Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group.
METHODS
The implications of the detection of residual disease after treatment of acute lymphoblastic leukemia (ALL) are unclear. We conducted a prospective study at 11 centers to determine the predictive value of the presence or absence of detectable residual disease at several points in time during the first six months after complete remission of childhood ALL had been induced. Junctional sequences of T-cell-receptor or immunoglobulin gene rearrangements were used as clonal markers of leukemic cells. Residual disease was quantitated with a competitive polymerase-chain-reaction (PCR) assay. Of 246 patients enrolled at diagnosis and treated with a uniform chemotherapy protocol, 178 were monitored for residual disease with one clone-specific probe (in 74 percent) or more than one probe (in 26 percent). The median follow-up period was 38 months.


RESULTS
The presence or absence and level of residual leukemia were significantly correlated with the risk of early relapse at each of the times studied (P<0.001). PCR measurements identified patients at high risk for relapse after the completion of induction therapy (those with > or =10(-2) residual blasts) or at later time points (those with > or =10(-3) residual blasts). Multivariate analysis showed that as compared with immunophenotype, age, risk group (standard or very high risk), and white-cell count at diagnosis, the presence or absence and level of residual disease were the most powerful independent prognostic factors.


CONCLUSIONS
Residual leukemia after induction of a remission is a powerful prognostic factor in childhood ALL. Detection of residual disease by PCR should be used to identify patients at risk for relapse and should be taken into account in considering alternative treatment.
Laboratoire de Biochimie Génétique, Hôpital Robert Debré, Paris, France.
H
H
Cavé
J
J
van der Werff ten Bosch
S
S
Suciu
C
C
Guidal
C
C
Waterkeyn
J
J
Otten
M
M
Bakkus
K
K
Thielemans
B
B
Grandchamp
E
E
Vilmer
D000293:Adolescent; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D002999:Clone Cells; D004273:DNA, Neoplasm / Q000032:analysis; D015321:Gene Rearrangement; D016694:Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007223:Infant; D018365:Neoplasm, Residual / Q000175:diagnosis*; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics; D012074:Remission Induction
D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D016692:Receptors, Antigen, T-Cell, gamma-delta