Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow.
OBJECTIVE
Speed of blast clearance is an indicator of outcome in childhood acute lymphoblastic leukemia (ALL). Availability of measurement of minimal residual disease (MRD) at an early time point with a reduced-cost method is of clinical relevance. In the AIEOP-BFM-ALL (Associazione Italiana Ematologia Oncologia Pediatrica and Berlin-Frankfurt-Münster Study Group) 2000 trial, patients were stratified by levels of polymerase chain reaction (PCR) MRD at day +33 and +78. AIEOP studied the prognostic impact of MRD measured by flow cytometry (FCM) at day 15 of induction therapy.


METHODS
Bone marrow samples from 830 Italian patients were collected on day 15, after 14 days of steroids, and one dose of intrathecal methotrexate, vincristine, daunorubicine, and asparaginase. Cells were analyzed by four-color FCM for detection of leukemia-associated immunophenotypes.


RESULTS
Three patient risk groups were identified by FCM: standard (< 0.1% blast cells; 42% of the total), intermediate (0.1 to < 10%; 47%), and high (> or = 10%; 11%). Their 5-year cumulative incidences of relapse were 7.5% (SE, 1.5), 17.5% (SE, 2.1), and 47.2% (SE, 5.9), respectively. In multivariate analysis, FCM was the most important prognostic factor among those available by day 15, with two-fold and five-fold increase in the risk of relapse compared with patients with less than 0.1%. PCR MRD, when added to the model, had significant prognostic impact; yet high levels of FCM MRD retained an independent ability to detect a significantly higher risk of relapse.


CONCLUSIONS
Measurement of FCM MRD in day 15 bone marrow was the most powerful early predictor of relapse, applicable to virtually all patients; it may complement PCR MRD-based stratification including later time points, thus allowing additional treatment tailoring.
Basso
Giuseppe
G
Laboratorio di Oncoematologia Pediatrica, Department of Pediatrics, University, Padova, Italy.
Veltroni
Marinella
M
Valsecchi
Maria Grazia
MG
Dworzak
Michael N
MN
Ratei
Richard
R
Silvestri
Daniela
D
Benetello
Alessandra
A
Buldini
Barbara
B
Maglia
Oscar
O
Masera
Giuseppe
G
Conter
Valentino
V
Arico
Maurizio
M
Biondi
Andrea
A
Gaipa
Giuseppe
G
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D005434:Flow Cytometry; D006801:Humans; D053208:Kaplan-Meier Estimate; D018365:Neoplasm, Residual / Q000473:pathology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D011239:Prednisolone / Q000008:administration & dosage; D011379:Prognosis; D012008:Recurrence; D012306:Risk
D000305:Adrenal Cortex Hormones; D003907:Dexamethasone; D011239:Prednisolone