Risk factors for symptomatic venous thromboembolism during therapy for childhood acute lymphoblastic leukemia.

BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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. CONCLUSION: 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.

Improvement of overall survival after allogeneic hematopoietic stem cell transplantation for children and adolescents: a three-decade experience of a single institution.

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.

Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Acute childhood leukaemia and residence next to petrol stations and automotive repair garages: the ESCALE study (SFCE).

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.

Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring.

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 micromol.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 micromol.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.

[Adenovirus infections in children: experience in the field of the allogeneic stem cell transplantation]. / Les infections à adénovirus chez l'enfant: expérience dans le domaine de l'allogreffe de cellules souches hématopoïétiques.

UNLABELLED: Adenovirus (Adv) infections are frequent in pediatric patients, sometimes serious, above all in immunocompromised children. We report the cases of 2 children who presented an Adv infection after allogeneic stem cell transplantation (SCT). CASE REPORTS: Case n(o) 1 concerns a boy who received SCT at the age of 6 years. He had a hemorragic cystitis, which resolved after antiviral treatment and successful engraftment. Case n(o) 2 concerns a boy who received SCT at the age of 2. He shortly presented a disseminated infection, and died in spite of antiviral treatment and re-infusion of an autologous transplant. DISCUSSION: T-cell depletion (mainly carried out in vivo at present) is the major risk factor of Adv infection after allogeneic SCT. It is important to be recognized, in order to proceed to a routine screening among transplanted patients. Moreover, the detection of viral genoma by molecular biology is a predictive factor of disseminated disease development, with mortality rates higher than 50%. Early treatment is thus crucial. Immunotherapy is to be developed, by tapering of immunosuppression, or by manipulating grafts and donor lymphocyte infusions, in order to improve Adv specific responses. The possibility of a prophylaxis is still to be investigated.

Topotecan as a radiosensitizer in the treatment of children with malignant diffuse brainstem gliomas: results of a French Society of Paediatric Oncology Phase II Study.

BACKGROUND: The current Phase II study was conducted to evaluate the survival and toxicity observed in children with newly diagnosed brainstem gliomas who were treated with the daily radiotherapy with topotecan used as a radiosensitizer. METHODS: Eligible patients were those ages 3-18 years with previously untreated tumors arising in the pons diagnosed within the previous 6 months. Histologic confirmation was not mandatory provided that the clinical and magnetic resonance imaging findings were typical for a diffusely infiltrating brainstem lesion. Treatment was comprised of a 6-week course of topotecan administered intravenously at a dose of 0.4 mg/m(2)/day over 30 minutes within 1 hour before irradiation. Radiotherapy was comprised of a once-daily treatment of 1.8 grays (Gy) per fraction to a total dose of 54 Gy. RESULTS: Thirty-two patients were included in the current study between August 2000 and October 2002. All patients completed the combined treatment in accordance with the treatment design. Only partial responses were observed, occurring in 40% of the patients. The 9-month and 12-month survival rates were 34.4% +/- 8% and 25.5% +/- 8%, respectively. The median duration of survival for these 32 patients was 8.3 months. An intratumoral cystic/necrotic change was observed in five patients, with clinical impairment noted in two patients. One intratumoral hemorrhage occurred during radiotherapy, and was associated with transitory neurologic impairment. CONCLUSIONS: The findings of the current study regarding newly diagnosed brainstem glioma patients treated with topotecan given as a radiosensitizing agent did not reproduce the encouraging results obtained in preclinical studies. Therefore, the concomitant combination of topotecan and radiotherapy at this schedule and these doses cannot be recommended for the treatment of patients with brainstem gliomas.

Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit--multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group.

From 1989 to 1998, 341 children were included in the French multicentric LAME (Leucémie Aiguë Myéloblastique Enfant) trials. A total of 309 children were registered in the LAME 89/91 protocol. This intensive regimen included an induction phase (mitoxantrone plus cytarabine), two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine; 276 (90%) achieved a CR. The 5-year overall survival (OS) and event-free survival (EFS) were 60+/-4 and 48+/-4%, respectively. From 1997, timed-sequencing of the LAME SP induction chemotherapy led to an unacceptable frequency of consolidation delay; future improvements are unlikely to come from further increases in intensity. The role of allogenic bone-marrow transplantation from an HLA-identical sibling in CR1 was examined. The disease-free survival (DFS) was 52+/-4% for non-allografted patients and 57+/-7% for allografted patients (P=NS); a better OS for allografted patients was shown and could be related either to allo-BMT early in CR1 or to a second allo-BMT in CR2. For the complete responders after consolidation therapy, the 5-year OS was significantly better in patients randomized for no maintenance therapy (MT-) than in patients randomized for MT (77.6+/-8 vs 59+/-8%; P=0.05), while the 5-year DFS was not significantly different. Exposure to low-dose MT might contribute to clinical drug resistance and treatment failure in relapsing patients.

Long-term renal and hearing toxicity of carboplatin in infants treated for localized and unresectable neuroblastoma: results of the SFOP NBL90 study.

BACKGROUND: A secondary end point of the NBL90 protocol (Rubie H et al. Pediatr Oncol 2001;36:247-250) was the concern in this infant population for possible carboplatin-(CBDCA) induced late side effects including impaired renal and hearing functions. PROCEDURE: Glomerular filtration rate (GFR), tubular function (TF), pure tone audiometry (PTA), high-frequency, and transient evoked-otoacoustic emission were prospectively assessed in 30 children alive and disease-free 6 years after the end of the treatment. RESULTS: Median age at diagnosis and at assessment was 4.7 months and 7 years, respectively. Blood pressure was < or =97.5 centile in all children. The mean estimated GFR was 114 +/- 13 ml/min/1.73 m(2) by Schwartz formula [range 87-145]. TF assessment failed to demonstrate any impairment. 29/30 children had grade 0 ototoxicity and all transient evoked otoacoustic emission were normal. CONCLUSIONS: With a 6-year follow-up the combination of VP16 and carboplatin given at conventional doses is safe on renal and hearing functions in infants with unresectable neuroblastomas treated according to SFOP NB90.

Maintenance therapy in childhood acute myeloid leukemia.

PURPOSE: To determine whether, after very intensive induction and consolidation therapy in childhood AML, further maintenance therapy (MT) confers any advantage. PATIENTS AND METHODS: Three hundred-nine children with previously untreated AML were registered in the LAME 89/91 protocol. This three-cycle intensive regimen included an induction phase (mitoxantrone plus cytarabine) and, for non-allografted patients, two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine. In the LAME 89 study, patients were given an additional MT consisting of mercaptopurine and cytarabine for 18 months. In the LAME 91 trial, patients were randomized to be given or not MT after consolidation therapy. RESULTS: Out of 309 patients, 276 (90%) achieved a complete remission. The overall survival (OS) and event-free survival at 6 years for all patients were 60% +/- 6% and 48% +/- 6%, respectively. For the complete responders after consolidation therapy, the 5-year OS was significantly better in patients randomized for no further treatment than in patients randomized for MT (81% +/- 13% vs 58% +/- 15%; p = 0.04) whilst the 5-year disease-free survival was not significantly different (60% +/- 19% vs 50% +/- 15%; p = 0.25). The improvement of OS in MT-patients appeared to be related to a higher salvage rate after relapse. CONCLUSION: Over 50% of patients can be cured of AML in childhood. In the context of a very short and drug-intensive regimen, low-dose MT, owing to the lack of improvement in disease control and the worsening of survival, should not be recommended. Over the past 20 years, the outcome of acute myeloid leukemia (AML) in children has improved substantially. In the eighties, complete remission (CR) was achieved in nearly 90% of patients but event-free survival (EFS) was poor. Myeloablative therapy followed by allogenic bone-marrow transplantation (allo BMT) from an HLA-identical sibling was demonstrated, in our experience, to be the treatment of choice for improving DFS in children with AML in first remission. The major issue was how best to maintain complete remission for patients without an HLA sibling donor. Whereas several groups continued to include low-dose MT and others decided to omit it, in 1991, our group undertook a prospective randomized trial (LAME 91 protocol), the main aim of which was to assess the efficacy of MT in addition to an intensive induction and consolidation chemotherapy. The main results have been published previously and are now updated and described in a higher number of patients.

Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia.

The objective of the present study was to investigate the role of early common infections and perinatal characteristics in the aetiology of childhood common leukaemia. A case-control study was conducted from 1995 to 1998 in France, and included 473 incident cases of acute leukaemia (AL) (408 acute lymphoblastic leukaemia (ALL), 65 acute myeloid leukaemia (AML) age-, sex- and region-matched with 567 population-based controls. Data on the medical history of the child and his/her environment were collected using self-administered questionnaires. Analyses were conducted using nonconditional logistic regression. A slight negative association with early infections was observed (OR=0.8; 95% CI (0.6-1.0)). The association was stronger for early gastrointestinal infections. Early day-care was found to be associated with a decreased risk of AL (OR=0.6; 95% CI (0.4-0.8) and OR=0.8; 95% CI (0.5-1.2) for day-care starting before age 3 months and between 3 and 6 months, respectively). No association with breast-feeding was observed, irrespective of its duration. A birth order of 4 or more was associated with a significantly increased risk of AL (OR=2.0; 95% CI (1.1-3.7) with ALL). A history of asthma was associated with a decreased risk of ALL (OR 0.5; 95% CI (0.3-0.90). Although the results regarding birth order and breast-feeding do not fit with Greaves' hypothesis, the study supports the hypothesis that early common infections may play a protective role in the aetiology of childhood leukaemia, although this effect was not more marked for common ALL.

Treatment of stage 4s neuroblastoma--report of 10 years' experience of the French Society of Paediatric Oncology (SFOP).

Stage 4s neuroblastoma (NB) is usually associated with a favourable outcome, despite a large tumour burden, as spontaneous regression frequently occurs. However, in some infants rapid disease progression can be observed with severe functional impairment. Thus, for all patients the potential risks of cytotoxic therapy must be weighed against the benefits of early medical intervention. We have retrospectively reviewed the charts of 94 infants treated for stage 4s NB in centres of the French Society of Paediatric Oncology between 1990 and 2000, and describe the different first-line treatment approaches that were, successively, liver irradiation, chemotherapy using a cyclophosphamide-vincristine regimen, and chemotherapy using a carboplatin-etoposide regimen. The overall survival was 88% (+/-7.6%), with a mean follow-up of 64 months. Elevated serum neuron-specific enolase (>100 nmol ml(-1)), ferritin (>280 ng ml(-1)) and urinary dopamine levels (>2500 nmol mmol(-1) creatinine) were associated with a poor outcome, as were the genetic markers N-myc amplification and chromosome 1p deletion (P<0.0005 and P=0.0016, respectively). Patients who required medical intervention at diagnosis fared worse than those who received supportive treatment only (P<0.005). The clinical evolution observed with the different successive treatment approaches suggests that if infants do require therapy, the prompt initiation of a more intensive regimen such as carboplatin-etoposide may be more beneficial.

Amplification of AML1 gene is present in childhood acute lymphoblastic leukemia but not in adult, and is not associated with AML1 gene mutation.

The AML1/CBFA2/RUNX1 gene is the target of many recurrent translocations seen in different leukemia subtypes. The t(12;21)(p13;q22) is the most frequent translocation observed in childhood B acute lymphoblastic leukemia (ALL), occurring in 20% to 25% of cases. In adult ALL this rearrangement is scarce. Another route of AML1deregulation could be point mutations in the runt domain. We now report on AML1amplification in two cases of childhood ALL, found in a series of 107 consecutive children with B-lineage ALL analyzed by fluorescence in situ hybridization (FISH). A parallel analysis of 42 adult B-ALL failed to detect any AML1 rearrangement by FISH. The two patients with AML1 amplification were further analyzed using molecular techniques. SSCP analysis did not detect any mutation. Furthermore, direct sequencing of the cDNA did not reveal any mutation. In conclusion, AML1amplification seems to be observed only in childhood ALL and is not associated with AML1 gene mutation. Other mechanisms, such as gene dosage effects could be hypothesized.

Front-line high-dose therapy with autologous stem cell transplantation for high risk Hodgkin's disease: comparison with combined-modality therapy.

This retrospective study compares high-dose therapy (HDT) with autologous stem cell transplantation and combined-modality treatment (CT) as a first-line therapy for Hodgkin's disease (HD) for patients with both a clinical stage (CS) IV and/or a mediastinal mass > or =0.45 of the thoracic diameter (MM > or =0.45) at diagnosis, and an incomplete response after the first-line chemotherapy. Data on 42 grafted patients (GP) in Nantes Hospital, France and on 108 combined-modality treated patients (CTP) from two protocols of the GOELAMS group, France (POF 81 and H90) was analyzed. Both groups were comparable except for pulmonary disease in excess in the grafted group (P = 0.01). Among GP, 95% were in complete response at the end of first-line treatment and 77% among CTP. Median follow-up was 53 months (range, 7 to 128 months) for GP and 88 months (range, 25 to 181 months) for CTP. The 5-year freedom from progression (FFP) and event-free survival (EFS) rates were better for GP (87% vs 55% for FFP: P = 0.0004 and 81% vs 51% for EFS: P = 0.0004) whereas the overall survival (OS) rates did not differ significantly (85% for GP vs 71% for CTP: P = 0.06). Similar results were obtained for the groups with a response > or =50% after initial chemotherapy: 91% vs 65% for FFP, P = 0.01; 87% vs 61% for EFS, P = 0.02; and 92% vs 77% for OS, P = 0.2; and for the groups with a response <50%: 80% vs 22% for FFP, P = 0.0003; 72% vs 13% for EFS, P = 0.0001; and 76% vs 46% for OS, P = 0.04. This study shows a better control of the disease with HDT.

Carboplatin before and during radiation therapy for the treatment of malignant brain stem tumours: a study by the Société Française d'Oncologie Pédiatrique.

Childhood malignant brain stem tumours have a very poor prognosis with a median survival of 9 months despite radiotherapy. No chemotherapy has improved survival. However, carboplatin has been reported to have activity in glial tumours as well as antitumour synergy with radiation. Our aims were to test the response rate of these tumours to carboplatin alone and to evaluate the efficacy on survival of carboplatin alone followed by concurrent carboplatin and radiotherapy. Patients younger than 16 years with typical clinical and radiological presentation of infiltrating brain stem tumour, as well as histologically-documented cases in the atypical forms, were eligible. Two courses of carboplatin (1050 mg/m2 over 3 days) were administered initially. This treatment was followed by a chemoradiotherapy phase including five weekly carboplatin courses (200 mg/m2) and conventional radiotherapy. 38 eligible patients were included. No tumour response was observed after the initial phase. This schedule of first-line carboplatin followed by concurrent carboplatin and radiotherapy did not improve survival.

Granulocyte colony-stimulating factor in induction treatment of children with non-Hodgkin's lymphoma: a randomized study of the French Society of Pediatric Oncology.

PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF; lenograstim) decreases the incidence of febrile neutropenia after induction courses in treatment of childhood non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients were randomized to receive (G-CSF+) or not receive (G-CSF-) prophylactic G-CSF, 5 microg/kg/d, from day 7 until an absolute neutrophil count > or = 500/microL was sustained over 48 hours, after two consecutive induction courses of cyclophosphamide 1.5 or 3 g/m(2), vincristine 2 mg/m(2), prednisone 60 mg/m(2)/d x 5, doxorubicin 60 mg/m(2), high-dose methotrexate 3 or 8 g/m(2), and intrathecal injections (COPAD[M]) on protocols LMB89, LMT89, and HM91 of the French Society of Pediatric Oncology. RESULTS: One hundred forty-eight patients were assessable, 75 G-CSF+ and 73 G-CSF-. Although duration of neutropenia less than 500/microL was 3 days shorter in G-CSF+ patients (P = 10(-4)), incidence of febrile neutropenia (89% v. 93% in the first course, 88% v. 88% in the second course), durations of hospitalization and antimicrobial therapy, percentages of infections, mucositis, and transfusions were not significantly different. Although the percentage of G-CSF+ patients commencing the following course on day 21 was significantly higher (84% v 68% after the first and 57% v. 38% after the second course; P <.05), the median delay between the two courses was only 1 day less in G-CSF+ patients (median delay after first COPAD(M), 19 v. 20 days, P =.01; after second, 21 v. 22 days, P = not significant). Remission and survival rates were similar in both arms. CONCLUSION: This study demonstrates that G-CSF did not decrease treatment-related morbidity, nor increase the dose-intensity in children undergoing COPAD(M) induction chemotherapy for NHL.