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. Findings: 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. Interpretation: New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL. Funding: 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.