[The prospects for children with acute lymphoblastic leukemia of being cured has increased in the Czech Republic in the 21st century to 90% - outcome of the ALL-IC BFM 2002 trial]. / Sance na vylécení detí s akutní lymfoblastickou leukémií stoupla v Ceské republicev 21. století na 90 % - výsledky studie ALL IC-BFM 2002.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy. Treatment has been unified in the middle of 1980 in the Czech Republic. In 2002-2007 children and adolescents with acute lymphoblastic leukemia were treated in an international randomized trial ALL-IC BFM 2002 in the Czech Republic. 291 patients aged 1-18 years were enrolled; infants below 1 year entered a separate trial. METHODS AND RESULTS: Patients were stratified into three risk groups according to their age, initial leukocyte count, prednisone response, presence of fusion genes BCR/ABL or MLL/AF4, bone marrow D+15 and remission status D+33. The whole therapy took 24 months. Randomized late intensification compared standard BFM therapy with extended, usually more intensive experimental treatment. The median follow-up was 8.7 years. Complete remission was achieved in 97.9% patients, 1% died in remission. 11% of children relapsed, 1.7% with CNS involvement. Six children (2.1%) developed secondary malignancy. Event free survival (EFS) 8 years from diagnosis was 83.5%, overall survival (OS) 91.4%. EFS and OS of the risk groups were: standard risk: 89.4%; 98.1%; intermediate risk: 82.6%; 89.6%; high risk: 68.8%; 78.1%. Male sex and age above 10 years were adverse prognostic factors. CONCLUSIONS: In comparison with the previous trial ALL-BFM 95, significant improvement was achieved.

Covert preleukemia driven by MLL gene fusion.

Acute leukemia is considered to be a two- or multiple-step process. Although there is a considerable knowledge regarding the character of the "first hit," the nature of the "second hit" remains unanswered in most of the cases including leukemias with MLL gene rearrangement. We demonstrate here a striking sequence of events, which include a covert, protracted preleukemic phase characterized by a dominant MLL/FOXO3A clone with intact myeloid differentiation and the subsequent acquisition of a secondary genetic abnormality, leading to overt lymphoblastic leukemia. Backtracking of the secondary acute lymphoblastic leukemia (sALL) with the MLL rearrangement showed no blasts in the bone marrow (BM) during the protracted preleukemic phase. However, at the same time (more than 1 year before the sALL diagnosis) the MLL/FOXO3A was present in up to 90% of BM cells including myeloid lineage, suggesting that the fusion arose in a multipotent progenitor. To identify potential "second hit" precipitating sALL we compared DNA in preleukemic versus fully leukemic samples. The analysis revealed a 10 Mb gain on 19q13.32 in the sALL, absent in the preleukemic specimen. These data provide insight into the dynamics of leukemogenesis in secondary leukemia with MLL rearrangement.