January 14, 2009 — Several subgroups of pediatric acute lymphoblastic leukemia (ALL) have poorer outcomes, and separating cases into genetic subtypes can help determine risk and management. Researchers have now identified a new subtype of ALL that is associated with an unfavorable outcome, according to an article published online January 8 in the Lancet Oncology.
An examination of cases that would generally be considered to be in the B-other subtype revealed that 15% to 20% of children newly diagnosed with ALL had genetic abnormalities that were similar to but distinct from the BCR–ABL1-positive subtype. Patients with this BCR–ABL1 subtype had a poorer prognosis than children with other types of precursor B-cell ALL.
The researchers also observed that cells isolated from this patient group were more resistant to conventional treatments. The cells obtained from patients with BCR–ABL1-like ALL were a median of 73 times more resistant to L-asparaginase and 1.6 times more resistant to daunorubicin than patients with other types of precursor B-cell ALL, but no significant difference was seen in the cytotoxic effects of prednisolone or vincristine.
“These data suggest that the BCR–ABL1-like [subtype] constitutes a large subgroup with poor prognosis that is unrecognized with current diagnostic markers,” said lead author Monique L. Den Boer, PhD, from Erasmus Medical Center–Sophia Children’s Hospital, in Rotterdam, the Netherlands, in a statement. “These patients should receive more intensive therapy with available drugs or with new more targeted drugs for which the biology of the BCR–ABL1-like subtype needs further study. Improved treatment of this high-risk leukemia will have a great effect on the overall cure rate of childhood ALL.”
BCR–ABL1-Like Disease Identified
About 25% of precursor B-cell ALL cases remain genetically unclassified (B-other) and have an intermediate prognosis, indicating a need for new biological insights and treatment options. An international multidisciplinary team, led by Dr. Den Boer, aimed to analyze whether gene-expression signatures could improve genetic classification of ALL in children.
Bone-marrow and peripheral-blood samples were obtained from children with newly diagnosed ALL who were enrolled in the German Cooperative ALL Study Group (n = 190) or in the Dutch Childhood Oncology Group (n = 107) before they received treatment. The researchers used a “double-loop cross-validation method,” which uses an inner loop to establish the minimum number of probe sets needed to classify ALL subtypes, and an outer loop to determine the predictive value of the constructed prediction model (classifier). They constructed a classifier, based on gene expression from the children in the German group, using double-loop cross-validation, to select a number of probes that could be used to classify subtypes of pediatric ALL. The accuracy of the classifier was validated using samples from the Dutch cohort.
The classifier identified the correct ALL subtype with a median accuracy of 90% in the patients in the German cohort and 87.9% in the validation cohort. Hierarchical clustering, identified by the classifier, showed that many genetically unclassified cases clustered with BCR–ABL1-positive cases. The BCR–ABL1-like disease was detected in 30 (19%) of 154 children with precursor B-cell ALL in the German cohort and in 14 (15%) of 92 children with precursor B-cell ALL in the Dutch cohort.
Subtype Has Unfavorable Prognosis
Children with BCR–ABL1-like disease had poorer outcomes than patients with other types of B-cell ALL. Among those in the German group, 5-year disease-free survival was 59.5%, compared with 84.4% in patients with other disease types. This prognosis, the researchers note, was similar to rates for patients with BCR–ABL1-positive ALL (51.9%).
Outcomes were similar in the Dutch cohort. The 5-year disease-free survival was 57.1% for BCR–ABL1-like disease and 79.2% for other precursor B-ALL groups. It was also similar to survival among patients with BCR–ABL1-positive disease (32.5%).
Further analysis showed that 36 (82%) children with BCR–ABL1-like disease had deletions in genes that are involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1, whereas only 9 (36%) of 25 patients with B-other ALL had deletions in these genes.
“Our study has developed and validated a new gene-expression classifier that identifies the major subtypes of childhood ALL with a high level of accuracy and sensitivity,” they conclude. “Importantly, we identified a new high-risk subtype with a gene-expression pattern similar to that of ALL cases containing the BCR–ABL1 gene fusion.”
They also noted that since the “new BCR–ABL1-like subtype is the most common poor-prognostic subtype of childhood ALL, improved treatment of this high-risk leukemia should have a great effect on the overall cure rate of childhood ALL.”
Dr. Den Boer and coauthor Rob Pieters, PhD, from Erasmus Medical Center–Sophia Children’s Hospital and a member of the Dutch Childhood Oncology Group, have submitted a patent application for classification of leukemia by gene-expression signatures. All other authors have disclosed no relevant financial relationships.
Lancet Oncology. Published online before print January 8, 2009. Abstract