A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.
BACKGROUND
Genetic subtypes of acute lymphoblastic leukaemia (ALL) are used to determine risk and treatment in children. 25% of precursor B-ALL cases are genetically unclassified and have intermediate prognosis. We aimed to use a genome-wide study to improve prognostic classification of ALL in children.


METHODS
We constructed a classifier based on gene expression in 190 children with newly diagnosed ALL (German Cooperative ALL [COALL] discovery cohort) by use of double-loop cross-validation and validated this in an independent cohort of 107 newly diagnosed patients (Dutch Childhood Oncology Group [DCOG] independent validation cohort). Hierarchical cluster analysis with classifying gene-probe sets revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics.


RESULTS
Our classifier predicted ALL subtype with a median accuracy of 90.0% (IQR 88.3-91.7) in the discovery cohort and correctly identified 94 of 107 patients (accuracy 87.9%) in the independent validation cohort. Without our classifier, 44 children in the COALL cohort and 33 children in the DCOG cohort would have been classified as B-other. However, hierarchical clustering showed that many of these genetically unclassified cases clustered with BCR-ABL1-positive cases: 30 (19%) of 154 children with precursor B-ALL in the COALL cohort and 14 (15%) of 92 children with precursor B-ALL in the DCOG cohort had this BCR-ABL1-like disease. In the COALL cohort, these patients had unfavourable outcome (5-year disease-free survival 59.5%, 95% CI 37.1-81.9) compared with patients with other precursor B-ALL (84.4%, 76.8-92.1%; p=0.012), a prognosis similar to that of patients with BCR-ABL1-positive ALL (51.9%, 23.1-80.6%). In the DCOG cohort, the prognosis of BCR-ABL1-like disease (57.1%, 31.2-83.1%) was worse than that of other precursor B-ALL (79.2%, 70.2-88.3%; p=0.026), and similar to that of BCR-ABL1-positive ALL (32.5%, 2.3-62.7%). 36 (82%) of the patients with BCR-ABL1-like disease had deletions in genes involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1; only nine (36%) of 25 patients with B-other ALL had deletions in these genes (p=0.0002). Compared with other precursor B-ALL cells, BCR-ABL1-like cells were 73 times more resistant to L-asparaginase (p=0.001) and 1.6 times more resistant to daunorubicin (p=0.017), but toxicity of prednisolone and vincristine did not differ.


CONCLUSIONS
New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL.


BACKGROUND
Dutch Cancer Society, Sophia Foundation for Medical Research, Paediatric Oncology Foundation Rotterdam, Centre of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute, and American Lebanese Syrian Associated Charities.
Den Boer
Monique L
ML
Department of Paediatric Oncology and Haematology, Erasmus MC-Sophia Children's Hospital, University Medical Centre, Rotterdam, Netherlands. m.l.denboer@erasmusmc.nl
van Slegtenhorst
Marjon
M
De Menezes
Renée X
RX
Cheok
Meyling H
MH
Buijs-Gladdines
Jessica G C A M
JG
Peters
Susan T C J M
ST
Van Zutven
Laura J C M
LJ
Beverloo
H Berna
HB
Van der Spek
Peter J
PJ
Escherich
Gaby
G
Horstmann
Martin A
MA
Janka-Schaub
Gritta E
GE
Kamps
Willem A
WA
Evans
William E
WE
Pieters
Rob
R
D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D015870:Gene Expression; D020869:Gene Expression Profiling; D016313:Genes, abl / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D016896:Treatment Outcome