Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study.
The Associazione Italiana di Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Acute Lymphoblastic Leukemia (AIEOP-BFM ALL 2000) study has for the first time introduced standardized quantitative assessment of minimal residual disease (MRD) based on immunoglobulin and T-cell receptor gene rearrangements as polymerase chain reaction targets (PCR-MRD), at 2 time points (TPs), to stratify patients in a large prospective study. Patients with precursor B (pB) ALL (n = 3184) were considered MRD standard risk (MRD-SR) if MRD was already negative at day 33 (analyzed by 2 markers, with a sensitivity of at least 10(-4)); MRD high risk (MRD-HR) if 10(-3) or more at day 78 and MRD intermediate risk (MRD-IR): others. MRD-SR patients were 42% (1348): 5-year event-free survival (EFS, standard error) is 92.3% (0.9). Fifty-two percent (1647) were MRD-IR: EFS 77.6% (1.3). Six percent of patients (189) were MRD-HR: EFS 50.1% (4.1; P < .001). PCR-MRD discriminated prognosis even on top of white blood cell count, age, early response to prednisone, and genotype. MRD response detected by sensitive quantitative PCR at 2 predefined TPs is highly predictive for relapse in childhood pB-ALL. The study is registered at http://clinicaltrials.gov: NCT00430118 for BFM and NCT00613457 for AIEOP.
Department of Pediatrics, University of Milano-Bicocca, Ospedale S Gerardo, Monza, Italy.
Valentino
V
Conter
Claus R
CR
Bartram
Maria Grazia
MG
Valsecchi
André
A
Schrauder
Renate
R
Panzer-Grümayer
Anja
A
Möricke
Maurizio
M
Aricò
Martin
M
Zimmermann
Georg
G
Mann
Giulio
G
De Rossi
Martin
M
Stanulla
Franco
F
Locatelli
Giuseppe
G
Basso
Felix
F
Niggli
Elena
E
Barisone
Günter
G
Henze
Wolf-Dieter
WD
Ludwig
Oskar A
OA
Haas
Giovanni
G
Cazzaniga
Rolf
R
Koehler
Daniela
D
Silvestri
Jutta
J
Bradtke
Rosanna
R
Parasole
Rita
R
Beier
Jacques J M
JJ
van Dongen
Andrea
A
Biondi
Martin
M
Schrappe
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D015322:Gene Rearrangement, B-Lymphocyte; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell