Biosimilars in the management of neutropenia: focus on filgrastim

Advances in chemotherapy and surgery allows the majority of patients to survive cancer diseases. Yet, the price may be a proportion of patients dying of complications due to treatment-induced infectious complications, such as neutropenia. With the aim of decreasing morbidity and mortality related to infectious complications, recombinant human granulocyte colony-stimulating factor (G-CSF), filgrastim, and pegylated filgrastim have been used to reduce time and degree of neutropenia. A biosimilar is a copy of an approved original biologic medicine whose data protection has expired. The patent for filgrastim expired in Europe in 2006 and in the US in 2013. This review analyses the available evidence to be considered in order to design a strategy of use of G-CSF and its biosimilars. The clinical and safety outcomes of biosimilars are well within the range of historically reported data for originator filgrastim. This underscores the clinical effectiveness and safety of biosimilar filgrastim in daily clinical practice. Biosimilars can play an important role by offering the opportunity to reduce costs, thus contributing to the financial sustainability of treatment programs

2B4 dysfunction in XLP1 NK cells: More than inability to control EBV infection

X-linked lymphoproliferative disease 1 (XLP1) is a monogenic disorder caused by mutations in SH2D1A, resulting in the absence/dysfunction of the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). Consequently, SLAM receptors as 2B4 (CD244) and NTB-A (SLAMF6), upon ligand engagement, exert inhibitory instead of activating function. This causes an immune dysfunction that is worsened by the selective inability of NK and T cells to kill EBV-infected B cells with dramatic clinical sequelae (e.g. fulminant mononucleosis, hyperinflammation, lymphoma). Here we outline recent findings on the interplay between inhibitory 2B4 and the various activating receptors in NK cells. 2B4 engagement selectively blocks ITAM-dependent activating receptors as NCR and CD16, while it does not affect NKG2D and DNAM-1. Furthermore, inhibitory 2B4 participates to NK cell education, as highlighted by the existence in XLP1 patients of a large subset of fully functional NK cells that lack self-HLA specific inhibitory receptors and exert autoreactivity against mature dendritic cells

Familial hemophagocytic lymphohistiocytosis type 3 diagnosed at school age: a case report

Familial hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition characterized by immune hyperactivation and clinical signs of extreme inflammation. We describe a 7-year-old male who presented with fever resistant to antibiotic therapy, pancytopenia, splenomegaly, hypertriglyceridemia, and hyperferritinemia. Bone marrow aspirate showed hemophagocytosis. Epstein-Barr virus genome was positive in blood. Functional screening showed reduced capacity of cytotoxic degranulation. Mutation analysis of the FHL-related genes revealed compound heterozygous for UNC13D mutations: c. 753+1G>T, and the novel c.544C>T (p.P182S). Patients with a clinical presentation of HLH, even if older than typically seen, should be screened for familial HLH by mutation analysis

Il contributo dell\u2019Associazione italiana di ematologia e oncologia pediatrica (AIEOP) - The contribution of the Italian Association of paediatric haematology and oncology (AIEOP)

Since 1972, children affected by cancer took advantage from multi-centric diagnostic and therapeutic protocols produced by the Italian Association of paediatric haematology and oncology (AIEOP). At the beginning, these protocols were used in few well-trained centres, later in almost all Italian haemato-oncological centres. The need of a careful monitoring of his own activity induced AIEOP to achieve, in 1989, an Italian hospital- based registry (database Mod.1.01) of malignant tumours diagnosed and treated in the participating centres, with the aim to quantify the number of cases diagnosed and treated in the different centres, the agreement (or not) to official diagnostic- therapeutic protocols, and the extraregional migration. The database Mod.1.01, which is available via web to the current 55 AIEOP centres since 2000, recruits annually about 1,400 children (0-14 years) and 200 adolescents (15-19 years). While the first accounts for over 90% of expected subjects, the latter are only 25%. Leukaemias (30% of cases) are the most frequent childhood cancers, followed by central nervous system (CNS) tumours and lymphomas, 18% of cases both. In children, leukaemias (34%) are prevalent, mostly acute lymphoblastic leukaemia (26%), followed by CNS tumours (18%); in adolescents, lymphomas (30%) are prevalent, mostly Hodgkin lymphomas (22%), followed by bone sarcomas (16%). The recruitment of registered cases in AIEOP protocols is overall good both for children (70%) and for adolescents (60%), achieving outstanding results in leukaemia protocols. Extraregional migration of patients for diagnosis and therapy is decreasing over time, being currently about 20%, higher in adolescents, in solid tumours, and in residents in South Italy and in the islands. On the contrary, an increase of subjects born and resident abroad who are hospitalised in AIEOP centres for diagnosis and treatment, accounting at present for 5% of all cases, was observed. The results confirm that the database Mod.1.01 can be a valid tool able to contribute to epidemiologic research on childhood cancer in Italy

[The contribution of the Italian Association of paediatric haematology and oncology (AIEOP)]

Since 1972, children affected by cancer took advantage from multi-centric diagnostic and therapeutic protocols produced by the Italian Association of paediatric haematology and oncology (AIEOP). At the beginning, these protocols were used in few well-trained centres, later in almost all Italian haemato-oncological centres. The need of a careful monitoring of his own activity induced AIEOP to achieve, in 1989, an Italian hospital- based registry (database Mod.1.01) of malignant tumours diagnosed and treated in the participating centres, with the aim to quantify the number of cases diagnosed and treated in the different centres, the agreement (or not) to official diagnostic- therapeutic protocols, and the extraregional migration. The database Mod.1.01, which is available via web to the current 55 AIEOP centres since 2000, recruits annually about 1,400 children (0-14 years) and 200 adolescents (15-19 years). While the first accounts for over 90% of expected subjects, the latter are only 25%. Leukaemias (30% of cases) are the most frequent childhood cancers, followed by central nervous system (CNS) tumours and lymphomas, 18% of cases both. In children, leukaemias (34%) are prevalent, mostly acute lymphoblastic leukaemia (26%), followed by CNS tumours (18%); in adolescents, lymphomas (30%) are prevalent, mostly Hodgkin lymphomas (22%), followed by bone sarcomas (16%). The recruitment of registered cases in AIEOP protocols is overall good both for children (70%) and for adolescents (60%), achieving outstanding results in leukaemia protocols. Extraregional migration of patients for diagnosis and therapy is decreasing over time, being currently about 20%, higher in adolescents, in solid tumours, and in residents in South Italy and in the islands. On the contrary, an increase of subjects born and resident abroad who are hospitalised in AIEOP centres for diagnosis and treatment, accounting at present for 5% of all cases, was observed. The results confirm that the database Mod.1.01 can be a valid tool able to contribute to epidemiologic research on childhood cancer in Italy

Hematopoietic Stem Cell Transplantation for Hemophagocytic Lymphohistiocitosis : A National Retrospective Analysis of Data from the Italian Association of Pediatric Hematology Oncology (AIEOP)

Retrospective study on the outcome of allogeneic stem cell transplantation for HLH patients recorded in AIEOP registr

A National Retrospective Analysis of Data from the Italian Association of Pediatric Hematology Oncology (AIEOP).

Hematopoietic Stem Cell Transplantation for Hemophagocytic Lymphohistiocitosis : A National Retrospective Analysis of Data from the Italian Association of Pediatric Hematology Oncology (AIEOP

Outcomes of Children with Hemophagocytic Lymphohistiocytosis Given Allogeneic Hematopoietic Stem Cell Transplantation in Italy

We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34+ cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft