Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol

Abstract

Summary. The single most important prognostic determinant in childhood acute lymphoblastic leukaemia (ALL) is effective therapy and changes in therapy may influence the significance of other risk factors. The effect of intensified therapy on the importance of currently recognized phenotypic and genotypic determinants of outcome was assessed in 2090 children enrolled on the Medical Research Council United Kingdom acute lymphoblastic leukaemia XI (MRC UKALL XI) protocol. Treatment allocation was not determined by risk factors. Multivariate analysis confirmed the dominant influence on prognosis of age, sex and presenting white cell count (WCC). After allowing for these features, blast karyotype, d 8 marrow blast percentage and remission status at the end of induction therapy were the only remaining significant predictors of outcome. Organomegaly, haemoglobin concentration, French±American±British type, body mass index, presence of central nervous system disease at diagnosis, immunophenotype and presence of TEL/AML1 fusion gene (examined in a subset of 659 patients) either had no significant effect on outcome or were significant only in univariate analysis. Among karyotype abnormalities with an independent influence on prognosis, high hyperdiploidy (. 50 chromosomes) was shown to be favourable, whereas near haploidy (23±29 chromosomes), presence of the Philadelphia chromosome, t(4;11) and abnormalities affecting the short arm of chromosome 9 [abn (9p)] were adverse risk factors. Early responders to therapy, determined by residual marrow infiltration after 8 d of induction therapy, had a good outcome, while the small proportion of patients who did not achieve a complete remission by the end of induction therapy had a poor outcome. A third block of late intensification was shown to improve event-free survival by 8% at 5 years. The effect of these risk factors was not significantly different between those randomized to the third intensification block and those not randomized to a third block.

Genome complexity in acute lymphoblastic leukemia is revealed by array-based comparative genomic hybridization

“…Cytogenetically visible 9p abnormalities have been reported to confer an adverse clinical outcome (Hann et al, 2001), whereas recent data on specific loss of CDKN2A showed no link with outcome (van Zutven et al, 2005;Mirebeau et al, 2006;). All 9p deletions in our series encompassed the CDKN2A locus.…”

Anemia and survival in childhood acute lymphoblastic leukemia

“…However, in multivariate models, Hb was not identified as an independent risk factor. 3,4 Despite the fact that Hb is not applicable for risk stratification in clinical trials, the relationship between anemia and prognosis might hold some important biological information that warrants further investigation.…”

“…Several studies have demonstrated a correlation between degree of anemia and survival. [1][2][3][4] Evidence suggests that patients presenting with higher hemoglobin (Hb) levels at diagnosis have an increased risk of poor outcome compared to patients with lower Hb levels. However, in multivariate models, Hb was not identified as an independent risk factor.…”

A unique complex translocation involving six different chromosomes in a case of childhood acute lymphoblastic leukemia with the Philadelphia chromosome and adverse prognosis

“…At least 32% of the ALL cases show clonal chromosomal abnormalities (11). The so-called Philadelphia (Ph) chromosome t(9;22) is present in 4% of pediatric ALL patients and confers an unfavorable prognosis, particularly when associated with either a high whole blood cell count (WBC) or slow early response to initial therapy (12)(13)(14).…”