Among risk factors for developing thromboembolism (VTE) in children with acute lymphoblastic leukemia were Escherichia coli asparaginase, concomitant steroid use, presence of central venous lines, ...and thrombophilic abnormalities. Developing a predictive model for determining children at increased risk would be beneficial in targeting interventional studies to high-risk groups (HRGs). Predictive variables were incorporated into a risk assessment model, which was evaluated in 456 children and then validated in 339 patients. VTE risk by score was no greater than 2.5 for low-risk group (LRG) and greater than 2.5 for HRG. VTE rates at 3.5 months (validation cohorts) were 2.5% in LRG and 64.7% in HRG. In multivariate analysis adjusted for age, duration of asparaginase administration, enoxaparin prophylaxis, and T-immunophenotype, the HRG was significantly associated with VTE compared with the LRG (hazard/95% confidence interval CI, 8.22/1.85-36.53). Model specificity was 96.2% and sensitivity was 63.2%. As secondary objective we investigated the use of enoxaparin for VTE prophylaxis in the HRG. HRG patients without enoxaparin prophylaxis showed a significantly reduced thrombosis-free survival compared with children on low-molecular-weight heparin (LMWH). On the basis of the high specificity, the model may identify children with leukemia at risk of VTE. LMWH may help prevent VTE in the HRG; this warrants assessment in larger cooperative clinical trials.
...the (genetic) diagnostic delay was long for many patients (see below). ...we looked at whether the patients' region of residence within France (which potentially influences access to a genetic ...diagnosis) was associated with the likelihood of receiving a genetic diagnosis. The progressive shift in genetic testing strategy from candidate-gene sequencing to gene panels or whole-exome or whole-genome sequencing4-6,9 is likely to have a major effect on the overall identification of PID-causing gene mutations. ...the present study might serve as a baseline for analyzing the contribution of next-generation sequencing–based testing to the genetic diagnosis of PIDs in the next 10 years.Methods The French National Reference Center for PIDs (CEREDIH) encompasses a network of pediatricians, adult clinicians, and immunologists working in immunology laboratories throughout mainland France and the overseas French territories. ...these factors were unlikely to significantly affect our overall results.
We present a rapid strategy based on Restriction Fragment Length Polymorphism (RFLP) analysis to characterize the more frequent glucose 6-phosphate dehydrogenase (G6PD) variants observed in a ...population with high gene flow. During a study involving more than 600 patients, we observed mainly G6PD A(-) (c.202G>A, c.376A>G; p.Val68Met, p.Asn126Asp), G6PD Mediterranean (Med) (c.563C>T, p.Ser188Phe), and G6PD Betica (c.376A>G, 542A>T; p.126Asn>Asp, 181Asp>Val) with addition of a few rare ones. A number of 10 abnormalities amounted to 92% of all the molecular defects. In addition, seven new mutations were found: three presented with acute hemolytic anemia following oxidative stress G6PD Nice (c.1380G>C, p.Glu460Asp), G6PD Roubaix (c.811G>C, p.Val271Leu), and G6PD Toledo (c.496C>T, p.Arg166Cys), three with different degrees of chronic hemolytic anemia G6PD Lille (c.821A>T, p.Glu274Val), G6PD Villeurbanne (c.1000_1002delACC, p.Thr334del), and G6PD Amiens (c.1367A>T, p.Asp456Val) and one found fortuitously G6PD Montpellier (c.1132G>A, p.Gly378Ser).
Thromboembolic events are currently among the most serious complications occurring during treatment of acute lymphoblastic leukaemia (ALL), and account for cases of morbidity and even mortality. The ...role of L-Asparaginase, particularly that of E. coli L-Asparaginase (L-ASPA) in association or not with corticotherapy has been demonstrated by several authors. Most of the time, these thromboses are located within the central nervous system. Our retrospective study was carried out from December 2000 to December 2004 within 18 French centres. 902 children were prospectively included in the FRALLE 2000 protocol and were assigned to two risk groups: the A group with standard risk ALL (n=502) received dexamethasone during induction and 9 infusions of 6000 U/m2 of L-ASPA, while the B group with high risk ALL (n=400) was to receive prednisone. Both groups received a delayed intensification with dex and L-ASPA. 27 thrombotic events were reported, 16 of which were cerebrovascular accidents. The thromboses lay in the superior sagittal sinus (n=14), in the lateral sinus (n=7) and in the sinus rectus (n=2) and were revealed by convulsions in 30,7% of the cases and by diffuse neurologic signs in 68,7% of the cases. The course turned out positively 15 times out of 16, but one child died of haemorrhage. Hereditary thrombophilic factors were evaluable in 15 patients out of 16. We found out a congenital Protein C deficiency in one patient, but no Protein S or anti-thrombin deficiencies. We found out two Factor V G1691A heterozygous mutations and two Factor II G20210A heterozygous mutations. Five patients out of 14 have a MTHFR C677T mutation: one is homozygous in combination with a Factor V G1691A mutation, and 4 are heterozygous, isolated in two cases, in combination with a Factor V G1691A mutation in one case, and in combination with a Factor II G20210A in the other. Hereditary thrombophilic factors (isolated heterozygous MTHFR C677T mutations excepted) were thus reported in 31,2% (n = 5) of the cases.
Conclusion: even if the frequency of thrombophilia may be underestimated in this study due to its retrospective design and non exhaustivity (APL antibodies, lipoprotein A were not investigated), it nevertheless points out CNS thrombosis represents an important cause of morbidity in childhood ALL treated with high dose steroid and L-ASPA. A prospective analysis of all thrombophilic factors seems justified in this setting for prevention possibly based on LMWH.
This retrospective study was designed to determine the prevalence of inherited prothrombotic risk factors (Factor V Leiden (FV) G1691A and prothrombin G20210A mutations, TT677 genotype of the ...methylenetetrahydrofolate reductase (MTHFR), protein C, protein S, antithrombin deficiencies) in a population of children with ALL treated according to the FRALLE 2000 study Protocol (High Risk and Standard Risk groups). The study was performed in 5 French Centers including Amiens, Angers, Paris Trousseau, Rouen and Saint-Etienne. From December 2000 to March 2006, 354 children aged 1 to 18 years old were consecutively admitted for ALL and were enrolled in the FRALLE 2000 Protocol. Among them, 281 patients were investigated for hereditary prothrombotic defects at the time of ALL diagnosis. Informed parental consent was required for gene analysis. Abnormal test results for protein S (functional activity and free protein S antigen concentration), protein C and antithrombin were controlled on a second blood sample after induction. In the population studied, the prevalence of one established prothrombotic risk factor was 19,2%: the FV G1691A mutation was diagnosed in 10 patients (3.6%), all heterozygous, 10 patients (3.6%) showed the heterozygous prothrombin G20210A mutation, the TT677 MTHFR genotype was found in 34 children (12.7%), 1 patient showed protein C deficiency (0.4%). No antithrombin deficiency was detected. The prevalence of inherited protein S deficiency could not be evaluated because of missing data in the family medical history. Combined prothrombotic defects were found in 2 patients (0.71%): heterozygous FV G1691A mutation combined with heterozygous prothrombin G20210A mutation in 1 patient and combined with TT677 MTHFR genotype in the second patient. Except for TT677 MTHFR genotype, the prevalence of hereditary prothrombotic risk factors in children with ALL in France were found within the prevalence reported for children treated for ALL (table 1) and comparable to the prevalence in healthy Europeans (Junker et al. 1999, Margaglione et al 2001, Mueller et al. 2005).
Comparison of the prevalence of inherited prothrombotic risk factors in children with ALLCountryPopulationFV G1691A +/− ++PT G20210A +/− +/+MTHFR TT677ATPCNowakGöttl et al 1999 (n=301)GermanyALL children5.3% 0.3%2% 0%7.7%0.7%2.3%Mauz-Körholz et al. 2000 (n=108)GermanyALL children5.6% 0%2.8% 0%5.6%0%2.7%Mitchell et al. 2002 (n=60)CanadaALL children3.3% 0%2% 0%NENENEPresent study (n=281)FranceALL children3.6% 0% (n=277)3.6% 0%(n=279)2.7% (n=268)0%0.4%AT: antithrombin deficiency ; PC: protein C deficiency ; NE : non evaluated
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