• The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse

      Schmiegelow, K; Heyman, M; Gustafsson, G; Lausen, B; Wesenberg, F; Kristinsson, J; Vettenranta, K; Schroeder, H; Forestier, E; Rosthoej, S; et al. (Nature Publishing Group, Specialist Journals, 2010-04-01)
      Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (>or=10 years) and 176 non-adolescents (<10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) <50 x 10(9)/l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS(12y):0.71 vs 0.83, P=0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (r(S)=0.36, P=0.02), which became nonsignificant for those who relapsed (r(S)=0.05, P=0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P=0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient=0.65, P=0.003) than for non-adolescents (coefficient=0.42, P=0.04). Adolescents had higher mean neutrophil counts (P=0.002) than non-adolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (r(S)=0.38, P=0.02), which was not the case for those who developed a relapse (r(S)=0.15, P=0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.
    • Dic(9;20)(p13;q11) in childhood acute lymphoblastic leukaemia is related to low cellular resistance to asparaginase, cytarabine and corticosteroids.

      Lönnerholm, G; Nordgren, A; Frost, B-M; Jonsson, O G; Kanerva, J; Nygaard, R; Schmiegelow, K; Larsson, R; Forestier, E (Nature Publishing Group, Specialist Journals, 2009-01-01)
      Dic(9;20)(p13;q11) was first described as a nonrandom chromosome abnormality in B-cell precursor acute lymphoblastic leukaemia (BCP ALL) in the mid 1990s,1, 2 and 71 dic(9;20)-positive cases have since then been reported.3, 4, 5 Approximately 90% of these cases were children or adolescents, with dic(9;20) occurring in about 2% of childhood BCP ALL.6 The recent review by Forestier et al.5 describes that dic(9;20)-leukaemias are of B-cell precursor immunophenotype, never have a high hyperdiploid modal number, show a female predominance, and have a significant age incidence peak at 3 years. Most patients are allocated to non-standard risk treatment arms due to high WBC (median 24 109/l) and a relatively high frequency of CNS disease or other extra-medullary leukaemia (EML) at diagnosis. The prognostic implications of dic(9;20) are to a large extent unknown. A relatively large proportion of the relapses reported in the literature have been extra-medullary, and post-relapse treatment including block therapy has been successful in several patients, as illustrated by a p-EFS of 0.62 and a predicted overall survival of 0.82 at 5 years for the 24 Nordic cases.5
    • Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia

      Schmiegelow, K; Forestier, E; Hellebostad, M; Heyman, M; Kristinsson, J; Söderhäll, S; Taskinen, M; Faculty of Medicine, The Institute of Gynaecology, Obstetrics, and Paediatrics, University of Copenhagen, Copenhagen, Denmark. kschmiegelow@rh.dk (Nature Publishing Group, Specialist Journals, 2010-02-01)
      Analysis of 2668 children with acute lymphoblastic leukemia (ALL) treated in two successive Nordic clinical trials (Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-92 and ALL-2000) showed that 75% of all patients are cured by first-line therapy, and 83% are long-term survivors. Improvements in systemic and intrathecal chemotherapy have reduced the use of central nervous system (CNS) irradiation to <10% of the patients and provided a 5-year risk of isolated CNS relapse of 2.6%. Improved risk stratification and chemotherapy have eliminated the previous independent prognostic significance of gender, CNS leukemia and translocation t(1;19)(q23;p13), whereas the post-induction level of minimal residual disease (MRD) has emerged as a new risk grouping feature. Infant leukemia, high leukocyte count, T-lineage immunophenotype, translocation t(4;11)(q21;q23) and hypodiploidy persist to be associated with lower cure rates. To reduce the overall toxicity of the treatment, including the risk of therapy-related second malignant neoplasms, the current NOPHO ALL-2008 protocol does not include CNS irradiation in first remission, the dose of 6-mercaptopurine is reduced for patients with low thiopurine methyltransferase activity, and the protocol restricts the use of hematopoietic stem cell transplantation in first remission to patients without morphological remission after induction therapy or with high levels of MRD after 3 months of therapy.
    • Translocation t(1;19) is related to low cellular drug resistance in childhood acute lymphoblastic leukaemia

      Frost, B M; Forestier, E; Gustafsson, G; Nygren, P; Hellebostad, M; Jonmundsson, G; Kanerva, J; Schmiegelow, K; Larsson, R; Lönnerholm, G (Nature, 2005-01-01)
      Presents a letter to the editor about a study indicating that translocation t(1;19) is related to low cellular drug resistance in childhood acute lymphoblastic leukaemia.