Genome-Wide Study Identifies New Type Of Childhood Acute Lymphoblastic Leukaemia Associated With Poor Treatment Outcome

Main Category: Lymphoma / Leukemia / Myeloma
Also Included In: Blood / Hematology;  Pediatrics / Children's Health
Article Date: 09 Jan 2009 - 3:00 PST

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A genetic analysis of children with newly diagnosed acute lymphoblastic leukaemia (ALL) has identified a new subtype of this disease that is associated with a poor treatment outcome, according to an Article published early Online and in the February issue of The Lancet Oncology.

Patients who have particular subtypes of ALL have an unfavourable prognosis. About 25% have genetically unclassified disease, and the high frequency of relapse in these patients highlights the need for further understanding of the biological causes of this disease and for further treatment options. Studies of the genome are one way that researchers have gained insight into the subtypes of ALL and their characteristics. This approach can aid disease classification and help guide treatment decisions.

Dr Monique Den Boer (Erasmus MC, University Medical Centre, Rotterdam, Netherlands) led an international multidisciplinary team, who aimed to analyse whether a genome-wide study could improve the prognostic classification of ALL in children. This research team used an innovative method to characterise the genetic profile of children with ALL, and validated this method in a separate group of children to test its accuracy.

Dr Den Boer and colleagues obtained bone-marrow and peripheral-blood samples from children with newly diagnosed ALL who were enrolled in a study by the German Cooperative ALL Study Group (190 children) or in a study by the Dutch Childhood Oncology Group (107 children). Samples were obtained with consent before the children had received treatment. The researchers used genetic material from a proportion of patients from the German study group to select a number of probes that were combined into a so-called gene-expression classifier that could be used to classify subtypes of paediatric ALL; genetic material from the remaining patients in this study group was used to estimate the predictive accuracy of the probes. The accuracy of this classifier was investigated and validated using samples from the children in the Dutch study group.

The gene-expression classifier identified the correct subtype of ALL in 90% of children in the German study group and 88% of children in the Dutch validation group. Importantly, detailed analysis of the German group identified 30 patients without known genetic abnormalities who had a gene-expression pattern that resembled patients who are positive for the aberrant BCR-ABL1 fusion gene characteristic of a rare subtype of ALL with a very poor outcome. The relapse rate among these 30 patients was double that of patients in a control group, and these patients had poor 5-year disease-free survival, similar to that of patients with BCR-ABL1-positive ALL.

In the Dutch validation group, 14 children were classified as having BCR-ABL1-like ALL. These children also had a relapse rate double that of children who had B-cell lineage ALL and had poor 5-year disease-free survival compared with patients with B-cell lineage ALL. Further detailed genetic studies showed that more than 80% of these BCR-ABL1-like patients had abnormalities in genes that control B-cell development. The BCR-ABL1-like group thus seems to represent 15-20% of precursor B-ALL cases, forming a larger subgroup of patients than the currently known poor prognostic subgroups (BCR-ABL1-positive and MLL-rearranged ALL).

"These data suggest that the BCR-ABL1-like [subtype] constitutes a large subgroup with poor prognosis that is unrecognised with current diagnostic markers. 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", says Dr Den Boer. "Improved treatment of this high-risk leukaemia will have a great effect on the overall cure rate of childhood ALL."

The Lancet Oncology

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Tony Kirby
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