simona PAGLIUCA - Academia.edu (original) (raw)
Papers by simona PAGLIUCA
Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a... more Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. Immunogenetic patterns associated with self-antigenic presentation remain unclear. Herein we analyzed the molecular landscape of HLA complexes and T-cell receptor (TCR) repertoires of a large cohort of IAA patients and controls. We show that antigen binding sites of class II HLA molecules in IAA are characterized by a high level of structural homology, only partially explained by specific risk allele profiles, implying reduced binding capabilities compared to controls. Few amino acids within the synapsis HLA-DRB1-antigen-TCR, are identified as strongly associated with IAA phenotype. Those structural patterns may affect TCR repertoires, promoting immunological cross-reactivity and autoimmunity. These findings inform on the immunogenetic risk associated with IAA and on general pathophysiological mechanisms poten...
Blood
Somatic mutations of X-chromosomal PIGA gene in hematopoietic stem cells are the key molecular ev... more Somatic mutations of X-chromosomal PIGA gene in hematopoietic stem cells are the key molecular events in the pathogenesis of PNH. PIGA mutations lead to impaired biosynthesis of glycosylphosphoinositol (GPI)-anchor. Resultant lack of GPI-anchored proteins (GPI-AP) leads to a clonal expansion of PNH clone and increased sensitivity of PNH red cells (RBCs) to complement-mediated hemolysis. Based on immunofluorescent staining, the severity of GPI-APs deficiency on the RBCs can be distinguished in: PNH type-1 (TI) with a normal expression; PNH type-2 (TII) with a partial reduction; and PNH type-3 (TIII) PNH with a total absence of CD55 and CD59.1 Fractions of these RBC types are believed to be a result of the molecular spectrum of PIGA mutations ranging from missense in various amino acids positions to truncations and locus deletions, which can be concurrent in some patients. Consequently, the presence of TII and TIII cells indicates the overall severity of PIGA defect and thus individua...
Cancers
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders chara... more Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, progressive cytopenias and increased risk of transformation to acute myeloid leukemia. The improved understanding of the underlying biology and genetics of MDS has led to better disease and risk classification, paving the way for novel therapeutic opportunities. Indeed, we now have a vast pipeline of targeted agents under pre-clinical and clinical development, potentially able to modify the natural history of the diverse disease spectrum of MDS. Here, we review the latest therapeutic approaches (investigational and approved agents) for MDS treatment. A deep insight will be given to molecularly targeted therapies by reviewing new agents for individualized precision medicine.
Blood
Background. While childhood leukemia and bone marrow failure disorders always raise suspicions of... more Background. While childhood leukemia and bone marrow failure disorders always raise suspicions of a familial trait, recognition of germ line (GL) contribution to the pathogenesis of adult presentation of these disorders may be difficult because of the absent and unreliable family history, long disease anticipation and incomplete penetrance due to various factors, including competing mortality and interaction with environmental factors. The search for such GL alterations may involve unbiased whole exome sequencing or genome wide analysis studies approaches or, as we conducted here, rely on identification of GL variants in a rationally selected panel of genes previously involved in leukemia and bone marrow failure (BMF). Methods. We hypothesize that, in analogy to pediatric disease, pathogenic GL alterations may exist also in a subset of adult patients with BMF and myeloid neoplasia (MN). Such lesions may contribute to the clinical features and the preferential occurrence of somatic h...
Blood
Up to 15% of AA patients (pts) treated conservatively with immunosuppression will evolve to myelo... more Up to 15% of AA patients (pts) treated conservatively with immunosuppression will evolve to myeloid neoplasia (MN), either MDS or AML, over a median time of 10 years regardless of response (0-18 years; n=238). The pathogenesis of MN secondary to AA is diverse and will often include antecedent clonal facilitating events that herald progression. Minor clones have been described in AA, some of which are not contributory to later evolution while other may result in subsequent progression. MDS evolution in inherited bone marrow failure (BMF) syndromes suggests that germ line (GL) alterations can be predisposing. In addition, progression to MN may reflect immune escape due to selection pressure e.g., through acquisition of HLA mutations. Here, we studied the molecular landscape of MN arising from AA, to better understand its pathogenesis and ultimately to develop measures of early detection, prevention, and therapeutic strategies. Among 350 pts diagnosed with AA and PNH, 38 (11%) develope...
Blood Cells, Molecules, and Diseases
Bone Marrow Transplantation
Biology of Blood and Marrow Transplantation
Stem Cell Investigation
Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) represent the ... more Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) represent the milestones of the treatment algorithm for idiopathic and inherited bone marrow failure (BMF) disorders. However, patients lacking a suitable donor or failing IST still have a poor prognosis. Cord blood transplantation (CBT) has extended the possibility of HSCT for many patients in case of the absence of an eligible donor, and although in the last years, this procedure is less used in several hematological diseases, it remains an option for the treatment of patients with BMF syndromes. Nevertheless, optimization of conditioning regimen and cord blood unit selection is warranted to reduce the risk of graft failure and transplant-related mortality. This review summarizes the state of art of CBT in the field of BMF diseases, focusing on historical and recent issues in idiopathic aplastic anemia and inherited disorders.
Blood
Bone marrow failure (BMF) syndrome is a group of rare hereditary or idiopathic disorders occurrin... more Bone marrow failure (BMF) syndrome is a group of rare hereditary or idiopathic disorders occurring at all ages. For BMF patients under 40 years of age and having an HLA-identical related donor, allogeneic bone marrow transplantation (HSCT) is indicated. The use of cord blood transplantation (CBT) from an HLA-identical sibling donor is of interest in non-malignant disease due to the low risk of graft-versus-host disease (GVHD) associated with this type of stem cell source and the absence of risk to the donor. We analyzed outcomes of 122 children and young adults with inherited or acquired BMF syndrome, who received a CBT from an HLA-identical related donor. Patients were transplanted in EBMT centers between 1988 and 2014 and reported to Eurocord and EBMT. Ninety-six patients had an inherited and 26 patients had an acquired BMF. The specific diagnosis were: Fanconi anemia (n=48), Diamond Blackfan anemia (n=25), Amegakariocytic thrombocytopenia (n=6), Kostmann syndrome (n=4), Dyskerato...
Blood
The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is... more The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including acute and chronic graft-versus-host disease (GVHD), relapse and death. Classical endpoints such as overall survival (OS), desease free survival (DFS) and non relapse-mortality (NRM) had become more and more unsuitable for transplant research because of their inability to a dynamic mesure of transplant-associated comorbidity. For this reason several composite endpoints taking into account also GVHD-associated comorbidity were proposed in the last years. GVHD free/relapse free survival (GRFS), proposed by Holtan et al (Blood 2015), includes grades 3-4 acute GVHD, systemic therapy requiring chronic GVHD, primary disease relapse , or death for any cause considered as events. This endpoint seems to completely characterize the survival without mortality or ongoing morbidity. With the intent to analyse the outcomes ...
Blood
Paroxysmal nocturnal hemoglobinuria (PNH) may present as hemolytic (classical PNH) or aplastic (A... more Paroxysmal nocturnal hemoglobinuria (PNH) may present as hemolytic (classical PNH) or aplastic (AA/PNH syndrome) PNH. While classical PNH patients requires anti-complement treatment (eculizumab), the treatment of AA/PNH patients should target their bone marrow failure (BMF) by immunosuppression (IST), or even bone marrow transplantation (BMT). However, in a few patients clinically meaningful AA and hemolysis may be concomitant, eventually justifying both IST and eculizumab. To date there is no standard treatment for this rare condition. Here we investigated the prevalence of this condition based on a large cohort of PNH patients seen at our reference centers at St. Louis Hospital (Paris) and Federico II University (Naples), looking for patients who have received "intensive IST" in combination with eculizumab. Amongst a total of 145 PNH patients seen between 2007 and 2016, we have identified 6 patients who have received intensive IST during eculizumab treatment ; thus, roug...
Blood
Introduction Consistent data show that the real goal in CML therapy is to obtain a very rapid and... more Introduction Consistent data show that the real goal in CML therapy is to obtain a very rapid and deep response because the cinetic of molecular response (MR) is important for quickly reducing the tumor burden by reducing the BCR/ABL level. The second generation TKIs Nilotinib was designed to have enhanced selectivity and potency toward BCR-ABL compared with imatinib and was able to obtain very rapid and deeper response as shown by many clinical trials. Nilotinib has been approved in multiple countries for use in first line therapy in CML-CP Pts. In order to verify the efficacy and safety of Nilotinib used in first line treatment, we collected the results of a real life cohort of Pts treated in some italian hematological Institutions. Patients and Methods 68 Pts affected by CML-CP were treated in 9 hematologic units with Nilotinib as first line therapy from 2010 to 2014. The median age was 47.7y with equal distribution by sex. Cytogenetic analysis at diagnosis showed in 66/68 Pts th...
Bone Marrow Transplantation
Acute graft-versus-host disease (aGVHD) remains one of the leading causes of morbidity and mortal... more Acute graft-versus-host disease (aGVHD) remains one of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. No consensus exists on the best second-line treatment of steroid-refractory acute GVHD (SR-aGVHD). Previously published smaller studies on the use of sirolimus in SR-aGVHD treatment report a response rate of 57 to 86%, with 40% overall survival. The association of tacrolimus and mTOR inhibitor is supported by pre-clinical data and has been used as GVHD prophylaxis. We report 42 patients who received tacrolimus and mTOR inhibitor as a second-or third-line treatment of SR-aGVHD. Thirty-one patients were treated in second-line, with an overall response rate of 48.5% (complete response: 42%). Eleven patients were treated in third-line, with an overall response rate of 27%. Thirty-eight patients had at least one episode of infection, due to bacteria, viruses, fungi and parasites in 61, 42, 12 and two episodes, respectively. For patients treated in second-line, six-month and one-year survival were 61% and 42%, respectively. None of the patients treated in third-line survived. These results were not promising enough to initiate a phase three randomized clinical trial, but tacrolimus and mTOR inhibitor can be discussed among other options for patients with SR-aGVHD.
Blood Advances
Endothelial cell (EC) activation has been suspected of triggering a group of rare and dismal comp... more Endothelial cell (EC) activation has been suspected of triggering a group of rare and dismal complications that can occur after allogeneic hematopoietic stem cell transplantation (HSCT). Capillary leak syndrome, engraftment syndrome, transplant-associated microangiopathy, diffuse alveolar hemorrhage, and idiopathic pneumonia syndrome are the main nosological entities. Post-HSCT endotheliitis can be triggered by chemotherapy, infections, and calcineurin inhibitors, but allogeneic reactivity is claimed to be the common denominator. Endothelial damages are thought to activate several deleterious pathways (proapoptotic, procoagulant, proinflammatory) and can lead to multiorgan failure; however, clinical manifestations of each syndrome overlap, and their relationship with graft-versus-host disease could be minimal. The lack of well-defined diagnostic criteria does not allow for a clear-cut comparison in the current literature. Therapeutic efforts have been made to intercept the pathogeni...
Bone Marrow Transplantation
Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a... more Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. Immunogenetic patterns associated with self-antigenic presentation remain unclear. Herein we analyzed the molecular landscape of HLA complexes and T-cell receptor (TCR) repertoires of a large cohort of IAA patients and controls. We show that antigen binding sites of class II HLA molecules in IAA are characterized by a high level of structural homology, only partially explained by specific risk allele profiles, implying reduced binding capabilities compared to controls. Few amino acids within the synapsis HLA-DRB1-antigen-TCR, are identified as strongly associated with IAA phenotype. Those structural patterns may affect TCR repertoires, promoting immunological cross-reactivity and autoimmunity. These findings inform on the immunogenetic risk associated with IAA and on general pathophysiological mechanisms poten...
Blood
Somatic mutations of X-chromosomal PIGA gene in hematopoietic stem cells are the key molecular ev... more Somatic mutations of X-chromosomal PIGA gene in hematopoietic stem cells are the key molecular events in the pathogenesis of PNH. PIGA mutations lead to impaired biosynthesis of glycosylphosphoinositol (GPI)-anchor. Resultant lack of GPI-anchored proteins (GPI-AP) leads to a clonal expansion of PNH clone and increased sensitivity of PNH red cells (RBCs) to complement-mediated hemolysis. Based on immunofluorescent staining, the severity of GPI-APs deficiency on the RBCs can be distinguished in: PNH type-1 (TI) with a normal expression; PNH type-2 (TII) with a partial reduction; and PNH type-3 (TIII) PNH with a total absence of CD55 and CD59.1 Fractions of these RBC types are believed to be a result of the molecular spectrum of PIGA mutations ranging from missense in various amino acids positions to truncations and locus deletions, which can be concurrent in some patients. Consequently, the presence of TII and TIII cells indicates the overall severity of PIGA defect and thus individua...
Cancers
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders chara... more Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, progressive cytopenias and increased risk of transformation to acute myeloid leukemia. The improved understanding of the underlying biology and genetics of MDS has led to better disease and risk classification, paving the way for novel therapeutic opportunities. Indeed, we now have a vast pipeline of targeted agents under pre-clinical and clinical development, potentially able to modify the natural history of the diverse disease spectrum of MDS. Here, we review the latest therapeutic approaches (investigational and approved agents) for MDS treatment. A deep insight will be given to molecularly targeted therapies by reviewing new agents for individualized precision medicine.
Blood
Background. While childhood leukemia and bone marrow failure disorders always raise suspicions of... more Background. While childhood leukemia and bone marrow failure disorders always raise suspicions of a familial trait, recognition of germ line (GL) contribution to the pathogenesis of adult presentation of these disorders may be difficult because of the absent and unreliable family history, long disease anticipation and incomplete penetrance due to various factors, including competing mortality and interaction with environmental factors. The search for such GL alterations may involve unbiased whole exome sequencing or genome wide analysis studies approaches or, as we conducted here, rely on identification of GL variants in a rationally selected panel of genes previously involved in leukemia and bone marrow failure (BMF). Methods. We hypothesize that, in analogy to pediatric disease, pathogenic GL alterations may exist also in a subset of adult patients with BMF and myeloid neoplasia (MN). Such lesions may contribute to the clinical features and the preferential occurrence of somatic h...
Blood
Up to 15% of AA patients (pts) treated conservatively with immunosuppression will evolve to myelo... more Up to 15% of AA patients (pts) treated conservatively with immunosuppression will evolve to myeloid neoplasia (MN), either MDS or AML, over a median time of 10 years regardless of response (0-18 years; n=238). The pathogenesis of MN secondary to AA is diverse and will often include antecedent clonal facilitating events that herald progression. Minor clones have been described in AA, some of which are not contributory to later evolution while other may result in subsequent progression. MDS evolution in inherited bone marrow failure (BMF) syndromes suggests that germ line (GL) alterations can be predisposing. In addition, progression to MN may reflect immune escape due to selection pressure e.g., through acquisition of HLA mutations. Here, we studied the molecular landscape of MN arising from AA, to better understand its pathogenesis and ultimately to develop measures of early detection, prevention, and therapeutic strategies. Among 350 pts diagnosed with AA and PNH, 38 (11%) develope...
Blood Cells, Molecules, and Diseases
Bone Marrow Transplantation
Biology of Blood and Marrow Transplantation
Stem Cell Investigation
Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) represent the ... more Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) represent the milestones of the treatment algorithm for idiopathic and inherited bone marrow failure (BMF) disorders. However, patients lacking a suitable donor or failing IST still have a poor prognosis. Cord blood transplantation (CBT) has extended the possibility of HSCT for many patients in case of the absence of an eligible donor, and although in the last years, this procedure is less used in several hematological diseases, it remains an option for the treatment of patients with BMF syndromes. Nevertheless, optimization of conditioning regimen and cord blood unit selection is warranted to reduce the risk of graft failure and transplant-related mortality. This review summarizes the state of art of CBT in the field of BMF diseases, focusing on historical and recent issues in idiopathic aplastic anemia and inherited disorders.
Blood
Bone marrow failure (BMF) syndrome is a group of rare hereditary or idiopathic disorders occurrin... more Bone marrow failure (BMF) syndrome is a group of rare hereditary or idiopathic disorders occurring at all ages. For BMF patients under 40 years of age and having an HLA-identical related donor, allogeneic bone marrow transplantation (HSCT) is indicated. The use of cord blood transplantation (CBT) from an HLA-identical sibling donor is of interest in non-malignant disease due to the low risk of graft-versus-host disease (GVHD) associated with this type of stem cell source and the absence of risk to the donor. We analyzed outcomes of 122 children and young adults with inherited or acquired BMF syndrome, who received a CBT from an HLA-identical related donor. Patients were transplanted in EBMT centers between 1988 and 2014 and reported to Eurocord and EBMT. Ninety-six patients had an inherited and 26 patients had an acquired BMF. The specific diagnosis were: Fanconi anemia (n=48), Diamond Blackfan anemia (n=25), Amegakariocytic thrombocytopenia (n=6), Kostmann syndrome (n=4), Dyskerato...
Blood
The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is... more The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including acute and chronic graft-versus-host disease (GVHD), relapse and death. Classical endpoints such as overall survival (OS), desease free survival (DFS) and non relapse-mortality (NRM) had become more and more unsuitable for transplant research because of their inability to a dynamic mesure of transplant-associated comorbidity. For this reason several composite endpoints taking into account also GVHD-associated comorbidity were proposed in the last years. GVHD free/relapse free survival (GRFS), proposed by Holtan et al (Blood 2015), includes grades 3-4 acute GVHD, systemic therapy requiring chronic GVHD, primary disease relapse , or death for any cause considered as events. This endpoint seems to completely characterize the survival without mortality or ongoing morbidity. With the intent to analyse the outcomes ...
Blood
Paroxysmal nocturnal hemoglobinuria (PNH) may present as hemolytic (classical PNH) or aplastic (A... more Paroxysmal nocturnal hemoglobinuria (PNH) may present as hemolytic (classical PNH) or aplastic (AA/PNH syndrome) PNH. While classical PNH patients requires anti-complement treatment (eculizumab), the treatment of AA/PNH patients should target their bone marrow failure (BMF) by immunosuppression (IST), or even bone marrow transplantation (BMT). However, in a few patients clinically meaningful AA and hemolysis may be concomitant, eventually justifying both IST and eculizumab. To date there is no standard treatment for this rare condition. Here we investigated the prevalence of this condition based on a large cohort of PNH patients seen at our reference centers at St. Louis Hospital (Paris) and Federico II University (Naples), looking for patients who have received "intensive IST" in combination with eculizumab. Amongst a total of 145 PNH patients seen between 2007 and 2016, we have identified 6 patients who have received intensive IST during eculizumab treatment ; thus, roug...
Blood
Introduction Consistent data show that the real goal in CML therapy is to obtain a very rapid and... more Introduction Consistent data show that the real goal in CML therapy is to obtain a very rapid and deep response because the cinetic of molecular response (MR) is important for quickly reducing the tumor burden by reducing the BCR/ABL level. The second generation TKIs Nilotinib was designed to have enhanced selectivity and potency toward BCR-ABL compared with imatinib and was able to obtain very rapid and deeper response as shown by many clinical trials. Nilotinib has been approved in multiple countries for use in first line therapy in CML-CP Pts. In order to verify the efficacy and safety of Nilotinib used in first line treatment, we collected the results of a real life cohort of Pts treated in some italian hematological Institutions. Patients and Methods 68 Pts affected by CML-CP were treated in 9 hematologic units with Nilotinib as first line therapy from 2010 to 2014. The median age was 47.7y with equal distribution by sex. Cytogenetic analysis at diagnosis showed in 66/68 Pts th...
Bone Marrow Transplantation
Acute graft-versus-host disease (aGVHD) remains one of the leading causes of morbidity and mortal... more Acute graft-versus-host disease (aGVHD) remains one of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. No consensus exists on the best second-line treatment of steroid-refractory acute GVHD (SR-aGVHD). Previously published smaller studies on the use of sirolimus in SR-aGVHD treatment report a response rate of 57 to 86%, with 40% overall survival. The association of tacrolimus and mTOR inhibitor is supported by pre-clinical data and has been used as GVHD prophylaxis. We report 42 patients who received tacrolimus and mTOR inhibitor as a second-or third-line treatment of SR-aGVHD. Thirty-one patients were treated in second-line, with an overall response rate of 48.5% (complete response: 42%). Eleven patients were treated in third-line, with an overall response rate of 27%. Thirty-eight patients had at least one episode of infection, due to bacteria, viruses, fungi and parasites in 61, 42, 12 and two episodes, respectively. For patients treated in second-line, six-month and one-year survival were 61% and 42%, respectively. None of the patients treated in third-line survived. These results were not promising enough to initiate a phase three randomized clinical trial, but tacrolimus and mTOR inhibitor can be discussed among other options for patients with SR-aGVHD.
Blood Advances
Endothelial cell (EC) activation has been suspected of triggering a group of rare and dismal comp... more Endothelial cell (EC) activation has been suspected of triggering a group of rare and dismal complications that can occur after allogeneic hematopoietic stem cell transplantation (HSCT). Capillary leak syndrome, engraftment syndrome, transplant-associated microangiopathy, diffuse alveolar hemorrhage, and idiopathic pneumonia syndrome are the main nosological entities. Post-HSCT endotheliitis can be triggered by chemotherapy, infections, and calcineurin inhibitors, but allogeneic reactivity is claimed to be the common denominator. Endothelial damages are thought to activate several deleterious pathways (proapoptotic, procoagulant, proinflammatory) and can lead to multiorgan failure; however, clinical manifestations of each syndrome overlap, and their relationship with graft-versus-host disease could be minimal. The lack of well-defined diagnostic criteria does not allow for a clear-cut comparison in the current literature. Therapeutic efforts have been made to intercept the pathogeni...
Bone Marrow Transplantation