CNS-3 status remains an independent adverse prognosis factor in children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: Results of EORTC Children Leukemia Group study 58951.

AIM: To evaluate the prognostic significance of initial central nervous system (CNS) involvement of children with acute lymphoblastic leukemia (ALL) enrolled in the EORTC 58951 trial. PATIENTS AND METHODS: From 1998 to 2008, 1930 ALL patients were included in the randomized EORTC 58951 trial. Overall treatment intensity was adjusted according to known prognostic factors including the level of minimal residual disease after induction treatment. CNS-directed therapy comprised four to 11 courses of i.v. methotrexate (5g/m2), and 10 to 19 intrathecal chemotherapy injections, depending on risk group and CNS status. Cranial irradiation was omitted for all patients. RESULTS: The overall 8-year event-free survival (EFS) and overall survival (OS) rates were 81.3% and 88.1%, respectively. In the CNS-1, TPL+, CNS-2, and CNS-3 groups, the 8-year EFS rates were 82.1%, 77.1%, 78.3%, and 57.4%, respectively. Multivariable analysis indicated that initial CNS-3 status, but not CNS-2 or TLP+, was an independent adverse predictor of outcome. The 8-year incidence of isolated CNS relapse was 1.7% and of isolated or combined CNS relapse it was 3.7%. NCI high-risk group, male sex, CNS-2 and CNS-3 status were independent predictors for a higher incidence of any CNS relapse. CONCLUSIONS: CNS-3 status remains associated with poor prognosis and requires intensification of both systemic and CNS-directed therapy. This trial was registered at https://clinicaltrials.gov/under/NCT00003728.

Prevalence and risk factors of iron overload after hematopoietic stem cell transplantation for childhood acute leukemia: a LEA study.

Data on post-transplant iron overload (IO) are scarce in pediatrics. We conducted a prospective multicenter cohort study (Leucémie de l'Enfant et de l'Adolescent cohort) to determine the prevalence and risk factors of IO in 384 acute leukemia survivors transplanted during childhood. Prevalence of IO (ferritin level ⩾350 ng/mL) was 42.2% (95%CI 37.2-47.2%). Factors significantly associated with IO were: 1) in univariate analysis: older age at transplant (P<0.001), allogeneic versus autologous transplantation (P<0.001), radiation-based preparative regimen (P=0.035) and recent period of transplantation (P<0.001); 2) in multivariate analysis: older age at transplant in quartiles (Odds Ratio (OR)=7.64, 95% CI: 3.73-15.64 for age >12.7 years and OR=5.36, 95% CI: 2.63-10.95 for age from 8.2 to 12.7 years compared to age < 4.7 years), acute myeloid leukemia (OR=3.23, 95% CI: 1.47-7.13), allogeneic graft (OR=4.34, 95% CI: 2.07-9.12 for alternative donors and OR=2.53, 95% CI: 1.2-5.33 for siblings, compared to autologous graft) and radiation-based conditioning regimen (OR=2.45, 95% CI: 1.09-5.53). Graft-versus-host disease was an additional risk factor for allogeneic graft recipients. In conclusion, IO is a frequent complication in pediatric long-term survivors after transplantation for acute leukemia, more frequently observed in older children, those transplanted from alternative donors or with graft-versus-host disease.

[Fatal central nervous system hemorrhage during acute lymphoblastic leukemia induction]. / Hémorragie cérébrale fatale en cours d'induction d'une leucémie aiguë lymphoblastique.

Intracerebral hemorrhage (ICH) remains a cause of death in hematologic malignancies. Asparaginase represents a key agent in the treatment of acute lymphoblastic leukemia (ALL). The toxicity of asparaginase includes coagulopathy such as thrombotic or bleeding tendency. We report a case of fatal cerebral hemorrhage in a 12-year-old girl treated for ALL. Cerebral hemorrhage occurred after three injections of L-asparaginase. The patient presented with hypofibrinogenemia (0.36g/L), associated with thrombocytopenia (24,000/mm3). Despite maximal medical and surgical treatment (platelets and fresh-frozen plasma transfusions, red blood cells transfusion, fibrinogen replacement therapy, and craniotomy discharge), the patient died. L-asparaginase is well known for its prothrombotic action. By inhibiting the synthesis of fibrinogen and factors V, VII, VIII, and IX, it causes an increased risk of bleeding, including intracranial bleeding. Predictive scores for ICH onset have been established but there is no consensus on the management of coagulation disorders induced by L-asparaginase. It is recommended to check fibrinogen and antithrombin (AT) blood values in order to substitute them if they drop to < 1 g/L for fibrinogen and < 60% for AT. The management of asparaginase-induced ICH does not differ from that of ICH of other origin. The risk of death is high, and surgical treatment has not proven superior to medical therapy in terms of mortality rates and 6-month survival. Further studies are needed to define consensus guidelines for coagulation disorders induced by asparaginase and also to define the specific management in cases of ICH in childhood hematological malignancies.

[Early type 2 neurofibromatosis and congenital retinal hamartoma]. / Neurofibromatose de type 2 précoce et hamartome rétinien congénital.

Neurofibromatosis type 2 (NF2) is a heritable syndrome characterized by multifocal proliferation of neural crest-derived cells. It has long been regarded as an adolescent- and adult-onset disease. We report here on a case of a 6-year-old girl with infantile-onset clinical signs. The girl, who had a history of amblyopia and congenital retinal hamartoma, presented with rough dimness of visual acuity. Cerebral magnetic resonance imaging found a left voluminous fronto-temporal tumor including the chiasma and optical nerves. Vestibular and cervical nerve schwannomas were also found. She underwent a first neurosurgical partial excision and histopathology revealed meningioma. Postoperative radiotherapy was necessary due to a secondary increase of the tumor size. Subsequent molecular testing revealed a NF2 gene abnormality. NF2 can become evident in infancy but clinical early symptomatology is often different: ocular symptoms and neurological problems are common. There is no consensus on the treatment of tumors involving the central and peripheral nervous system, abstention being usual. In case of severe signs, surgery and radiotherapy can be proposed. The diagnosis of a hamartoma must lead to multidisciplinary follow-up.

IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951.

The added value of IKZF1 gene deletion (IKZF1(del)) as a stratifying criterion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is still debated. We performed a comprehensive analysis of the impact of IKZF1(del) in a large cohort of children (n=1223) with BCR-ABL1-negative BCP-ALL treated in the EORTC-CLG trial 58951. Patients with IKZF1(del) had a lower 8-year event-free survival (EFS, 67.7% versus 86.5%; hazard ratio (HR)=2.41; 95% confidence interval (CI)=1.75-3.32; P<0.001). Importantly, despite association with high-risk features such as high minimal residual disease, IKZF1(del) remained significantly predictive in multivariate analyses. Analysis by genetic subtype showed that IKZF1(del) increased risk only in the high hyperdiploid ALLs (HR=2.57; 95% CI=1.19-5.55; P=0.013) and in 'B-other' ALLs, that is, lacking classifying genetic lesions (HR=2.22; 95% CI=1.45-3.39; P<0.001), the latter having then a dramatically low 8-year EFS (56.4; 95% CI=44.6-66.7). Among IKZF1(del)-positive patients randomized for vincristine-steroid pulses during maintenance, those receiving pulses had a significantly higher 8-year EFS (93.3; 95% CI=61.3-99.0 versus 42.1; 95% CI=20.4-62.5). Thus, IKZF1(del) retains independent prognostic significance in the context of current risk-adapted protocols, and is associated with a dismal outcome in 'B-other' ALL. Addition of vincristine-steroid pulses during maintenance may specifically benefit to IKZF1(del) patients in preventing relapses.

[Life-threatening hypercalcemia as the initial presentation of childhood acute lymphoblastic leukemia]. / Hypercalcémie menaçante révélatrice d'une leucémie aiguë lymphoblastique de l'enfant.

Hypercalcemia in childhood acute lymphoblastic leukaemia (ALL) is a well-known but uncommon complication. Here, we report a case of B-ALL in which the first signs were life-threatening hypercalcemia associated with diffuse osteolytic lesions with no hematologic abnormalities. We draw attention to the difficulties formally establishing the ALL diagnosis. Bone marrow examinations must be repeated if necessary. Furthermore, biological, cytogenetic, and molecular aspects need to be investigated. Measurement of intact PTH can exclude hyperparathyroidism. PTHrP is possibly involved in hypercalcemia processes induced by tumor cells. The t(17;19) translocation and its E2A-HLF transcript fusion, which have been thought to be a poor prognostic factor, must be determined. Regarding severe hypercalcemia control, treatment is based on both underlying disease management and serum calcium level reduction with aggressive hydration and if necessary bisphosphonates.

Achromobacter bacteraemia outbreak in a paediatric onco-haematology department related to strain with high surviving ability in contaminated disinfectant atomizers.

BACKGROUND: Achromobacter spp. are Gram-negative bacilli from aqueous environments, occasionally involved in bacteraemia in immunocompromised hosts and in outbreaks. AIM: We describe the characteristics of an achromobacter bacteraemia outbreak in a paediatric onco-haematology department. METHODS: Throughout a one-year period, 16 blood cultures from seven patients were positive for Achromobacter sp. All patients were immunocompromised, febrile, and central venous catheter (CVC) holders. A microbiological study was performed in patients' rooms, completed with an analysis of the disinfectant atomizers (didecyl diammonium chloride 0.25%, Surfanios, DMA). In total, 41 clinical and environmental strains were analysed by enterobacterial repetitive intergenic consensus (ERIC) polymerase chain reaction (PCR), repetitive PCR, and random amplified polymorphic DNA (RAPD)-PCR, and pulsed-field gel electrophoresis (PFGE). The bactericidal activity of DMA was studied on two Achromobacter sp. representative strains and one Pseudomonas aeruginosa reference strain, comparing biofilm and planktonic growth models. FINDINGS: The seven patients, including two severe cases, were successfully treated by systemic antimicrobial therapy and/or catheter removal. The 25 environmental isolates were recovered with the following chronology: hospital filtered tap water, disinfectant atomizers, and patients' rooms. All environmental, patient, and atomizer strains had identical PCR and PFGE patterns. The disinfectant susceptibility assay revealed that the strain isolated from the atomizers had high survival abilities in biofilm conditions and remained resistant to DMA after short contact periods. CONCLUSION: The use of disinfectant atomizers associated with the survival of Achromobacter in the atomizer pipes may explain the contamination and colonization of the CVC. Control measures (non-atomizer containers and use of sterile water) allowed the eradication of the source and the outbreak control.

Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study.

The purpose of this multicenter study was to compare the long-term impact of a preparative regimen with either BUBU or TBI on health status and quality of life (QoL) in childhood acute leukemia survivors treated with hematopoietic SCT (HSCT). Two-hundred and forty patients were included. Sixty-six had received BU, while 174 had received TBI. Median follow-up from HSCT was 10.1 years. Multivariate analyses were performed to assess the occurrence of late effects according to treatment. QoL was assessed in 130 adults using SF-36 questionnaires. Patients developed fewer late complications after BU (2.35 vs 3.01, P=0.03) while the risk to present with at least one complication was equivalent in both groups (87.9% after BU and 93.1% after TBI, P=0.66). Detailed multivariate analyses revealed a lower risk of height growth failure (OR=0.2), cataract (OR=0.1) and iron overload (OR=0.2) after BU, and an increased risk of overweight (OR=3.9) and alopecia (OR=11.2). SF-36 mental and physical composite scores were similar in both treatment groups and proved significantly lower than French norms. Late effects induced by BU might differ from those experienced after TBI. Although less frequent, they are still of considerable importance and may affect patients' QoL.

[Prophylactic antibiotics for immunocompromised children]. / Antibioprophylaxie chez les enfants immunodéprimés.

Infections are the most common cause of morbidity and mortality in pediatric immunocompromised children. The emergence of pan-drug resistant bacteria is particularly concerning for these patients. The risk of infection can be reduced by educational rules, immunizing these patients and sometimes antibiotic prophylaxis. But the individual level of risk is very difficult to assess. Using antibiotics may lead to adverse effects such as allergic reactions, cross-reactions with other drugs, development of super-infections, pseudomembranous colitis and overall development of antibioticresistant bacterial strains. Recommendations for preventing infections in these patients exist for specific case such as inherited disorder or stem cell transplantation. In others cases it depends on physicians' habits: the increase of bacterial resistance could lead to reduce the prescriptions non evidence based and not included in official guidelines. Pneumococcal and meningococcal vaccinations might change guidelines and habits.

A 6-year antifungal stewardship programme in a teaching hospital.

PURPOSE: To describe the antifungal stewardship programme in our hospital and to assess its impact on total antifungal prescriptions and their cost, and on the process of care measures regarding the diagnostic and therapeutic management of invasive aspergillosis and candidaemia. METHODS: We conducted a prospective observational study describing the multifaceted antifungal stewardship programme in place at our French teaching tertiary-care hospital since 2005. Several actions were implemented successively, including the systematic evaluation of all costly antifungal prescriptions (echinocandins, lipid formulations of amphotericin B, posaconazole and voriconazole). RESULTS: A total of 636 antifungal prescriptions were discussed by the antifungal management team from 2005 to 2010 inclusive, mainly from the haematology department (72 %). In 344/636 cases (54 %), a piece of advice was fed back to the physician in charge of the patient, with an 88 % compliance rate. Optimal standard of care was achieved for galactomannan antigen testing, performance of chest computed tomography (CT) scan and voriconazole therapeutic drug monitoring for invasive aspergillosis, with no combination therapies used since 2008. Regarding candidaemia, optimal standard of care was achieved for the timing of antifungal therapy, recommended first-line therapy, duration of therapy and the removal of central venous catheters. Total antifungal prescriptions (in defined daily doses, DDD) and their cost were contained between 2003 and 2010. CONCLUSIONS: The implementation of an antifungal stewardship programme was feasible, sustainable and well accepted. We observed an improved quality of care for some process of care measures, and antifungal use and cost were contained in our hospital.

Growth hormone treatment impact on growth rate and final height of patients who received HSCT with TBI or/and cranial irradiation in childhood: a report from the French Leukaemia Long-Term Follow-Up Study (LEA).

The literature contains a substantial amount of information about factors that adversely influence the linear growth in up to 85% of patients undergoing haematopoietic SCT (HSCT) with TBI and/or cranial irradiation (CI) for acute leukaemia (AL). By contrast, only a few studies have evaluated the impact of growth hormone (GH) therapy on growth rate and final height (FH) in these children. We evaluated growth rates during the pre- and post-transplant periods to FH in a group of 25 children treated with HSCT (n=22), TBI (n=21) or/and CI (n=8) for AL and receiving GH therapy. At the start of GH treatment, the median height Z-score was -2.19 (-3.95 to 0.02), significantly lower than at AL diagnosis (P<0.001). Overall height gain from start of GH treatment to FH was 0.59Z (-2.72 to 2.93) with a median height Z-score at FH of -1.35 (-5.35 to 0.27). This overall height gain effect was greater in girls than in boys (P=0.04). The number of children with heights in the reference population range was greater after than before GH therapy (P=0.07). At FH the GVHD and GH treatments lasting <2 years were associated with shorter FH (P=0.02 and 0.05). We found a measurable beneficial effect of GH treatment on growth up to FH.