Prognostic relevance of ALL-1 gene rearrangement in infant acute leukemias

We and others have recently reported a high frequency (70-80%) of ALL-1 (MLL, HRX, HTRX) gene rearrangements in infants with acute leukemias (AL) aged less than 1 year. Preliminary observations in limited series also suggested that ALL-1 gene configuration is an important prognostic factor in this leukemic subset. We have now extended our study to a series of 45 AL patients aged between 0 and 18 months. The genomic configuration of ALL-1 in leukemic DNAs was determined by Southern blot hybridization and correlated with biological and clinical features at presentation, as well as with treatment outcome. Twenty-nine out of 45 (64%) patients showed ALL-1 rearrangements, including 4/11 (36%) infants aged between 13 and 18 months. Considering morphological types, 24/38 cases with acute lymphoblastic leukemia and 5/7 patients with acute myeloid leukemia showed ALL-1 rearrangements. The features more frequently found in association with ALL-1 rearrangements were hyperleukocytosis (P < 0.007) and CD19+/CD10- blast immunophenotype (P < 0.02). ALL-1 status was an independent prognostic marker of event-free survival (EFS) in a multivariate model including age, sex and WBC count, and maintained its statistical significance when FAB morphology was considered in the analysis by including AML patients. Considering the ALL cases the actuarial EFS was 57 and 9% for infants with germline and rearranged ALL-1 configuration, respectively (P = 0.008). A high frequency of ALL-1 gene alterations in infant AL is confirmed by this study. In addition, our results emphasize the need for extending the analysis of ALL-1 gene status to infants with AL aged > 12 months. We show that this genetic lesion is the most important variable negatively affecting prognosis in a multivariate model including other known risk factors. This latter observation should influence the choice of risk-adapted treatment strategies in this AL subset.