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1.
Haematologica ; 2023 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-37981895

RESUMEN

Juvenile myelomonocytic leukemia (JMML) is a rare, generally aggressive myeloproliferative neoplasm affecting young children. It is characterized by granulomonocytic expansion, with monocytosis infiltrating peripheral tissues. JMML is initiated by mutations upregulating RAS signaling. Approximately 10% of cases remain without an identified driver event. Exome sequencing of 2 unrelated cases of familial JMML of unknown genetics and analysis of the French JMML cohort identified 11 patients with variants in SH2B3, encoding LNK, a negative regulator of the JAK-STAT pathway. All variants were absent from healthy population databases, and mutation spectrum was consistent with a loss of function of the LNK protein. A stoploss variant was shown to affect both protein synthesis and stability. The other variants were either truncating or missense, the latter affecting the SH2 domain that interacts with activated JAK. Of the 11 patients, 8 from 5 families inherited pathogenic bi-allelic SH2B3 germline variants from their unaffected heterozygous parents. These children represent half of the cases with no identified causal mutation in the French cohort. They displayed typical clinical and hematological JMML features with neonatal onset and marked thrombocytopenia. They were characterized by absence of additional genetic alterations and a hypomethylated DNA profile with fetal characteristics. All patients showed partial or complete spontaneous clinical resolution. However, progression to thrombocythemia and immunity-related pathologies may be of concern later in life. Bi-allelic SH2B3 germline mutations thus define a new condition predisposing to a JMML-like disorder, suggesting that the JAK pathway deregulation is capable of initiating JMML, and opening new therapeutic options.

2.
Genes Chromosomes Cancer ; 60(10): 657-667, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33982372

RESUMEN

Acute lymphoblastic leukemias (ALL) are characterized by a large number of cytogenetic abnormalities of clinical interest that require the use of several complementary techniques. Optical genome mapping (OGM) is based on analysis of ultra-high molecular weight DNA molecules that provides a high-resolution genome-wide analysis highlighting copy number and structural anomalies, including balanced translocations. We compared OGM to standard techniques (karyotyping, fluorescent in situ hybridization, single nucleotide polymorphism-array and reverse transcription multiplex ligation-dependent probe amplification) in 10 selected B or T-ALL. Eighty abnormalities were found using standard techniques of which 72 (90%) were correctly detected using OGM. Eight discrepancies were identified, while 12 additional anomalies were found by OGM. Among the discrepancies, four were detected in raw data but not retained because of filtering issues. However, four were truly missed, either because of a low variant allele frequency or because of a low coverage of some regions. Of the additional anomalies revealed by OGM, seven were confirmed by another technique, some of which are recurrent in ALL such as LMO2-TRA and MYC-TRB fusions. Despite false positive anomalies due to background noise and a case of inter-sample contamination secondarily identified, the OGM technology was relatively simple to use with little practice. Thus, OGM represents a promising alternative to cytogenetic techniques currently performed for ALL characterization. It enables a time and cost effective analysis allowing identification of complex cytogenetic events, including those currently inaccessible to standard techniques.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Variaciones en el Número de Copia de ADN , Regulación Neoplásica de la Expresión Génica , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética , Adolescente , Adulto , Biomarcadores de Tumor/genética , Niño , Preescolar , Mapeo Cromosómico , Análisis Citogenético , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Adulto Joven
3.
Br J Haematol ; 191(5): 825-834, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32700439

RESUMEN

The nucleoside analogue, 2-chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO-) involvement. However, we lack data on long-term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long-term tolerance. This study included 44 children from the French LCH registry, treated for a RO- LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3-19·7 years) and the median follow-up after was 5·4 years (range, 0·6-15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five-year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases [72% below absolute lymphocyte count (ALC) of 0·5 G/l], was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five-year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long-term therapy for treating patients with RO- LCH. Appropriate management of induced immune deficiency is mandatory.


Asunto(s)
Cladribina/administración & dosificación , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Histiocitosis de Células de Langerhans/mortalidad , Sistema de Registros , Adolescente , Niño , Preescolar , Cladribina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Francia , Histiocitosis de Células de Langerhans/sangre , Humanos , Lactante , Recuento de Linfocitos , Masculino , Tasa de Supervivencia
4.
Br J Haematol ; 183(4): 608-617, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30421536

RESUMEN

Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late-onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND-LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND-LCH. The 10-year cumulative incidence of cND-LCH was 4·1%. cND-LCH typically affected patients previously treated for a multisystem, risk organ-negative LCH, represented in 69·4% of cND-LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0·001) in cND-LCH patients compared to those without cND-LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The 'cND susceptible patients' (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10-year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAFV600E status added important information among these cND susceptible patients, with the 10-year cND risk of 33·1% if a BRAFV600E mutation was present compared to 2·9% if it was absent (P = 0·002).


Asunto(s)
Histiocitosis de Células de Langerhans/epidemiología , Enfermedades Neurodegenerativas/epidemiología , Sistema de Registros , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Histiocitosis de Células de Langerhans/metabolismo , Histiocitosis de Células de Langerhans/patología , Humanos , Incidencia , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Factores de Riesgo
5.
Br J Haematol ; 178(3): 457-467, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28444728

RESUMEN

The BRAFV600E mutation is reported in half of patients with Langerhans cell histiocytosis (LCH). This study investigated the detection of the BRAFV600E allele in circulating cell-free (ccf) DNA in a paediatric LCH cohort. Children with BRAFV600E -mutated LCH were investigated to detect ccf BRAFV600E at diagnosis (n = 48) and during follow-up (n = 17) using a picolitre-droplet digital PCR assay. At diagnosis, ccf BRAFV600E was positive in 15/15 (100%) patients with risk-organ positive multisystem (RO+ MS) LCH, 5/12 (42%) of patients with RO- MS LCH and 3/21 (14%) patients with single-system (SS) LCH (P < 0·001, Fisher's exact test). The positive BRAFV600E load was higher for RO+ patients (mean, 2·90%; range, 0·04-11·4%) than for RO- patients (mean, 0·16%; range, 0·01-0·39) (P = 0·003, Mann-Whitney U test). After first-line vinblastine-steroid induction therapy, 7/7 (100%) of the non-responders remained positive for ccf BRAFV600E compared to 2/4 (50%) of the partial-responders and 0/4 of the complete responders (P = 0·002, Fisher's exact test). Six children treated with vemurafenib showed a clinical response that was associated with a decrease in the ccf BRAFV600E load at day 15. Thus, ccf BRAFV600E is a promising biomarker for monitoring the response to therapy for children with RO+ MS LCH or RO- LCH resistant to first-line chemotherapy.


Asunto(s)
Histiocitosis de Células de Langerhans/diagnóstico , Proteínas Proto-Oncogénicas B-raf/sangre , Adolescente , Alelos , Biomarcadores/sangre , Sistema Libre de Células/metabolismo , Niño , Preescolar , Monitoreo de Drogas/métodos , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Glucocorticoides/uso terapéutico , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Histiocitosis de Células de Langerhans/genética , Humanos , Indoles/uso terapéutico , Lactante , Masculino , Mutación , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Sulfonamidas/uso terapéutico , Vemurafenib , Vinblastina/uso terapéutico
6.
Ann Hematol ; 94(8): 1401-6, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25862234

RESUMEN

While the vast majority of pediatric Hodgkin lymphoma (HL) is curable, the prognosis of early relapses and refractory diseases remains poor. Recently, the combination of gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) displayed encouraging results on adults with relapsed/refractory diseases. Here, we retrospectively report the results of the GVD salvage regimen on four pediatric patients of our ward with a heavily pretreated relapsed/refractory HL. Three of them had nodular sclerosis subtype. They achieved a complete remission after two, three, or four courses of GVD and received high-dose chemotherapy followed by a stem-cell transplantation (auto-auto, auto-allo, and auto). They have been in sustained remission respectively for almost 2, 4, and 5 years. The fourth patient had a lymphocyte-depleted subtype which was initially diagnosed as anaplastic large cell lymphoma. After four courses of GVD, his disease stabilized then progressed again. In total, 15 cycles of GVD were applied to the patients. The toxicity of each course of GVD was mainly hematologic. No cardiotoxicity occurred despite a prior exposure to anthracyclines and radiotherapy. Thus, the GVD combination seems to be an effective pre-transplant rescue treatment for pediatric patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/tratamiento farmacológico , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Adolescente , Niño , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Femenino , Humanos , Masculino , Polietilenglicoles/administración & dosificación , Estudios Retrospectivos , Terapia Recuperativa/métodos , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , Vinorelbina , Gemcitabina
7.
Lancet Child Adolesc Health ; 6(4): 260-268, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34871572

RESUMEN

BACKGROUND: In 2017, international guidelines proposed new management of febrile neutropenia in children with cancer, adapted to the risk of severe infection by clinical decision rules (CDRs). Until now, none of the proposed CDRs has performed well enough in high-income countries for use in clinical practice. Our study aimed to build and validate a new CDR (DISCERN-FN) to predict the risk of severe infection in children with febrile neutropenia. METHODS: We did two prospective studies. First, a prospective derivation study included all episodes of febrile neutropenia in children (aged <18 years) with a cancer diagnosis and receiving treatment for it who were admitted for an episode of febrile neutropenia, excluding patients already treated with antibiotics for this episode, febrile neutropenia not induced by chemotherapy, those receiving palliative care, and those with a stem cell allograft for less than 1 year, from April 1, 2007, to Dec 31, 2011 from two paediatric cancer centres in France. We collected the children's medical history, and clinical and laboratory data, and analysed their associations with severe infection. Sipina software was used to derive the CDR as a decision tree. Second, a prospective, national, external validation study was done in 23 centres from Jan 1, 2012, to May 31, 2016. The primary outcome was severe infection, defined by bacteraemia, a positive bacterial culture from a usually sterile site, a local infection with a high potential for extension, or an invasive fungal infection. The CDR was applied a posteriori to all episodes to evaluate its sensitivity, specificity, and negative likelihood ratio. FINDINGS: The derivation set included 539 febrile neutropenia episodes (270 episodes in patients with blood cancer [median age 7·5 years, IQR 3·7-11·2; 158 (59 %) boys and 112 (41%) girls] and 269 in patients with solid tumours [median age 6·6 years, IQR 2·9-14·2; 140 (52 %) boys and 129 (48%) girls]). Significant variables introduced into the decision tree were cancer type (solid tumour vs blood cancer), age, high-risk chemotherapy, level of fever, C-reactive protein concentration (at 24-48 h after admission), and leucocyte and platelet counts and procalcitonin (at admission and at 24-48 h after admission). For the derivation set, the CDR sensitivity was 98% (95% CI 93-100), its specificity 56% (51-61), and the negative likelihood ratio 0·04 (0·01-0·15). 1806 febrile neutropenia episodes were analysed in the validation set (mean age 8·1 years [SD 4·8], 1014 (56%) boys and 792 (44%) girls), of which 332 (18%, 95% CI 17-20) were linked with severe infection. For the validation set, the CDR had a sensitivity of 95% (95% CI 91-97), a specificity of 38% (36-41), and a negative likelihood ratio of 0·13 (0·08-0·21). Our CDR reduced the risk of severe infection to a post-test probability of 0·8% (95% CI 0·2-2·9) in the derivation set and 2·4% (1·5-3·9) in the validation set. The validation study is registered at ClinicalTrials.gov, NCT03434795. INTERPRETATION: The use of our CDR substantially reduced the risk of severe infection after testing in both the derivation and validation groups, which suggests that this CDR would improve clinical practice enough to be introduced in appropriate settings. FUNDING: Ligue Nationale Contre le Cancer.


Asunto(s)
Neutropenia Febril , Infecciones , Neoplasias , Niño , Reglas de Decisión Clínica , Árboles de Decisión , Neutropenia Febril/complicaciones , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Humanos , Infecciones/epidemiología , Masculino , Neoplasias/tratamiento farmacológico , Estudios Prospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad
8.
J Clin Oncol ; 37(31): 2857-2865, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31513482

RESUMEN

PURPOSE: Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS: LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION: VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.


Asunto(s)
Histiocitosis de Células de Langerhans/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Vemurafenib/uso terapéutico , Adolescente , Factores de Edad , Niño , Preescolar , Resistencia a Medicamentos , Europa (Continente) , Femenino , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/genética , Humanos , Lactante , Masculino , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas B-raf/genética , Índice de Severidad de la Enfermedad , Transducción de Señal , Factores de Tiempo , Resultado del Tratamiento , Vemurafenib/efectos adversos
9.
J Clin Oncol ; 34(25): 3023-30, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27382093

RESUMEN

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Histiocitosis de Células de Langerhans/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Adolescente , Corticoesteroides/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Niño , Preescolar , Estudios de Cohortes , Resistencia a Antineoplásicos , Femenino , Francia/epidemiología , Histiocitosis de Células de Langerhans/enzimología , Histiocitosis de Células de Langerhans/epidemiología , Humanos , Lactante , Recién Nacido , Masculino , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sistema de Registros , Vinblastina/administración & dosificación
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