MRI features of intra-axial histiocytic brain mass lesions.

AIM: To describe MRI features, including diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS), and perfusion-weighted imaging (PWI), of intra-axial tumour-like presentations of four different subtypes of histiocytosis. MATERIAL AND METHODS: The brain MRI findings of 23 patients with histologically proven histiocytosis were reviewed retrospectively (11 Langerhans cell histiocytosis [LCH], eight Erdheim-Chester disease [ECD], one overlap form LCH/ECD, two Rosai-Dorfman disease [RDD], and one haemophagocytic lymphohistiocytosis [HLH]) with single or multiple enhancing intraparenchymal brain lesions. RESULTS: Histiocytic brain mass lesions show some similar MRI features including Supra and/or infratentorial and/or paraventricular subcortical well-delineated masses, linear ependymal enhancement along the ventricles and brain stem lesions. Masses always present with mixed hyper- and hypointense signal on T2-weighted imaging (WI). Their enhancement is often homogeneous. Apparent diffusion coefficient (ADC) values are often normal or elevated. CONCLUSION: The presence of multiple periventricular and subcortical enhancing lesions with mixed signal intensity on T2WI and normal or high ADC values should lead radiologists to consider the diagnosis of histiocytic lesions and search for associated systemic lesions.

Combined therapy in children and adolescents with classical Hodgkin's lymphoma: A report from the SFCE on MDH-03 national guidelines.

Hodgkin's lymphoma (HL) in children and adolescents is highly curable, but children are at risk of long-term toxicity. The MDH-03 guidelines were established in order to decrease the burden of treatment in good-responder patients, and this report should be considered a step toward further optimization of treatment within large collaborative trials. We report the therapy and long-term outcomes of 417 children and adolescents treated according to the national guidelines, which were applied between 2003 and 2007 in France. The patients were stratified into three groups according to disease extension. Chemotherapy consisted of four cycles of VBVP (vinblastine, bleomycin, VP16, prednisone) in localized stages (G1/95 pts/23%), four cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, adriamycin, bleomycin, vinblastine) cycles in intermediate stages (G2/184 pts/44%) and three cycles of OPPA (vincristine, procarbazine, prednisone, adriamycin) plus three cycles of COPP in advanced stages (G3/138 pts/33%). Radiation therapy of the involved field was given to 97% of the patients, with the dose limited to 20 Gy in good responders (88%). With a median follow-up of 6.6 years, the 5-year event-free survival (EFS) and overall survival (OS) were 86.7% (83.1-89.7%) and 97% (94.5-98.1%), respectively. EFS and OS for G1, G2, and G3 were 98% and 100%, 81% and 97%, and 87% and 95%, respectively. Low-risk patients treated without alkylating agents and anthracycline had excellent outcomes and a low expected incidence of late effects. Intensification with a third OPPA cycle in high-risk group patients, including stage IV patients, allowed for very good outcomes, without increased toxicity.

[SFGM-TC recommendation on indications for allogeneic stem cell transplantation in children with congenital neutropenia]. / Indications d'allogreffe dans les neutropénies constitutionnelles : recommandation de la SFGM-TC.

In this report, we address the issue of allogeneic stem cell transplantation in children with congenital neutropenia. Constitutional disorders with neutropenia are exceptional. Treatment and prevention of severe infections are a major concern in the management of chronic neutropenia. These disorders, especially Kostmann's disease and Shwachman-Bodian-Diamond syndrome, are associated with an increased risk of leukemia. The role of allogeneic stem cell transplantation in these patients is still unclear. In an effort to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille.

Progress towards molecular-based management of childhood Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing abundant CD1a+ CD207+ histiocytes that lead to the destruction of affected tissues. This disease has a remarkable pleiotropic clinical presentation and most commonly affects young children. Although the current mortality rate is very low for childhood LCH patients (<2%), reactivation frequently occurs after a long period of disease control and the rates of permanent complications and sequelae remain high. Advances in genomic sequencing technologies in this past decade have highlighted somatic molecular alterations responsible for the disease in around 80% of childhood LCH cases. More than half of these cases harbored the BRAFV600E mutation, and most other mutations also concerned proteins involved in the MAPKinase pathway. In addition to improving what is known about the LCH pathology, this molecular knowledge provides opportunities to optimize patient management. The BRAFV600E mutation is associated with more severe presentations of the disease, a high reactivation rate, and a high permanent complication rate; this mutation therefore paves the way for future stratified management approaches. These therapies may be based on the patient's molecular status as well as other clinical characteristics of the disease that are independently associated with undesired events. Moreover, as observed in patients with solid tumors, the BRAFV600E allele can be detected in the circulating cell-free DNA of patients with severe BRAFV600E-mutated LCH. Quantification of the plasmatic BRAFV600E load for this group of patients can precisely monitor response to therapy. Finally, targeted therapies, such as BRAF inhibitors, are new therapeutic options especially designed for refractory multisystemic LCH involving risk organs. However, the long-term efficacy, long-term tolerance, optimal protocol scheme, and appropriate modalities of administration for these innovative therapies for children still need to be defined, a huge challenge.

Clinical spectrum of gammadelta+ T cell LGL leukemia: analysis of 20 cases.

We report on the clinico-biological characteristics of 20 cases of gammadelta T cell large granular lymphocyte (LGL) leukemia. All the data were compared to that of 196 cases with alphabeta T cell subtype, which represents the majority of T cell LGL leukemias. Clinical findings were quite similar in the two groups regarding age, sex ratio, recurrent infections, and association with auto-immune diseases especially rheumatoid arthritis. Gammadelta LGL predominantly expressed a CD3+/CD4-/CD8+/CD16+/CD57+ phenotype, in 50% of cases. Clinical outcome was favorable for these patients with overall survival of 85% at 3 years. Fifty percent of gammadelta patients required treatment and the response to therapy was estimated at 55%. gammadelta and alphabeta T cell LGL leukemia harbor a very similar clinico-biological behavior and represent part of an antigen-driven T cell lymphoproliferation.

Intermittent chronic neutropenia in a patient with familial Mediterranean fever.

A 12-year-old daughter of consanguineous Moroccan parents was diagnosed with cyclic neutropenia, based on a combination of recurrent gingivostomatitis, a fluctuating neutrophil count, and several episodes of severe neutropenia. No ELA2 gene mutations were found. At age 19 years she presented with edema of the limbs, proteinuria and renal failure. Renal amyloidosis AA was diagnosed by biopsy. Gene mutations associated with family Mediterranean fever (FMF) were sought, and a homozygous mutation (M694V) was found in the MFEV gene. This is the novel finding of FMF that masqueraded as cyclic neutropenia.

[Rosai-Dorfman disease: Diagnosis and therapeutic challenges]. / La maladie de Destombes-Rosai-Dorfman : évolution du concept, classification et prise en charge.

Rosai-Dorfman disease (RDD) was first described by the French pathologist Paul Destombes in 1965. It frequently affects children or young adults and is characterized by the presence of large histiocytes with emperipolesis. More than 50 years after this first description, the pathogenesis of this rare disease is still poorly understood. The revised classification of histiocytoses published in 2016 identified various forms of RDD, from familial RDD to IgG4-associated RDD. Almost 90% of the patients with RDD have cervical lymph nodes involvement although all the organs may virtually be involved. Outcomes are typically favorable. Treatments may be necessary in case of compression or obstruction, and are not well codified. The main therapeutic strategies rely on surgery, radiotherapy, steroids, immunosuppressive drugs or interferon-alpha and cladribine.

Localized childhood Hodgkin's disease: response-adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low-dose radiation therapy-results of the French Society of Pediatric Oncology Study MDH90.

PURPOSE: The French Society of Pediatric Oncology MDH82 study demonstrated the effectiveness of 20 Gy irradiation of involved fields after doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or mechlorethamine, vincristine, procarbazine, and prednisone/ABVD chemotherapy in children with localized Hodgkin's disease (HD). The response to primary chemotherapy was the only predictor of survival. To reduce long-term treatment complications without compromising efficacy, the MDH90 study was based on a new chemotherapy regimen devoid of both alkylating agents and anthracycline, followed by 20 Gy of radiotherapy (RT) for good responders. PATIENTS AND METHODS: From January 1990 to July 1996, 202 children were enrolled from 30 institutions. Good responders to four cycles of vinblastine, bleomycin, etoposide (VP16), and prednisone (VBVP) were given 20 Gy of RT and no further therapy. Poor responders were given vincristine, procarbazine, prednisone, and doxorubicin. After a second evaluation, good responders were given 20 Gy of RT, and poor responders were given 40 Gy of RT. RESULTS: One hundred seventy-one patients (85%) were good responders to VBVP, 27 (15%) were poor responders, and four did not respond. With a median follow-up of 74 months (range, 25 to 117 months), the 5-year overall survival rate (mean +/- SD) is 97.5% +/- 2.1%, and the event-free survival rate (mean +/- SD) is 91.1% +/- 1.8%. Significant predictors of worse event-free survival in multivariate analysis were hemoglobin < 10.5 g/L, "b" biologic class, and nodular sclerosis. CONCLUSION: These results suggest that most children with clinical stage I and II HD can be treated with chemotherapy devoid of alkylating agents and anthracycline, followed by low-dose RT.

Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction.

The aim of this study was to assess the efficacy and adverse effects of 2-chlorodeoxyadenosine (2-CdA) and cytosine arabinoside (Ara-C) in children with refractory Langerhans cell histiocytosis (LCH) and haematopoietic dysfunction. Ten patients, with a median age at diagnosis of 0.5 years, were enrolled in this study. Treatment comprised at least two courses of Ara-C (1000 mg/m(2)/d) and 2-CdA (9 mg/m(2)/d) administered for 5d every 4 weeks; subsequent median follow-up was 2.8 years (range 0.03-6.4 years). Among the 7 patients who received at least two courses of therapy, disease activity decreased in 6 patients, and control of disease was achieved in all patients after a median delay of 5.5 months. All patients suffered World Health Organisation (WHO) grade 4 haematological toxicity. Two septic deaths occurred shortly after administration of the first course of 2-CdA/Ara-C; a third patient was withdrawn from the trial after the first course and subsequently died following haematopoietic stem cell transplantation. This series is small, but we conclude that 2-CdA and Ara-C combined chemotherapy probably has major activity in childhood refractory Langerhans cell histiocytosis.

Late thyroid toxicity in 153 long-term survivors of allogeneic bone marrow transplantation for acute lymphoblastic leukaemia.

The purpose of this study was to identify risk factors for hypothyroidism after bone marrow transplantation (BMT) for high-risk or relapsed acute lymphoblastic leukaemia (ALL) in children. In all, 388 children with acute lymphoblastic leukaemia underwent allogeneic bone marrow transplantation between 1984 and 1994. Overall 5-year survival was 54.6%. Thyroid function was assessed in the 153 patients with more than 5 years of follow-up. In total, 16 patients developed uncompensated hypothyroidism (UH) and 46 compensated hypothyroidism (CH) a median of 2.9 and 2.7 years, respectively, after BMT. Thyroid dysfunction-free survival rates were 73.2% after 5 years and 59.2% after 10 years. Three factors were significantly associated with the onset of hypothyroidism, namely age, bone marrow transplantation in second remission, and single-dose total body irradiation (TBI). Ultrasonography of the thyroid showed nodules in 10 of 35 patients. The median time from BMT to nodule detection was 7.8 years. Cytology (n=5) and surgery (n=4) showed no evidence of thyroid cancer. Four of the 14 patients who received cytoreduction without TBI but with busulphan and cyclophosphamide developed UH (n=2) or CH (n=2). We concluded that children who undergo BMT for ALL are at a high risk of subsequent thyroid dysfunction.

Hematopoietic stem cell transplantation in severe congenital neutropenia: experience of the French SCN register.

Our objective was to study the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with severe congenital neutropenia (SCN). Among 101 cases of SCN included in the French Severe Chronic Neutropenia Registry, nine patients received HSCT between 1993 and 2003, in seven institutions. The indications were nonresponse to G-CSF therapy in four cases, bone marrow failure in one case, and myelodysplastic syndrome or leukemia in four cases. The conditioning regimen consisted of total body irradiation in two cases and chemotherapy alone in the other seven cases. Seven patients received stem cells from unrelated donors and two from identical siblings. Engraftment occurred in all but one of the patients. Three patients died. The respective causes of death were graft-versus-host disease, infection, and EBV post-transplant lymphoproliferative disease. Six patients are alive and in complete remission, with a median follow-up of 3.1 years. These results indicate that HSCT is feasible for patients with SCN who do not respond to G-CSF, who have malignant transformation, or who are at a high risk of malignant transformation, even if an HLA-identical sibling donor is not available.

Hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: experience of the French neutropenia registry.

Our objective was to study the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for Shwachman-Diamond Syndrome (SDS). Among 71 SDS patients included in the French Severe Chronic Neutropenia Registry, 10 received HSCT between 1987 and 2004 in five institutions. The indications were bone marrow failure in five cases, and myelodysplastic syndrome (MDS) or leukemia in five cases. The median follow-up of patients who survived without relapse is 6.9 years (3.1-16.8 years). The conditioning regimen consisted of a busulfan-cyclophosphamide combination (n=6) or total body irradiation plus chemotherapy (n=4). Six patients received stem cells from unrelated donors and four from identical siblings. Engraftment was complete in eight patients and unassessable in two patients. These latter two patients died of infections 32 and 36 days after HSCT, with grade IV graft-versus-host disease and multiorgan dysfunction. A third patient died from an acute respiratory distress syndrome 17 months after HSCT with progressive granulocytic sarcoma. One patient had an MDS relapse 4 months after HSCT and died 10 months later. The overall 5-year event-free survival rate is 60+/-15%. We conclude that HSCT is feasible for patients with SDS who develop bone marrow failure or malignant transformation.

[Langerhans cell histiocytosis in adults]. / Histiocytose langerhansienne de l'adulte.

Langerhans cell histiocytosis (LCH) is a rare disease characterized by the infiltration of one or more organs by Langerhans cell-like dendritic cells, most often organized in granulomas. The disease has been initially described in children. The clinical picture of LCH is highly variable. Bone, skin, pituitary gland, lung, central nervous system, lymphoid organs are the main organs involved whereas liver and intestinal tract localizations are less frequently encountered. LCH course ranges from a fulminant multisystem disease to spontaneous resolution. Several randomized controlled trials have enable pediatricians to refine the management of children with LCH. Adult LCH has some specific features and poses distinct therapeutic challenges, knowing that data on these patients are limited. Herein, we will provide an overview of current knowledge regarding adult LCH and its management. We will also discuss recent advances in the understanding of the disease, (i.e. the role of BRAF oncogene) that opens the way toward targeted therapies.

Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes.

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential to cure patients with an inherited bone marrow failure syndrome (IBMFS). However, the procedure involves the risk of treatment-related mortality and may be associated with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks. IBMFS are rare, whereas case reports and small series in the literature illustrate highly heterogeneous practices in terms of indications for HSCT, timing, stem cell source and conditioning regimens. A consensus meeting was therefore held in Vienna in September 2012 on behalf of the European Group for Blood and Marrow Transplantation to discuss HSCT in the setting of IBMFS. This report summarizes the recommendations from this expert panel, including indications for HSCT, timing, stem cell source and conditioning regimen.

Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder involving developmental abnormalities, tissue and organ hyperplasia and an increased risk of embryonal tumours (most commonly Wilms tumour). This multigenic disorder is caused by dysregulation of the expression of imprinted genes in the 11p15 chromosomal region. Molecular diagnosis of BWS is currently difficult, mostly due to the large spectrum of genetic and epigenetic abnormalities. The other difficulty in managing BWS is the identification of patients at risk of tumour. An imprinted antisense transcript within KCNQ1, called KCNQ1OT (also known as LIT1), was recently shown to be normally expressed from the paternal allele. A loss of imprinting of the KCNQ1OT gene, associated with the loss of maternal allele-specific methylation of the differentially methylated region KvDMR1 has been described in BWS patients. The principal aim of this study was to evaluate the usefulness of KvDMR1 methylation analysis of leukocyte DNA for the diagnosis of BWS. The allelic status of the 11p15 region and the methylation status of the KCNQ1OT and H19 genes were investigated in leukocyte DNA from 97 patients referred for BWS and classified into two groups according to clinical data: complete BWS (CBWS) (n=61) and incomplete BWS (IBWS) (n=36). Fifty-eight (60%) patients (39/61 CBWS and 19/36 IBWS) displayed abnormal demethylation of KvDMR1. In 11 of the 56 informative cases, demethylation of KvDMR1 was related to 11p15 uniparental disomy (UPD) (nine CBWS and two IBWS). Thirteen of the 39 patients with normal methylation of KvDMR1 displayed hypermethylation of the H19 gene. These 13 patients included two siblings with 11p15 trisomy. These results show that analysis of the methylation status of KvDMR1 and the H19 gene in leukocyte DNA is useful in the diagnosis of 11p15-related overgrowth syndromes, resulting in the diagnosis of BWS in more than 70% of investigated patients. We also evaluated clinical and molecular features as prognostic factors for tumour and showed that mosaicism for 11p15 UPD and hypermethylation of the H19 gene in blood cells were associated with an increased risk of tumour.

Treatment of steroid-resistant acute graft-versus-host disease with an anti-IL-2-receptor monoclonal antibody (BT 563) in children who received T cell-depleted, partially matched, related bone marrow transplants.

Fifteen children with steroid-resistant acute graft-versus-host disease (GVHD, grade II-IV) were treated with a murine monoclonal antibody (BT 563) specific for the alpha subunit of the interleukin-2 receptor (IL-2R). All had inherited diseases of the bone marrow and had received T cell-depleted marrow from a partially matched related donor. BT 563 antibody was given at a daily dose of 0.2 mg/kg. Treatment was continued until GVHD was controlled and the methylprednisolone administration was tapered to < or = 2 mg/kg/day. No side-effects were noted. Eleven of the 15 patients reached complete remission and a partial remission occurred in two. This good response rate was associated with early treatment (mean time after GVHD onset 7.7 +/- 5.3 days) and prolonged treatment (mean 25.9 +/- 10.6 days) compared with previously published data on BT 563 antibody usage. Relapses occurred in six of the 13 responders but a further remission was induced by the same treatment. Chronic GVHD developed in six cases and one of them died of GVHD-associated infection. Ten of the 15 patients are long-term survivors and are free of chronic GVHD. The results of this pilot study indicate that early and lengthy treatment with anti-IL-2R monoclonal antibody is both safe and effective against steroid-resistant GVHD in young children and indicate that further trials of anti-IL-2R antibody as first-line therapy of acute GVHD are warranted.

Allogeneic bone marrow transplantation following a busulfan-based conditioning regimen in young children with acute lymphoblastic leukemia: a Cooperative Study of the Société Française de Greffe de Moelle.

A subgroup of children with ALL remains at high risk of relapse despite the administration of intensive chemotherapeutic protocols and may benefit from allogeneic BMT. The cytoreductive regimen used most often combines TBI with cyclophosphamide. Nevertheless, miscellaneous long-term sequelae have been consequent upon radiotherapy, especially in young children. This retrospective multicentric study analyzes the outcome of children with ALL under 4 years of age receiving an HLA-genoidentical BMT following a radiation-free preparative regimen. A busulfan-based regimen with cyclophosphamide or melphalan +/- etoposide +/- cytarabine was given to 21 children (median age: 28 months, range 6-48). Sixteen patients with initial poor prognostic factors were transplanted in first complete response (CR) and five patients in relapse or second CR. With a median follow-up of 47 months, the results show an overall 4-year DFS of 61.1%. Leukemic recurrence was observed in eight patients. The preparative regimen was well-tolerated and there were no transplant-related deaths. A busulfan-based BMT preparative regimen may be a therapeutic alternative to TBI-containing regimens in young children. Efforts are currently aimed at reducing the relapse rate in these children by optimizing the tumoricidal potential of chemotherapy and the graft-versus-leukemia effect of allogeneic BMT.

Treatment of juvenile chronic myelomonocytic leukemia by allogeneic bone marrow transplantation.

Twelve of 15 patients with juvenile chronic myelomonocytic leukemia (JCMML) referred to our unit underwent allogeneic bone marrow transplantation (BMT) between 1982 and 1992. BMT was not performed in the remaining three cases because of poor overall condition in two and disease progression in one. Six patients received marrow from HLA-identical siblings after a chemotherapy conditioning regimen in five cases. BMT failed in one case. Long-term remission was achieved in three patients and two others are in remission 6 and 11 months after BMT. Remission was associated with autologous recovery in one patient and minimal mixed chimerism in another. In one patient, a first BMT procedure resulted in autologous recovery and relapse. A second transplant, with chemotherapy conditioning including TBI, was successful. BMT with marrow from a matched unrelated donor was also successful. IN contrast, BMT with marrow from mismatched related donors (five patients) failed because of graft failure and/or relapse. This single-center series indicates that HLA-identical BMT is an appropriate treatment for JCMML. However, on the basis of these results it cannot be ascertained whether chemotherapy or splenectomy are necessary prior to BMT. The best chemotherapy conditioning regimen remains to be defined, as regimens consisting exclusively of chemotherapy resulted either in long-term remission or in autologous recovery with relapse.

Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langerhans Cell Study Group.

The aim of this study was to assess the results of hematopoietic stem cell transplantation (HSCT) in refractory Langerhans cell histiocytosis (LCH). Among 85 patients with LCH and hematological dysfunction diagnosed in France between 1987 and 2000, eight received HSCT in six institutions. Median age at diagnosis was 0.54 years. The median LCH activity score at diagnosis was 10 (range 3-20). All patients responded poorly to initial chemotherapy. At the time of HSCT, the median activity score was 16.5 (range 7-18). HSCT was autologous in three cases and allogeneic in five cases. The conditioning regimen consisted of TBI in two cases and chemotherapy alone in six cases. Conditioning had to be attenuated in two patients. All patients had persistent active disease after autologous HSCT, which was fatal in two cases and controlled by chemotherapy in one case. After allogeneic HSCT, two patients died from toxicity and three had complete responses; two patients had had no recurrences after 21 months and 7 years of follow-up, while the other patient relapsed and died from sepsis related to splenectomy. HSCT for refractory LCH can thus be highly toxic but can also achieve sustained disease control.