Results of successive EORTC-CLG 58 881 and 58 951 trials in paediatric T-cell acute lymphoblastic leukaemia (ALL)

Outcomes in childhood T-cell acute lymphoblastic leukaemia (T-ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T-ALL were enrolled in two successive European Organization for Research and Treatment of Cancer - Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin-Frankfurt-Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m(2)/day) versus prednisolone (60 mg/m(2)/day) and prolonged versus conventional asparaginase duration in trial 58951. 8-year event-free survival (EFS) increased from 65 center dot 1% to 74 center dot 0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts E. coli asparaginase was associated with longer EFS [hazard ratio (HR) 0 center dot 54, P = 0 center dot 0015] and overall survival (HR 0 center dot 51, P = 0 center dot 0018). Induction therapy with dexamethasone did not improve EFS compared to prednisolone. Remarkably, intensification of central nervous system (CNS)-directed therapy in trial 58951 resulted in fewer bone marrow relapses, while the incidence of CNS relapses remained low. In summary, we showed that adequate asparaginase therapy, intensified induction treatment and intensification of CNS-directed chemotherapy can result in an improvement of outcome in T-ALL patients with good prephase response and initial WBC counts <100 x 10(9)/l, representing approximately 50% of T-ALL patients

CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol

DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% +/- 1.2% for patients with deletions versus 83.5% +/- 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23-3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P<0.0001), but were also identified in patients who did not have any genetic abnormality that is currently used for risk stratification. Within the latter population of patients, the presence of CD200/BTLA deletions was associated with inferior event-free survival and overall survival. Moreover, the multivariate Cox model indicated that these deletions had independent prognostic impact on event-free survival when adjusting for conventional risk criteria. All together, these findings further underscore the rationale for copy number profiling as an important tool for risk stratification in human B-cell precursor acute lymphoblastic leukemia

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Complications thromboemboliques au cours du traitement des leucémies aiguës et des lymphomes lymphoblastiques de l'enfant par le protocole EORTC 58951

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Dépistage et devenir à 2 ans et 5 ans des enfants nés de mères séropositives pour le VIH à la maternité Jeanne de Flandre entre 2006 et 2010

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Le syndrome lipodystrophique associé au virus d'immunodéficience humaine (à propos d'une observation pédiatrique)

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Chimiothérapie anticancéreuse et développement dentaire

Les progrès du traitement des cancers de l’enfant posent le problème des séquelles dues aux thérapeutiques appliquées pendant l’odontogenèse. Si les effets iatrogènes des radiations ionisantes sont bien analysés, les répercussions des seuls antimitotiques sur la dentition sont moins connues. C’est pourquoi, afin d’éviter les biais liés à des observations rétrospectives, 13 enfants souffrant en majorité d’une leucémie aiguë lymphoblastique et tous traités par le même protocole chimiothérapique ont été suivis prospectivement ainsi que 11 enfants témoins. L’influence des antimitotiques sur la dentition est abordée sous deux angles : la mesure de la croissance de la deuxième molaire mandibulaire droite, dent choisie en référence, pendant les différentes phases du protocole chimiothérapique puis en rémission et la surveillance de l’apparition d’anomalies dentaires. Le support est l’utilisation d’orthopantomogrammes tirés à intervalles réguliers après étude du grandissement induit par le générateur. Les résultats convergent vers un ralentissement de la vitesse de minéralisation coronaire de la 47 par la chimiothérapie d’induction-consolidation alors que le rythme radiculaire semble insensible à toutes les phases de chimiothérapie. La non prise en compte possible pour le moment d’éventuels défauts structurels amélo-dentinaires sousestime certainement l’importance des troubles. Cependant déjà, 8 enfants sur 13 ont développé des anomalies dentaires corrélées à la période d’administration des antimitotiques. Les troubles les plus récurrents sont des racines dentaires grêles et/ou courtes (5 enfants) et les agénésies (3 enfants). Quelque soit l’anomalie, la dent la plus fréquemment touchée est la seconde prémolaire. Les atteintes les plus importantes (agénésies, microdonties) concernent les enfants traités les plus jeunes. (Med Buccale Chir Buccale 2003; 9: 7-20

l-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005-01 randomized trial.

International audiencel-asparaginase encapsulated within erythrocytes (GRASPA(®) ) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005-01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA(®) for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA(®) (50 iu/kg: n = 6,100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l-asparaginase (E. colil-ASNase) control group. GRASPA(®) was effective at depleting l-asparagine. One single injection of 150 iu/kg of GRASPA(®) provided similar results to 8 × 10,000 iu/m(2) intravenous injections of E. colil-ASNase. The safety profile of GRASPA(®) showed a reduction in the number and severity of allergic reactions and a trend towards less coagulation disorders. Other expected adverse events were comparable to those observed with E. colil-ASNase and there was also no difference between the three doses of GRASPA(®)

Impact of early molecular response in children with chronic myeloid leukemia treated in the French Glivec phase 4 study

International audienceStudies in adults have shown that an early molecular response to imatinib predicts clinical outcome in chronic myeloid leukemia (CML). We investigated the impact of the BCR-ABL1 transcript level measured 3 months after starting imatinib in a cohort of 40 children with CML. Children with a BCR-ABL1/ABL ratio higher than 10% at 3 months after the start of imatinib had a larger spleen size and a higher white blood cell count compared with those with BCR-ABL1/ABL ≤10%. Children with BCR-ABL1/ABL ≤10% 3 months after starting imatinib had higher rates of complete cytogenetic response and major molecular response at 12 months compared to those with BCR-ABL1/ABL \textgreater10%. With a median follow-up of 71 months (range: 22 to 96), BCR-ABL1/ABL ≤10% correlated with better progression free survival. Thus, early molecular response at 3 months predicts outcome in children treated with imatinib for CML. The study was registered at www.clinicaltrials.gov as NCT00845221