Déficit en facteur v induit par la 6-mercaptopurine au cours du traitement d'entretien des leucémies aigües lymphoblastiques de l'enfant

Le traitement d'entretien des leucémies aiguës lymphoblastiques (LAL) a pour but d'éradiquer les cellules leucémiques persistantes, après la rémission et les 6 mois de chimiothérapie intensive. Il est basé sur la 6-mercaptopurine (6-MP) quotidienne et le méthotrexate hebdomadaire. Les effets secondaires de la 6-MP (hépatotoxicité, myélotoxicité) sont corrélés aux concentrations de ses différents métabolites, et dépendent de polymorphismes génétiques des enzymes impliquées dans son métabolisme. Trois patients traités pour une LAL dans le service d'immuno-hématologie et oncologie pédiatrique du CHU de Rouen, ont développé un déficit en facteur V (FV) au cours du traitement d'entretien. Ce déficit était réversible à l'arrêt ou à la diminution de posologie de la 6-MP. Il s'y associait inconstamment une baisse du facteur VII, ou des facteurs II, VII et X. Ces troubles de l'hémostase étaient asymptomatiques. Des concentrations élevées en dérivés méthylés de la 6-MP ont été mises en évidence de façon concomitante à la baisse du FV. L'algorithme d'imputabilité de Naranjo indique une association certaine dans 2 cas et probable dans un cas entrer la 6-MP et la baisse du FV. Très peu de patients ayant présenté une toxicité similaire sont décrits dans la littérature. Le mécanisme d'action n'est pas connu. Il pourrait s'agir d'un défaut de modifications post-traductionnelles du FV induit par un métabolite de la 6-MP

Déficit en facteur v induit par la 6-mercaptopurine au cours du traitement d entretien des leucémies aigües lymphoblastiques de l enfant

Le traitement d entretien des leucémies aiguës lymphoblastiques (LAL) a pour but d'éradiquer les cellules leucémiques persistantes, après la rémission et les 6 mois de chimiothérapie intensive. Il est basé sur la 6-mercaptopurine (6-MP) quotidienne et le méthotrexate hebdomadaire. Les effets secondaires de la 6-MP (hépatotoxicité, myélotoxicité) sont corrélés aux concentrations de ses différents métabolites, et dépendent de polymorphismes génétiques des enzymes impliquées dans son métabolisme. Trois patients traités pour une LAL dans le service d immuno-hématologie et oncologie pédiatrique du CHU de Rouen, ont développé un déficit en facteur V (FV) au cours du traitement d entretien. Ce déficit était réversible à l arrêt ou à la diminution de posologie de la 6-MP. Il s y associait inconstamment une baisse du facteur VII, ou des facteurs II, VII et X. Ces troubles de l hémostase étaient asymptomatiques. Des concentrations élevées en dérivés méthylés de la 6-MP ont été mises en évidence de façon concomitante à la baisse du FV. L algorithme d imputabilité de Naranjo indique une association certaine dans 2 cas et probable dans un cas entrer la 6-MP et la baisse du FV. Très peu de patients ayant présenté une toxicité similaire sont décrits dans la littérature. Le mécanisme d action n est pas connu. Il pourrait s agir d un défaut de modifications post-traductionnelles du FV induit par un métabolite de la 6-MP.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

Ifosfamide-induced encephalopathy due to a novel formulation of ifosfamide

International audienc

Possible role of CYP2B6 genetic polymorphisms in ifosfamide-induced encephalopathy: report of three cases

International audienc

HSCT may lower leukemia risk in ELANE neutropenia: a before–after study from the French Severe Congenital Neutropenia Registry

International audienceELANE neutropenia is associated with myelodysplasia and acute leukemia (MDS–AL), and severe infections. Because the MDS–AL risk has also been shown to be associated with exposure to GCSF, since 2005, in France, patients receiving high daily GCSF doses (>15 μg/kg/day) are eligible for HSCT, in addition to classic indications (MDS–AL or GCSF refractoriness). We analyzed the effect of this policy. Among 144 prospectively followed ELANE-neutropenia patients enrolled in the French Severe Congenital Neutropenia Registry, we defined two groups according to period: “before 2005” for those born before 2005 and followed until 31/12/2004 (1588 person-years); and “after 2005” comprised of those born after 2005 or born before 2005 but followed after 2005 until 31/03/2019 (1327 person-years). Sixteen of our cohort patients underwent HSCT (14 long-term survivors) and six developed MDS–ALs. Six leukemic transformations occurred in the before-2005 group and none after 2005 (respective frequencies 3.8 × 10–3 vs. 0; P < 0.01), while four HSCTs were done before 2005 and 12 since 2005 (respective HSCT rates increased 2.5 × 10–3 vs. 9 × 10–3; P < 0.01). Our results support early HSCT for patients with ELANE mutations who received high GCSF doses, as it might lower the risk of leukemic transformation

Molecular and clinicopathologic characterization of pediatric histiocytoses

Molecular and clinicopathologic characterization of pediatric histiocytoses

A French national breast and thyroid cancer screening programme for survivors of childhood, adolescent and young adult (CAYA) cancers - DeNaCaPST programme

Abstract Background Survival of childhood, adolescent and young adult (CAYA) cancers has increased with progress in the management of the treatments and has reached more than 80% at 5 years. Nevertheless, these survivors are at great risk of second cancers and non-malignant co-morbidities in later life. DeNaCaPST is a non-interventional study whose aim is to organize a national screening for thyroid cancer and breast cancer in survivors of CAYA cancers. It will study the compliance with international recommendations, with the aim, regarding a breast screening programme, of offering for every woman living in France, at equal risk, an equal screening. Method DeNaCaPST trial is coordinated by the INSERM 1018 unit in cooperation with the LEA (French Childhood Cancer Survivor Study for Leukaemia) study’s coordinators, the long term follow up committee and the paediatric radiation committee of the SFCE (French Society of Childhood Cancers). A total of 35 centres spread across metropolitan France and la Reunion will participate. FCCSS (French Childhood Cancer Survivor Study), LEA and central registry will be interrogated to identify eligible patients. To participate, centers agreed to perform a complete “long-term follow-up consultations” according to good clinical practice and the guidelines of the SFCE (French Society of Children Cancers). Discussion As survival has greatly improved in childhood cancers, detection of therapy-related malignancies has become a priority even if new radiation techniques will lead to better protection for organs at risk. International guidelines have been put in place because of the evidence for increased lifetime risk of breast and thyroid cancer. DeNaCaPST is based on these international recommendations but it is important to recognize that they are based on expert consensus opinion and are supported by neither nonrandomized observational studies nor prospective randomized trials in this specific population. Over-diagnosis is a phenomenon inherent in any screening program and therefore such programs must be evaluated

Late toxicity comparison of alkylating-based maintenance regimen with cyclophosphamide (VAC) vs ifosfamide (VAI) in Ewing sarcoma survivors treated in the randomized clinical trial Euro-EWING99-R1 in France

International audienceIn Euro-EWING99-R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard-risk Ewing sarcoma (SR-EWS) after a common induction with VIDE (vincristine-ifosfamide-doxorubicin-etoposide). We present the results of the late effects analysis of VAC (vincristine-dactinomycin-cyclophoshamide) vs VAI (vincristine-dactinomycin-ifosfamide) conducted in Euro-EWING99-R1 French cohort. Of 267 French randomized patients, 204 were alive and free-of-relapse at 5-years including 172 with available long-term follow-up data concerning cardiac, renal and/or gonadal functions (sex-ratio M/F = 1.3, median age at diagnosis = 14 years): 84 randomized in VAC (median cumulative doses: cyclophosphamide = 9.7 g/m2, ifosfamide = 59.4 g/m2) and 88 in VAI (ifosfamide = 97.1 g/m2). With a median follow-up of 10 years (range = 5-17), five late relapses and five second malignancies were recorded. The 10-year event-free survival among 5-year free-of-relapse survivors was similar between VAC and VAI (93% vs 95%, P =.63). We estimated the 10-year cumulative probabilities of cardiac and kidney toxicities at 4.4% (95% confidence interval [95% CI] = 1.1%-7.6%) and 34.8% (95% CI = 26.8%-42.0%), respectively. Cardiac toxicity cumulative probability was similar in both arms, whereas kidney toxicity was higher in VAI (at 10 years, 43.0% vs 25.7%, P =.02), resulting from significant difference in glomerular toxicity (31.1% vs 13.1%, P &lt;.01). At 10 years, gonadal toxicity was observed in 27% and 28% of pubertal men and women, respectively, without significant difference between VAC and VAI. Kidney and gonadal toxicities represent major issues in Euro-EWING99-R1, with significantly higher risk of kidney toxicities with VAI, without significant gonadal toxicity reduction. These results support the need to limit cumulative doses of both alkylating agents and to use mixed regimen as in VIDE-VAC or VDC/IE (vincristine-doxorubicin-cyclophoshamide/ifosfamide-etoposide)

Molecular and clinicopathologic characterization of pediatric histiocytoses

International audienceThe spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E. Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E-mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches

Additional file 1: Document 2. of A French national breast and thyroid cancer screening programme for survivors of childhood, adolescent and young adult (CAYA) cancers - DeNaCaPST programme

Survey about LTFU care and specific questions about second cancers. (DOCX 13 kb