This study investigated the role of factors considered related to early stimulation of the immune system in the etiology of childhood acute leukemia. The national registry-based case-control study ...ESCALE was carried out in France in 2003–2004. Population controls were frequency matched to cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios were estimated using unconditional regression models adjusted for potential confounders. Included were 634 acute lymphoblastic leukemia cases, 86 acute myeloblastic leukemia cases, and 1,494 controls aged ≥1 year. Negative associations were observed between acute lymphoblastic leukemia and birth order (P for trend < 0.0001), attendance at a day-care center before age 1 year (odds ratio (OR) = 0.8, 95% confidence interval (CI): 0.6, 1.1), prolonged breastfeeding (OR = 0.7, 95% CI: 0.5, 1.0), repeated early common infections (OR = 0.7, 95% CI: 0.6, 0.9), regular contact with farm animals (OR = 0.6, 95% CI: 0.5, 0.8), frequent farm visits in early life (OR = 0.4, 95% CI: 0.3, 0.6), and history of asthma (OR = 0.7, 95% CI: 0.4, 1.0) or eczema (OR = 0.7, 95% CI: 0.6, 0.9). Results support the hypothesis that repeated early infections and asthma may play a role against childhood acute leukemia.
CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by ...excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types.
CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype.
A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.
Allogeneic stem cell transplantation (allo-SCT) has become an essential component of the treatment for a variety of diseases in pediatric patients. During the past decades, advances in the transplant ...technology, availability of hematopoietic stem cells and supportive care not only have resulted in improved outcomes, but also have expanded the transplant options. However, these features have been studied mainly in adult populations. This investigation analyzed changes in patient profile, transplantation, graft characteristics and outcome among 250 children and adolescent patients who received allo-SCT in a single center between 1983 and 2010. In the 2000-2010, compared with the 1983-1999 period, a significantly higher 5-year overall survival (64% versus 52%, P=0.03) was observed together with a significant decrease of non-relapse mortality (27% versus 9%, P=0.0002). The progression-free survival was comparable between the two periods (49% versus 57%; P=0.17). The 5-year cumulative incidence of relapse was 24% between 1983 and 1999, and 34% between 2000 and 2010 (P=0.08). Major advances in supportive care practice have been made over the past decade, resulting in a significant survival benefit for the pediatric population undergoing allo-SCT. However, post-transplant relapse remains the leading cause of failure of this therapeutic approach, and preventing relapse represents a major challenge today.
Symptomatic venous thromboembolism (VTE) is an unpredictable and life-threatening toxicity, which occurs early in childhood acute lymphoblastic leukemia (ALL) therapy. Approximately 5% of children ...will experience VTE which is treated with anticoagulation. Asparaginase and corticosteroids are etiologic factors for VTE, however other clinical factors may modify this risk.
We sought to i) assess published pre-treatment VTE risk factors ii) identify early clinical factors that were associated with VTE and iii) determine whether single nucleotide polymorphisms (SNPs) associated with VTE in non-cancer patients contributed to VTE in children with ALL. We performed a detailed, retrospective analysis of 1021 ALL patients treated between 1998 and 2013. Individual patient records were reviewed to ascertain VTE incidence and document treatment-related clinical variables.
The incidence of VTE was 5.1%. Extremes of weight at diagnosis (<5th or >95th centile) was an independent risk factor in multivariable analysis, when added to published risk factors of age ≥10 years and mediastinal mass. When factors during induction/consolidation were considered separately: bacteremia, elevated serum gamma-glutamyl transferase and bilirubin were associated with VTE occurrence. None of the SNPs associated with VTE in non-cancer populations were significantly associated with VTE in our cohort.
We found two known risk factors (age ≥ 10 years and mediastinal mass) in a large cohort of children treated for ALL and identified other factors associated with VTE such as weight extremes at diagnosis, bacteremia, and abnormal liver function which warrant further study. These VTE risk factors may form the basis of future thromboprophylaxis trials.
•Baseline and treatment-related factors were collected on 1021 consecutive children.•Risk from age ≥10 years and mediastinal mass were validated in a BFM-based cohort.•Baseline weight (<5th or >95th centile) was a risk factor for VTE in ALL therapy.•Bacteremia, raised GGT and bilirubin during early therapy contributed to VTE risk.•Genetic risk factors for VTE in ALL therapy may differ from non-malignant cohorts.
Background: The association between acute childhood leukaemia and residing next to petrol stations and automotive repair garages was analysed in a national registry-based case–control study carried ...out in France in 2003–2004. Methods: Population controls were frequency matched with cases on age and gender. Data were collected by standardised telephone interview with the mothers. The latter were asked to report the proximity of their homes to petrol stations, automotive repair garages and other businesses from the conception of the index child to the diagnosis (for cases) or interview (for controls). Odds ratios were estimated using unconditional regression models adjusted for age, gender, number of children under 15 years of age in the household, degree of urbanisation and type of housing. Results: 765 cases of acute leukaemia and 1681 controls were included. Acute leukaemia was significantly associated with residence next to petrol stations or automotive repair garages (OR 1.6, 95% CI 1.2 to 2.2) and next to a petrol station (OR 1.9, 95% CI 1.2 to 3.0). The OR showed no tendency to increase with duration of exposure. The results were not modified by adjustment for potential confounding factors including urban/rural status and type of housing. Conclusions: The results support the findings of our previous study and suggest that living next to a petrol station may be associated with acute childhood leukaemia. The results also suggest that the role of low-level exposure to benzene in acute childhood leukaemia deserves further evaluation.
Background: Ceritinib, a second generation ALK inhibitor, had shown 20-fold more potency than crizotinib with demonstrated durable activity in xenografts expressing crizotinib-resistant ALK ...mutations. Efficacy was observed in adult patients with ALK-mutated non-small cell lung cancer exposed to prior crizotinib treatment or not and in non-lung tumors. In this phase 1 study (NCT01742286) of ceritinib in pediatric malignancies, the recommended dose for expansion (RDE) was established as 510 mg/rn2 once daily in a fasted regimen (cohorts 1 to 6). Preliminary results from this part of the study demonstrated antitumor activity in patients with ALK- mutated inflammatory myofibroblastic tumor (IMT) and anaplastic large cell lymphoma (ALCL), with objective response rates of 63% (5/8 95% CI: 35, 97) and 100% (4/4 95% Cl: 40, 100), respectively (Geoerger B et al, ASCO 2015 Abstract #10005). The fed escalation part of this study (cohorts 7 to 9) evaluated alternative methods of ceritinib administration, utilizing potential benefit of dosing ceritinib with food to reduce gastro-intestinal toxicity, white maintaining PK exposure at lower doses. Methods: The trial enrolled pediatric patients ~1 to <18 years. ALK gene aberration was required, except in ALCL and in rhabdomyosarcoma, where ALK protein expression by immunohistochemistry was sufficient. In this fed, dose-escalation phase, patients received ceritinib at 320-500 mg/rn2 once daily to determine the RDE. Patients were assessed for safety, PK, and efficacy. Results: Fifteen patients were enrolled in 7 centers in 6 countries over 12 months into 3 cohorts: cohort 7 (320mg/rn2), cohort 8 (400 mg/m2), and cohort 9 (500 mg/m2). Diagnoses included: 2 ALCL, 1 IMT, 10 neuroblastoma, and 2 rhabdomyosarcoma. Completion of the fed escalation phase established a RDE of 500 mg/m2/day. One patient had a dose limiting grade 3 hepatic toxicity at 400 mg/rn2. As of 8 June 2016, 6 patients at 500 mg/m2 are ongoing in the fed-regimen (3 in fed escalation cohort 9 and 3 in the fed expansion phase). More mature results on safety, pharmacokinetics and early efficacy including neuroblastoma patients for the fed cohorts as well as those who entered the expansion phase will be reported during the congress. Conclusion: The RDE in children is 500 mg/m2/day with food. The study is currently enrolling in the expansion phase at this recommended dose.
Introduction
Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce ...this variability.
Purpose
A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated.
Method
Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16–23 kg; 0.95 mg/kg for >23–34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3–17.2 years (median 5.6 years).
Results
No difference in AUC values was observed between weight strata (mean ± SD 1248 ± 205 μmol·min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900–1500 μmol·min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.
We describe 4 cases of zygomycosis that occurred after prolonged use of voriconazole in severely immunocompromised patients with hematologic disease. An invasive infection was present in 3 patients ...who died soon after the diagnosis at 12, 13, and 45 days. Physicians should be mindful of this potential risk after treatment with voriconazole.
We present here the long-term results of three randomized clinical trials conducted on children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1983 and 1998 by the Children Leukemia ...Cooperative Group (CLCG) from EORTC. In study 58831/32, the overall event-free survival (EFS) rates (+/- s.e.) at 6 and 10 years were 66% +/- 1.8% and 65% +/- 1.8%, respectively, and the risk of isolated central nervous system (CNS) relapse was 6% +/- 1% and 7% +/- 1%, respectively. In patients with a standard risk of relapse the omission of cyclophosphamide had no adverse effect on disease-free survival rates at 10 years (trial 58831). In medium- and high-risk patients the omission of radiotherapy did not increase the risk of CNS or systemic relapse (trial 58832). In study 58881 (1989-1998) the overall EFS rate at 8 years was 68.4% +/- 1.2% and the risk of isolated CNS relapse was 4.2%+/-0.5%. In this trial which adressed three randomized questions, the following results were obtained: the combination of cytarabine at high doses with methotrexate at high doses during interval therapy did not improve prognosis. The addition of 6-mercaptopurine iv during maintenance increased the risk of late relapse. E. coli asparaginase was more toxic and has a higher efficacy than Erwinia asparaginase. Leukocyte counts >100 x 10(9)/l, specific genetic abnormalities, a poor initial response to steroids or a high level of minimal residual disease at early time points were consistently associated with an adverse prognosis in the 58881 trial.
CD19-specific CAR T cells were produced centrally for a global study in young people with relapsed B-cell ALL. The overall remission rate was 81%, and patients with a response were negative for ...minimal residual disease. High-grade toxic effects were frequent but treatable.
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