Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial.

BACKGROUND: Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis. METHODS: We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedman's test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960. FINDINGS: Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. INTERPRETATION: Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. FUNDING: Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).

Impact of early molecular response in children with chronic myeloid leukemia treated in the French Glivec phase 4 study.

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.

Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability.

Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrow failure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomere dysfunction and these diseases. By combining whole-genome linkage analysis and exome sequencing, we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans.

Development and Testing of Reduced Versions of the Manual Muscle Test-8 in Juvenile Dermatomyositis.

OBJECTIVE: To develop and test shortened versions of the Manual Muscle Test-8 (MMT-8) in juvenile dermatomyositis (JDM). METHODS: Construction of reduced tools was based on a retrospective analysis of individual scores of MMT-8 muscle groups in 3 multinational datasets. The 4 and 6 most frequently impaired muscle groups were included in MMT-4 and MMT-6, respectively. Metrologic properties of reduced tools were assessed by evaluating construct validity, internal consistency, discriminant ability, and responsiveness to change. RESULTS: Neck flexors, hip extensors, hip abductors, and shoulder abductors were included in MMT-4, whereas MMT-6 also included elbow flexors and hip flexors. Both shortened tools revealed strong correlations with MMT-8 and other muscle strength measures. Correlations with other JDM outcome measures were in line with predictions. Internal consistency was good (0.88-0.96) for both MMT-4 and MMT-6. Both reduced tools showed strong ability to discriminate between disease activity states, assessed by the caring physician or a parent (P < 0.001), and between patients whose parents were satisfied or not satisfied with illness course (P < 0.001). Responsiveness to change (assessed by both standardized response mean and relative efficiency) of MMT-4 and, to a lesser degree, MMT-6, was slightly superior to that of MMT-8. CONCLUSION: Overall, the metrologic performance of MMT-4 and MMT-6 was comparable to that of the other established muscle strength tools, which indicates that they may be suitable for use in clinical practice and research, including clinical trials. The measurement properties of these tools should be further tested in other patient populations and evaluated prospectively.

Profiles and seasonal distribution of airborne fungi in indoor and outdoor environments at a French hospital.

A one-year prospective survey of fungal air contamination was conducted in outdoor air and inside two haematological units of a French hospital. Air was sampled with a portable Air System Impactor. During this period of survey, the mean viable fungal load was 122.1 cfu/m(3) in outdoor air samples, and 4.1 and 3.9 cfu/m(3) in samples from adult and pediatric haematology units, respectively. In outdoor samples, Cladosporium was the dominant genus (55%) while in the clinical units, Penicillium sp. (23 to 25%), Aspergillus sp. (15 to 23%) and Bjerkandera adusta (11 to 13%) were the most frequently recovered airborne fungi. The outdoor fungal load was far higher in autumn (168 cfu/m(3)), spring (110 cfu/m(3)) and summer (138 cfu/m(3)) than in winter (49 cfu/m(3)). In indoor air, fungal concentrations were significantly lower in winter (2.7 to 3.1 cfu/m(3)) than in summer (4.2 to 5.0 cfu/m(3)) in both haematology units. In the outdoor environment, Penicillium sp. and Aspergillus sp. were more abundant in winter while the levels of Cladosporium were lowest during this season. In the haematological units, the presence of Aspergillus sp. was stable during the year (close to 20%), Bjerkandera sp. was particularly abundant in winter (close to 30%); levels of Penicillium sp. were highest in autumn while levels of Cladosporium sp. were highest in spring and summer.

Evans Syndrome in Children: Long-Term Outcome in a Prospective French National Observational Cohort.

Evans syndrome (ES) is a rare autoimmune disorder whose long-term outcome is not well known. In France, a collaborative pediatric network set up via the National Rare Disease Plan now provides comprehensive clinical data in children with this disease. Patients aged less than 18 years at the initial presentation of autoimmune cytopenia have been prospectively included into a national observational cohort since 2004. The definition of ES was restricted to the simultaneous or sequential association of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). Cases were deemed secondary if associated with a primitive immunodeficiency or systemic lupus erythematosus. In December 2014, we analyzed the data pertaining to 156 children from 26 centers with ES whose diagnosis was made between 1981 and 2014. Median age (range) at the onset of cytopenia was 5.4 years (0.2-17.2). In 85 sequential cases, the time lapse between the first episodes of AIHA and ITP was 2.4 years (0.1-16.3). The follow-up period as from ES diagnosis was 6.5 years (0.1-28.8). ES was secondary, revealing another underlying disease, in 10% of cases; various associated immune manifestations (mainly lymphoproliferation, other autoimmune diseases, and hypogammaglobulinemia) were observed in 60% of cases; and ES remained primary in 30% of cases. Five-year ITP and AIHA relapse-free survival were 25 and 61%, respectively. Overall, 69% of children required one or more second-line immune treatments, and 15 patients (10%) died at the age of 14.3 years (1.7-28.1). To our knowledge, this is the first consistent long-term clinical description of this rare syndrome. It underscores the high rate of associated immune manifestations and the burden of long-term complications and treatment toxicity. Future challenges include (1) the identification of the underlying genetic defects inducing immune dysregulation and (2) the need to better characterize patient subgroups and second-line treatment strategies.

'Agranular CD4+ CD56+ hematodermic neoplasm' (blastic NK-cell lymphoma) originates from a population of CD56+ precursor cells related to plasmacytoid monocytes.

In 1999, we reported seven cases of an unusual hematologic malignancy with primary cutaneous presentation that appeared as a distinct clinicopathologic entity characterized by medium-sized tumor cells with a peculiar CD3- CD4+ CD56+ CD43+ HLA-DR+ cell surface phenotype. Because the origin of tumor cells was not clear and they exhibited a nonlineage-specific phenotype, we hypothesized that such tumors likely originated from hematologic-myeloid precursor cells and were tentatively assigned the designation "agranular CD4+ CD56+ hematodermic neoplasms." In the present study we report 14 cases (seven already reported and seven additional cases) of these tumors, and simultaneously we present now a rare population of cells that we have identified in the peripheral blood of healthy volunteers treated with Flt3 ligand. These cells express all the characteristic markers of CD4+ CD56+ hematodermic neoplasms. This population appears to be related to plasmacytoid monocytes because they also expressed CD68 and bright levels of CD123. To confirm the relationship between these normal cells and CD4+ CD56+ hematodermic neoplasms, we conducted an extensive comparative phenotypic study. Results show that these two cell types are indeed related because they share many phenotypic features, including the presence of CD4, CD56, CD43, CD68, and HLA-DR and the absence of other T, B, NK, or myelomonocytic markers. More importantly, we found that the bright expression of CD123 by immunohistochemistry is a distinctive characteristic of CD4+ CD56+ hematodermic neoplasms because all (n = 14) cases expressed this marker, whereas only two specimens in a control panel comprising 30 samples of related tumors expressed comparable levels of CD123. We therefore propose that oncogenic transformation of NCAM-expressing plasmacytoid monocyte-like cells may lead to "agranular CD4+ CD56+ hematodermic neoplasm."

Diversity of the clinical presentation of the MMR gene biallelic mutations.

Constitutional mismatch repair-deficiency, due to biallelic mutations of MMR genes, results in a tumour spectrum characterized by leukaemias, lymphomas, brain tumours and adenocarcinomas of the gastro-intestinal tract, occurring mostly in childhood. We report here two families illustrating the phenotypic diversity associated with biallelic MMR mutations. In the first family, two siblings developed six malignancies including glioblastoma, lymphoblastic T cell lymphoma, rectal and small bowel adenocarcinoma with onset as early as 6 years of age. We showed that this dramatic clinical presentation was due to the presence of two complex genomic PMS2 deletions in each patient predicted to result into complete PMS2 inactivation. In the second family, the index case presented with an early form of Lynch syndrome with colorectal adenocarcinomas at ages 17 and 20 years, and urinary tract tumours at the age of 25 years. We identified in this patient two MSH6 mutations corresponding to a frameshift deletion and an in frame deletion. The latter was not predicted to result into complete inactivation of MSH6. These reports show that the clinical expression of biallelic MMR mutations depends on the biological impact of the second MMR mutation and that, in clinical practice, the presence of a second MMR mutation located in trans should also be considered in patients suspected to present a Lynch syndrome with an unusual early-onset of tumours.

Growth deceleration in children treated with imatinib for chronic myeloid leukaemia.

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.

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene.

Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.

Imatinib is effective in children with previously untreated chronic myelogenous leukemia in early chronic phase: results of the French national phase IV trial.

PURPOSE: Imatinib is the standard of care in adults with chronic myeloid leukemia (CML) in chronic phase (CP). Only a few studies to assess efficacy in children have been performed. We report on the results of the French prospective trial (ClinicalTrials.gov identifier NCT00845221) conducted in children and adolescents with newly diagnosed CML in CP. PATIENTS AND METHODS: A total of 44 patients from age 10 months to 17 years with newly diagnosed CML in CP received daily imatinib 260 mg/m(2). Progression-free survival, responses, and tolerance were evaluated. RESULTS: With a median follow-up times of 31 months (range, 11 to 64 months), the estimated progression-free survival rate at 36 months was 98% (95% CI, 85% to 100%). A complete hematologic response was achieved in 98% of the patients. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were 61% and 31% at 12 months, respectively. During follow-up, CCyR and MMR were achieved in 36 children (77%) and 25 children (57%), respectively. Overall, 30% of the patients discontinued imatinib, mainly because of unsatisfactory response. The most common adverse events were neutropenia and musculoskeletal events. CONCLUSION: Imatinib is effective in children with CML in CP with response rates similar to rates reported in adults. The adverse effects are acceptable, but longer follow-up studies are required to fully assess the long-term impact.

Efficacy of vinblastine in central nervous system Langerhans cell histiocytosis: a nationwide retrospective study.

BACKGROUND: Vinblastine (VBL) is the standard treatment for systemic Langerhans cell histiocytosis (LCH), but little is known about its efficacy in central nervous system (CNS) mass lesions. METHODS: A retrospective chart review was conducted. Twenty patients from the French LCH Study Group register met the inclusion criteria. In brief, they had CNS mass lesions, had been treated with VBL, and were evaluable for radiologic response. RESULTS: The median age at diagnosis of LCH was 11.5 years (range: 1-50). Intravenous VBL 6 mg/m2 was given in a 6-week induction treatment, followed by a maintenance treatment. The median total duration was 12 months (range: 3-30). Eleven patients received steroids concomitantly. Fifteen patients achieved an objective response; five had a complete response (CR: 25%), ten had a partial response (PR: 50%), four had stable disease (SD: 20%) and one patient progressed (PD: 5%). Of interest, four out of the six patients who received VBL without concomitant steroids achieved an objective response. With a median follow-up of 6.8 years, the 5-year event-free and overall survival was 61% and 84%, respectively. VBL was well-tolerated and there were no patient withdrawals due to adverse events. CONCLUSION: VBL, with or without steroids, could potentially be a useful therapeutic option in LCH with CNS mass lesions, especially for those with inoperable lesions or multiple lesions. Prospective clinical trials are warranted for the evaluation of VBL in this indication.