently new populations at relapse in 13 patients. In those cases where the new ‘relapse clone’ could be detected in the diagnosis population, there was a close correlation between length of first remission and quantity of the relapse clone in the diagnosis sample. A shorter length of time to first relapse correlated with a higher quantity of the relapsing clone at diagnosis. This observation, together with demonstrated differential chemosensitivity between sub-clones at diagnosis, indicates that relapse in ALL patients may commonly involve selection of a minor intrinsically resistant sub-clone that is undetectable by routine PCR-based methods. From a clinical perspective, relapse prediction may be improved with strategies to detect minor potentially resistant sub-clones early during treatment, hence allowing intensification of therapy. Together with the availability of relevant in vivo experimental models and powerful technology for detailed analysis of patient specimens, this new information will help shape future experimentation towards targeted therapy for high-risk ALL (Fig 1).

Figure 1: Alternative models to explain emergence of therapy-resistant clones at relapse in ALL. Two scenarios are presented (A and B) in which a considerable response to therapy is observed. (A) Mutations arising in cells that survive therapy could provide the material for generation of a resistant population of cells which are free to repopulate the bone marrow and cause relapse. (B) Alternatively, a sub-population of therapy-resistant cells could already exist at the time of diagnosis, yet go undetected due to its low abundance. Being unaffected by therapy, it eventually expands to cause relapse. (Reprinted from Henderson MJ, Choi S, Beesley AH, et al. Mechanism of relapse in pediatric acute lymphoblastic leukemia. Cell Cycle. 2008;7:1315-1320, with permission from Elsevier Ltd.)