Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, ...but clinical significance remains to be determined.
BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae.
Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001).
In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.
Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset ...systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).
To describe a cohort of patients with SAVI.
Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out.
Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good.
The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.
Summary
l‐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/m2 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®.
Abstract Purpose The aim is to study statural growth in a large cohort of children with chronic myeloid leukaemia (CML) treated with front-line imatinib. Methods Retrospective data from 81 children ...less than 18 years of age with CML identified in the French pediatric registry were analysed. Height was expressed as standard deviation score (SDS). Results A gradual decrease in height SDS was observed over time since starting imatinib. The height SDS was significantly lower 12 months and 24 months after the start of imatinib overall ( p < 10−4 ) irrespective of gender and pubertal age. The height SDS was significantly ( p < 10−4 ) lower 12 months after the start of imatinib in boys and girls, and in the prepubertal age group as well as in the postpubertal age group, respectively. A similar finding was observed in the subgroups of boys and girls starting imatinib at a prepubertal or postpubertal age. Loss in height SDS 12 months after the start of imatinib was of the same range in boys when compared to girls and in patients who started imatinib at a prepubertal age compared to those who started at a postpubertal age. Conclusion Growth velocity was altered during the first years of imatinib treatment in boys as well as in girls and in prepubertal age patients as well as in adolescents.
To describe and analyze the differences between infections in children with febrile neutropenia (FN) treated for solid tumor or blood cancer.
A prospective study included all episodes of FN in ...children from April 2007 to April 2016 in 2-pediatric cancer centers in France. Medical history, clinical and laboratory data available at admission and final microbiological data were collected. The proportion of FN, severe infection, categories of microorganisms and outcomes were compared between the two groups. The presumed gateway of the infection was a posteriori considered and evaluated.
We analyzed 1197 FN episodes (mean age: 8 years). 66% of the FN episodes occurred in children with blood cancer. Severe infections were identified in 23.4% of episodes overall. The rate of severe infection (28.4% vs. 10.4%), types of microorganisms and the need for a management in intensive care unit (2.6% vs. 0.5%) was significantly different between children with blood cancer and solid tumor. Digestive or respiratory presumed gateway of the infections was less frequent for patients with solid tumor.
Given these important microbiological and clinical differences, it may be appropriate to consider differently the risk of severe infection in these two populations and therefore the management of FN.
Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of ...non-very high-risk patients by comparing prolonged (long-asparaginase)
standard (short-asparaginase) native
asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children's Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native
asparaginase were switched to equivalent doses of
or pegylated
asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87;
=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89;
=0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70;
=0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3-4 infection during consolidation (25.2%
14.4%) and late intensification (22.6%
15.9%) and the incidence of grade 2-4 allergy were higher in the long-asparaginase arm (30%
21%). Prolonged native
asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy.
The gut microbiota plays a key role 63 in host physiology and is an actor in inflammatory bowel disease pathogenesis. Patients with primary immunodeficiency causing intestinal inflammation have ...disease-specific dysbiosis.
Objectives
Nationwide prospective cohort study exploring (i) the factors associated with treatment initiation (vs. watchful waiting) in children with primary immune thrombocytopenia (ITP) followed in ...routine clinical practice and (ii) the predictors of chronicity at 12 months.
Procedure
Between 2008 and 2013, 23 centers throughout France consecutively included 257 children aged 6 months–18 years and diagnosed with primary ITP over a 5‐year period. Data on ITP clinical features along with medical management were collected at baseline and 12 months. Multivariate logistic regressions were used to determine (i) and (ii) as defined above, providing odds ratio (OR) with 95% confidence interval (95% CI).
Results
One hundred thirty‐seven (53%) children were males, median age was 4.6 years, median platelet count was 7 × 109/l, and 214 (81%) patients initiated medication. Factors independently associated with treatment initiation included platelet counts <10 × 109/l (P < 0.0001) and mucocutaneous bleeding symptoms at baseline (P < 0.001). At 12 months, data were available for 211 (82%) children, of whom 160 (74%) had recovered. Predictors of chronicity included female gender (OR = 2.2; 95% CI = 1.0–4.8), age ≥10 years (OR = 2.6; 95% CI = 1.1–6.0), and platelet counts ≥10 × 109/l (OR = 3.2; 95% CI = 1.5–6.9).
Conclusions
In routine clinical practice, the decision to apply a watchful waiting strategy seems to be driven by platelet counts even in the absence of bleeding symptoms, resulting in treatment being initiated in more than 80% of the children surveyed. Overall, younger children with ITP showed good prognosis, with lower platelet counts and, to a lesser extent, male gender predicting more favorable outcomes.
Studies 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 with those with BCR-ABL1/ABL >10%. With a median follow-up of 71 months (range, 22-96 months), 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. This trial was registered at www.clinicaltrials.gov as #NCT00845221.
•Early molecular response at 3 months can predict outcome in children treated with imatinib for CML.•Children with CML may be less likely to achieve an early molecular response to imatinib than adults with CML.
Introduction
This study presents the results of a real-life, multicenter, prospective, post-approval safety evaluation of Clairyg® 50 mg/mL, a 5% intravenous immunoglobulin (IVIg) liquid, in 59 ...children (aged < 12 years) with primary immunodeficiency diseases (PID) (
n
= 32) or immune thrombocytopenia (ITP) (
n
= 27) in France.
Methods
The primary objective of the study was to assess the safety and tolerability of Clairyg®, recording all serious and non-serious adverse events (AEs), whether related (rAEs) or not related to the product. Secondary objectives aimed at evaluating the administration of Clairyg® under routine conditions and the available efficacy data to better document the benefit/risk ratio in this pediatric population. An exploratory objective was added to evaluate the potential factors associated with the occurrence of rAEs. Patients received Clairyg® according to the approved dosage under normal conditions of prescriptions over a median follow-up period of 11.8 months.
Results
A total of 549 infusions (PID:
n
= 464 and ITP:
n
= 85), were administered, of which 58.8% were preceded by premedication. The most frequent rAEs were headache, vomiting, and pyrexia in both indications. Most of them were considered non-serious and mild or moderate in intensity. A severe single rAE was observed (aseptic meningitis) in a 4-year-old girl presenting with chronic ITP. The exploratory multivariate analysis of potential co-factors showed that the occurrence of rAEs is significantly linked to high IVIg doses and possibly to female gender. The annualized rate of serious bacterial infections was 0.11 for patients with PID. For patients with ITP, 74.1% experienced at least one bleeding episode during the follow-up, mostly a cutaneous one, and none had gastrointestinal, genitourinary, or central nervous system bleeding.
Conclusion
Clairyg® was well tolerated and allowed for control of serious bacterial infection in PID and serious bleeding in ITP, which are the main complications in these respective pediatric disorders. No new safety signal was detected in children less than 12 years-old in real-life conditions of use.
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