Relapse in children with acute lymphoblastic leukemia involving selection of a preexisting drug-resistant subclone.
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.
Choi
Seoyeon
S
Children's Cancer Institute Australia for Medical Research, Sydney, Australia.
Henderson
Michelle J
MJ
Kwan
Edward
E
Beesley
Alex H
AH
Sutton
Rosemary
R
Bahar
Anita Y
AY
Giles
Jodie
J
Venn
Nicola C
NC
Pozza
Luciano Dalla
LD
Baker
David L
DL
Marshall
Glenn M
GM
Kees
Ursula R
UR
Haber
Michelle
M
Norris
Murray D
MD
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
D007136:Immunoglobulins; D011946:Receptors, Antigen