Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study.

Myeloid leukemia of Down syndrome has a better prognosis than sporadic pediatric acute myeloid leukemia. Most cases of myeloid leukemia of Down syndrome are characterized by additional cytogenetic changes besides the constitutional trisomy 21, but their potential prognostic impact is not known. We, therefore, conducted an international retrospective study of clinical characteristics, cytogenetics, treatment, and outcome of 451 children with myeloid leukemia of Down syndrome. All karyotypes were centrally reviewed before assigning patients to subgroups. The overall 7-year event-free survival for the entire cohort was 78% (± 2%), with the overall survival rate being 79% (± 2%), the cumulative incidence of relapse 12% (± 2%), and the cumulative incidence of toxic death 7% (± 1%). Outcome estimates showed large differences across the different cytogenetic subgroups. Based on the cumulative incidence of relapse, we could risk-stratify patients into two groups: cases with a normal karyotype (n=103) with a higher cumulative incidence of relapse (21%± 4%) than cases with an aberrant karyotype (n=255) with a cumulative incidence of relapse of 9% (± 2%) (P=0.004). Multivariate analyses revealed that white blood cell count ≥ 20 × 10(9)/L and age >3 years were independent predictors for poor event-free survival, while normal karyotype independently predicted inferior overall survival, event-free survival, and relapse-free survival. In conclusion, this study showed large differences in outcome within patients with myeloid leukemia of Down syndrome and identified novel prognostic groups that predicted clinical outcome and hence may be used for stratification in future treatment protocols.

Profile of thrombin generation in children with acute lymphoblastic leukemia treated by Berlin-Frankfurt-Münster (BFM) protocols.

Treatment with L-asparaginase is associated with coagulation disturbances with deep venous thrombosis being the most common clinical consequence. Use of the calibrated automated thrombogram allows precise estimation of thrombin generated in vitro. We show the first data on thrombin generation, measured by calibrated automated thrombography (CAT), in children with acute lymphoblastic leukemia treated with L-asparaginase. Thrombin generation was measured by means of CAT in 23 children treated for acute lymphoblastic leukemia. Samples were obtained at predefined time points during the induction and reinduction phase of acute lymphoblastic leukemia-intercontinental Berlin-Frankfurt-Münster (BFM) 2000 or Associazione Italiana Ematologica Oncologia Pedaitrica Interim BFM 2000 protocols. Antihrombin and fibrinogen were measured on the same sample. Twenty-eight sets of thrombin generation measurements were collected from 23 patients. We observed no significant effect of antithrombin deficiency and/or hypofibrinogenemia on thrombin generation. Endogenous thrombin generation and peak thrombin were significantly higher during induction than in the reinduction phase (P < 0.001). Four patients with severe infection experienced an increase in thrombin generation, reaching maximum in a median of 7.5 days after the onset of infection. Two of those patients developed deep venous thrombosis at the time of peaked endogenous thrombin generation. Thrombin generation in children with acute lymphoblastic leukemia treated according to BFM protocols is significantly higher during the induction phase compared with reinduction and is not substantially affected by hypofibrinogenemia and/or antithrombin deficiency. Severe infection during the induction phase enhances thrombin generation with subsequent risk of thrombosis.

Treatment of deep venous thrombosis with low molecular weight heparin in pediatric cancer patients: safety and efficacy.

Few complete reports exist regarding treatment of venous thromboembolism in children undergoing chemotherapy. We designed this study to unify the treatment of venous thromboembolism in oncology pediatric patients at our department. At the same time, we wanted to evaluate the safety and efficacy of our newly designed treatment schedule. Data from pediatric oncology patients with deep venous thrombosis (DVT) treated at the Department of Pediatric Oncology, Brno, was collected prospectively over a 2-year period (1 January 2006 to 31 December 2007). All patients received low molecular weight heparin (LMWH) at an initial dose of 1.2-1.5 mg/kg body weight subcutaneously (s.c.) twice daily for the first 7-10 days. Afterwards, the dose was lowered to 1.5 mg/kg s.c. once daily. We kept this dose unchanged for a minimum of 3 months. For the first 6 weeks of treatment, the platelet count was maintained 20 x 10/l or more with no concomitant LMWH withdrawal. For the rest of the treatment, LMWH was interrupted once platelets dropped below 20 x 10/l. A total of 33 patients were followed for a median of 6 months. DVT was symptomatic in 15 of 33 patients (46%) and asymptomatic in 18 of 33 (54%) patients. Complete thrombus resolution occurred in 22 of 33 (67%) patients, partial or no recanalization was achieved in 11 of 33 (33%) patients. Eight patients (eight of 33, 24%) were diagnosed with postthrombotic syndrome (PTS). The risk of PTS was significantly higher for patients with symptomatic DVT than in those with asymptomatic DVT. Neither patency rates nor the risk of PTS showed a positive correlation with the achievement of therapeutic anti-Xa activity. Thrombocytopenia less than 20 x 10/l occurred at least once during LMWH treatment in 30/33 (91%) patients. None of the patients experienced severe bleeding, whereas mild bleeding episodes were observed in five of 33 (15%) patients. Our treatment schedule has proved to be both well tolerated and reasonably efficient in treating DVT in children undergoing chemotherapy. Further studies on larger patient groups are warranted.

Pre-natal, clonal origin of acute lymphoblastic leukaemia in triplets.

A unique case of ALL in three monozygotic triplets diagnosed at the age of 24, 27 and 37 months is described. Archived bone marrow smears were available for molecular analysis of immunoglobulin heavy chain (IGH) and IGK genes and T-cell receptor (TCR)-delta and gamma gene rearrangements. A shared IGH rearrangement was found in triplets "A" and "B", and an identical rearrangement of TCR-delta in triplets "B" and "C". These data suggest a common, monoclonal initiation of ALL in one of these three triplets, followed by dissemination of clonal progeny to the other twins via vascular anastomoses within the single, monochorionic placenta that they shared in utero. Differences in IGH rearrangements in diagnostic samples also indicates divergent subclonal evolution of the original "pre-leukaemic" clone.