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Blood, 15 July 2007, Vol. 110, No. 2, pp. 632-639.
Prepublished online as a Blood First Edition Paper on March 19, 2007; DOI 10.1182/blood-2007-01-067785.
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Submitted January 12, 2007
Accepted March 12, 2007
Relapse in children with acute lymphoblastic leukaemia involving selection of a pre-existing drug resistant sub-clone
Seoyeon Choi, Michelle J Henderson, Edward Kwan, Alex H Beesley, Rosemary Sutton, Anita Y Bahar, Jodie Giles, Nicola C Venn, Luciano Dalla Pozza, David L Baker, Glenn M Marshall, Ursula R Kees, Michelle Haber, and Murray D Norris*
Children's Cancer Institute Australia for Medical Research, Sydney, Australia
Telethon Institute for Child Health Research, and Centre for Child Health Research, University of Western Australia, Perth, Australia
Oncology Unit, The Children's Hospital Westmead, Sydney, Australia
Department of Haematology-Oncology, Princess Margaret Hospital, Perth, Australia
Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Sydney, Australia
* Corresponding author; email: mnorris{at}ccia.unsw.edu.au.
Relapse following remission induction chemotherapy remains a barrier to survival in approximately 20% of children suffering from acute lymphoblastic leukaemia (ALL). To investigate the mechanism of relapse, 27 matched diagnosis and relapse ALL samples were analysed for clonal populations 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. More sensitive clone-specific PCR revealed that, in eight cases, these 'relapse clones' were present at diagnosis and a significant relationship existed between presence of the relapse clone at diagnosis and time to first relapse (P<0.007). Furthermore, in cases where the relapse clone could be quantified, time to first relapse was dependent upon the amount of the relapse clone at diagnosis (r=-0.84; P=0.018). This observation, together with demonstrated differential chemosensitivity between sub-clones at diagnosis, argues against therapy-induced acquired resistance as the mechanism of relapse in the informative patients. Instead these data indicate that relapse in ALL patients may commonly involve selection of a minor intrinsically resistant sub-clone that is undetectable by routine PCR-based methods. Relapse prediction may be improved with strategies to detect minor potentially resistant sub-clones early during treatment, hence allowing intensification of therapy.
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