title: Relapse in children with acute lymphoblastic leukemia involving selection of a preexisting drug-resistant subclone.
abstract: Relapse following remission induction chemotherapy remains a barrier to survival in approximately 20% of children suffering from acute lymphoblastic leukemia (ALL). To investigate the mechanism of relapse, 27 matched diagnosis and relapse ALL samples were analyzed for clonal populations using polymerase chain reaction (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 8 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 < .007). Furthermore, in cases where the relapse clone could be quantified, time to first relapse was dependent on the amount of the relapse clone at diagnosis (r = -0.84; P = .018). This observation, together with demonstrated differential chemosensitivity between subclones 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 subclone that is undetectable by routine PCR-based methods. Relapse prediction may be improved with strategies to detect minor potentially resistant subclones early during treatment, hence allowing intensification of therapy.
authors: Children's Cancer Institute Australia for Medical Research, Sydney, Australia.
authors: Seoyeon
authors: S
authors: Choi
authors: Michelle J
authors: MJ
authors: Henderson
authors: Edward
authors: E
authors: Kwan
authors: Alex H
authors: AH
authors: Beesley
authors: Rosemary
authors: R
authors: Sutton
authors: Anita Y
authors: AY
authors: Bahar
authors: Jodie
authors: J
authors: Giles
authors: Nicola C
authors: NC
authors: Venn
authors: Luciano Dalla
authors: LD
authors: Pozza
authors: David L
authors: DL
authors: Baker
authors: Glenn M
authors: GM
authors: Marshall
authors: Ursula R
authors: UR
authors: Kees
authors: Michelle
authors: M
authors: Haber
authors: Murray D
authors: MD
authors: Norris
mesh_terms: D017668:Age of Onset; D001402:B-Lymphocytes / Q000276:immunology; D002675:Child, Preschool; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D016130:Immunophenotyping; D007223:Infant; D008297:Male; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D011946:Receptors, Antigen / Q000235:genetics; D012008:Recurrence
chemical_list: D007136:Immunoglobulins; D011946:Receptors, Antigen