Pediatric Reports

321 KiB

Open AccessArticle

Severe Congenital Neutropenia, a Genetically Heterogeneous Disease Group With an Increased Risk of AML/MDS

by Peter Vandenberghe and Karolien Beel

Pediatr. Rep. 2011, 3(s2), e9; https://doi.org/10.4081/pr.2011.s2.e9 - 17 Jun 2011

Cited by 27 | Viewed by 1

Over the past decade, enormous progress has been made in the understanding of severe congenital neutropenia (SCN), by identification of several causal gene mutations: in ELANE, GFI1, HAX1, WAS and G3PC3. SCN is a preleukemic condition, independent of the genetic subtype. Acquired CSF3R [...] Read more.

Over the past decade, enormous progress has been made in the understanding of severe congenital neutropenia (SCN), by identification of several causal gene mutations: in ELANE, GFI1, HAX1, WAS and G3PC3. SCN is a preleukemic condition, independent of the genetic subtype. Acquired CSF3R mutations are specific for SCN and are strongly associated with malignant progression. In this review, we describe the known genetic subtypes of SCN, their molecular basis and clinical presentation and summarize the available evidence on CSF3R mutations and monosomy 7 in malignant conversion. Full article

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Open AccessArticle

Fanconi Anemia - Learning from Children

by Johanna Svahn and Carlo Dufour

Pediatr. Rep. 2011, 3(s2), e8; https://doi.org/10.4081/pr.2011.s2.e8 - 17 Jun 2011

Cited by 9 | Viewed by 1

Abstract

Fanconi Anemia (FA) is a rare autosomic recessive and X-linked disease with chromosomal instability after exposure to crosslinking agents as the hallmark. Clinical features of FA are somatic malformations, progressive bone marrow failure and cancer proneness, however there is wide clinical heterogeneity. The [...] Read more.

Fanconi Anemia (FA) is a rare autosomic recessive and X-linked disease with chromosomal instability after exposure to crosslinking agents as the hallmark. Clinical features of FA are somatic malformations, progressive bone marrow failure and cancer proneness, however there is wide clinical heterogeneity. The symptom most frequently and early associated with morbidity and mortality is progressive pancytopenia in the first decade of life although acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) can appear before aplastic anemia. Squamous cell carcinoma (SCC) of the head-neck, intestinal or genital tract has a very high incidence in FA and can appear at young age. This paper will focus on treatment of bone marrow failure in FA. Full article

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Open AccessArticle

Aplastic Anemia: Immunosuppressive Therapy in 2010

by Antonio M. Risitano and Fabiana Perna

Pediatr. Rep. 2011, 3(s2), e7; https://doi.org/10.4081/pr.2011.s2.e7 - 17 Jun 2011

Cited by 9 | Viewed by 1

Abstract

Acquired aplastic anemia (AA) is the typical bone marrow failure syndrome characterized by an empty bone marrow; an immune-mediated pathophysiology has been demonstrated by experimental works as well as by clinical observations. Immunusuppressive therapy (IST) is a key treatment strategy for aplastic anemia; [...] Read more.

Acquired aplastic anemia (AA) is the typical bone marrow failure syndrome characterized by an empty bone marrow; an immune-mediated pathophysiology has been demonstrated by experimental works as well as by clinical observations. Immunusuppressive therapy (IST) is a key treatment strategy for aplastic anemia; since 20 years the standard IST for AA patients has been anti-thymocyte globuline (ATG) plus cyclosporine A (CyA), which results in response rates ranging between 50% and 70%, and even higher overall survival. However, primary and secondary failures after IST remain frequent, and to date all attempts aiming to overcome this problem have been unfruitful. Here we review the state of the art of IST for AA in 2010, focusing on possible strategies to improve current treatments. We also discuss very recent data which question the equality of different ATG preparations, leading to a possible reconsideration of the current standards of care for AA patients. Full article

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Open AccessArticle

How Does the NPM1 Mutant Induce Leukemia?

by Paolo Sportoletti

Pediatr. Rep. 2011, 3(s2), e6; https://doi.org/10.4081/pr.2011.s2.e6 - 17 Jun 2011

Cited by 4 | Viewed by 4

Abstract

NPM1 is the most frequently mutated gene in AML and the role of the NPM1 mutant in acute myeloid leukemia along with its leukemogenic potential are still under investigation. NPM1 genetic alterations can contribute to leukemogenesis through the direct oncogenic effect of the [...] Read more.

NPM1 is the most frequently mutated gene in AML and the role of the NPM1 mutant in acute myeloid leukemia along with its leukemogenic potential are still under investigation. NPM1 genetic alterations can contribute to leukemogenesis through the direct oncogenic effect of the mutant protein and the concomitant loss of one functional allele. Npm1 loss determines tumor development in the mouse while in human NPM1 maps in a chromosomal region frequently loss in myelodysplastic syndrome (MDS). The NPM1 mutant cytoplasmic delocalization in leukemic blasts alters multiple cellular pathways through either loss or gain of function effects on different protein partners. Here we discuss the most relevant studies on the role of the NPM1 molecule in hematological malignancies and both in vitro and in vivo studies that are trying to elucidate the way by which the NPM1 mutation induces leukemia. Full article

307 KiB

Open AccessArticle

Pathobiology of ALK-Negative Anaplastic Large Cell Lymphoma

by Stefano A. Pileri, Claudio Agostinelli, Francesco Bacci, Elena Sabattini, Carlo Sagramoso, Brunangelo Falini and Pier Paolo Piccaluga

Pediatr. Rep. 2011, 3(s2), e5; https://doi.org/10.4081/pr.2011.s2.e5 - 17 Jun 2011

Cited by 11 | Viewed by 1

Abstract

The authors revise the concept of ALK-negative anaplastic large cell lymphoma (ALCL) in the light of the recently updated WHO classification of Tumors of Hematopoietic and Lymphoid Tissues both on biological and clinical grounds. The main histological findings are illustrated as well as [...] Read more.

The authors revise the concept of ALK-negative anaplastic large cell lymphoma (ALCL) in the light of the recently updated WHO classification of Tumors of Hematopoietic and Lymphoid Tissues both on biological and clinical grounds. The main histological findings are illustrated as well as the phenotypic, molecular and clinical characteristics. Finally, the biological rationale for possible innovative targeted therapies is presented. Full article

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Open AccessArticle

New Genetics and Diagnosis of Childhood B-Cell Precursor Acute Lymphoblastic Leukemia

by Christine Harrison

Pediatr. Rep. 2011, 3(s2), e4; https://doi.org/10.4081/pr.2011.s2.e4 - 17 Jun 2011

Cited by 3 | Viewed by 1

Abstract

Over the last 50 years, while significant advances have been made in the successful treatment of childhood leukaemia, similar progress has been made in understanding the genetics of the disease. In childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), the incidences of individual chromosomal [...] Read more.

Over the last 50 years, while significant advances have been made in the successful treatment of childhood leukaemia, similar progress has been made in understanding the genetics of the disease. In childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), the incidences of individual chromosomal abnormalities are well established and cytogenetics provides a reliable tool for risk stratification for treatment. In spite of this role, a number of patients will relapse. Increasing numbers of additional genetic changes, including deletions and mutations, are being discovered. Their associations with established cytogenetic subgroups and with each other remain unclear. Whether they have a link to outcome is the most important factor in terms of refinement of risk factors in relation to clinical trials. For a number of newly identified abnormalities, appropriately modified therapy has significantly improved outcome. Alternatively, some of these aberrations are providing novel molecular markers for targeted therapy. Full article

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Open AccessArticle

Myeloid/T-Cell Acute Lymphoblastic Leukemia in Children and Adults

by Sabina Chiaretti, Monica Messina, Simona Tavolaro and Robin Foà

Pediatr. Rep. 2011, 3(s2), e3; https://doi.org/10.4081/pr.2011.s2.e3 - 17 Jun 2011

Cited by 3 | Viewed by 1

Abstract

Until recently, few molecular aberrations were recognized in T-cell acute lymphoblastic leukemia (T-ALL) and they were restricted to aberrations involving the T-cell receptor (TCR). The introduction of powerful technologies has allowed to identify novel rearrangements. In this context, we have performed a gene [...] Read more.

Until recently, few molecular aberrations were recognized in T-cell acute lymphoblastic leukemia (T-ALL) and they were restricted to aberrations involving the T-cell receptor (TCR). The introduction of powerful technologies has allowed to identify novel rearrangements. In this context, we have performed a gene expression profiling analysis on a relatively large cohort (n=69) of adult patients with a diagnosis of T-ALL. By unsupervised clustering, we identified 5 subgroups. Of these, one branch included 7 patients (10%) whose gene expression profile resembled that of AML. These cases were characterized by the overexpression of a large set of myeloid-related genes, as well as of miR-223. Finally, these patients appear to have an unfavorable clinical course. This newly identified subset of T-ALL cases partly resembles the so-called ETP (early T-precursor) pediatric subgroup: both age groups have in fact a peculiar gene expression profile, an unfavorable outcome and an incidence of about 10%. Full article

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Open AccessArticle

Acute Lymphoblastic Leukemia: Age and Biology

by Robin Foà

Pediatr. Rep. 2011, 3(s2), e2; https://doi.org/10.4081/pr.2011.s2.e2 - 17 Jun 2011

Cited by 7 | Viewed by 1

Abstract

Acute lymphoblastic leukemia (ALL) is the most frequent neoplasm in children, while being relatively rare in adults. The outcome of children with ALL is far superior than that observed in adults, whose survival rates generally do not exceed 40%. A retrospective analysis recently [...] Read more.

Acute lymphoblastic leukemia (ALL) is the most frequent neoplasm in children, while being relatively rare in adults. The outcome of children with ALL is far superior than that observed in adults, whose survival rates generally do not exceed 40%. A retrospective analysis recently carried out on a large series of cases enrolled in the AIEOP and GIMEMA protocols for the treatment of pediatric and adult ALL has documented specific differences among the various age cohorts examined, particularly in terms of incidence of molecular rearrangements, with the BCR/ABL rearrangement being detected in more than half of patients in the 6th decade of life. These findings highlight the importance of a precise diagnostic screening at all ages, since elderly patients might benefit more from targeted approaches, that are associated with less toxic effects. Furthermore, extended biologic approaches aimed at identifying novel therapeutic targets should be regarded as a main goal to refine our therapeutic armamentarium. Finally, the introduction of pediatric-like protocols is progressively changing the outcome of young adult patients, although an important caveat is represented by the comorbidities and toxic effects associated with more aggressive chemotherapy; therefore, patients’ fitness should always be carefully considered. Full article

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Open AccessArticle

Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation with High Dose, Post-Transplantation Cyclophosphamide

by Ashley Munchel, Chimen Kesserwan, Heather J. Symons, Leo Luznik, Yvette L. Kasamon, Richard J. Jones and Ephraim J. Fuchs

Pediatr. Rep. 2011, 3(s2), e15; https://doi.org/10.4081/pr.2011.s2.e15 - 17 Jun 2011

Cited by 61 | Viewed by 2

Abstract

Allogeneic stem cell transplantation (SCT) from an HLA-haploidentical relative provides a potentially curative treatment option for hematologic malignancies patients who lack a suitably HLA-matched donor. The greatest challenge to performing HLA-haploidentical SCT has been high rates of graft failure and severe graft-versus-host disease [...] Read more.

Allogeneic stem cell transplantation (SCT) from an HLA-haploidentical relative provides a potentially curative treatment option for hematologic malignancies patients who lack a suitably HLA-matched donor. The greatest challenge to performing HLA-haploidentical SCT has been high rates of graft failure and severe graft-versus-host disease (GVHD). Our group has been exploring high dose, post-transplantation cyclophosphamide (Cy) as prophylaxis of GVHD after nonmyeloablative, HLA-haploidentical bone marrow transplantation, or <i>mini-haplo</i>BMT. Among 210 recipients of mini-haploBMT, 87% of patients have experienced sustained donor cell engraftment. The cumulative incidences of grades II-IV acute GVHD and chronic GVHD are 27% and 13%, respectively. Five-year cumulative incidence of non-relapse mortality is 18%, relapse is 55%, and actuarial overall survival and event-free survivals are 35% and 27%, respectively. These outcomes suggest that mini-haploBMT with post-transplantation Cy is associated with acceptably low toxicities and can provide longterm survival, if not cure, for many patients with advanced hematologic malignancies.
Full article

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Open AccessArticle

T Cell Depleted Haploidentical Transplantation: Positive Selection

by Franco Aversa

Pediatr. Rep. 2011, 3(s2), e14; https://doi.org/10.4081/pr.2011.s2.e14 - 17 Jun 2011

Cited by 3 | Viewed by 1

Abstract

Interest in mismatched transplantation arises from the fact that a suitable one-haplotype mismatched donor is immediately available for virtually all patients, particularly for those who urgently need an allogenic transplant. Work on one haplotype-mismatched transplants has been proceeding for over 20 years all [...] Read more.

Interest in mismatched transplantation arises from the fact that a suitable one-haplotype mismatched donor is immediately available for virtually all patients, particularly for those who urgently need an allogenic transplant. Work on one haplotype-mismatched transplants has been proceeding for over 20 years all over the world and novel transplant techniques have been developed. Some centres have focused on the conditioning regimens and post transplant immune suppression; others have concentrated on manipulating the graft which may be a megadose of extensively T celldepleted or unmanipulated progenitor cells. Excellent engraftment rates are associated with a very low incidence of acute and chronic GVHD and regimen-related mortality even in patients who are over 50 years old. Overall, event-free survival and transplant-related mortality compare favourably with reports on transplants from sources of stem cells other than the matched sibling. Full article

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Open AccessArticle

T Cell-Depleted HlA-Haploidentical Stem Cell Transplantation in Thalassemia Young Patients

by Pietro Sodani, Antonella Isgrò, Javid Gaziev, Katia Paciaroni, Marco Marziali, Maria Domenica Simone, Andrea Roveda, Cecilia Alfieri, Gioa De Angelis, Cristiano Gallucci, Torelli Fabio, Giancarlo Isacchi, Francesco Zinno, Fabiola Landi, Gaspare Adorno, Alessandro Lanti, Manuela Testi, Marco Andreani and Guido Lucarelli

Pediatr. Rep. 2011, 3(s2), e13; https://doi.org/10.4081/pr.2011.s2.e13 - 17 Jun 2011

Cited by 36 | Viewed by 1

Abstract

The cure for thalassemia involves correcting the genetic defect in a hematopoietic stem cell that results in reduced or absent β-globin synthesis and an excess of α-globin dimers. [...] Full article

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Open AccessArticle

HLA-Mismatched Hematopoietic Stem Cell Tranplantation for Pediatric Solid Tumors

by Andrea Pession, Riccardo Masetti, Corinne Di Leo, Monica Franzoni and Arcangelo Prete

Pediatr. Rep. 2011, 3(s2), e12; https://doi.org/10.4081/pr.2011.s2.e12 - 17 Jun 2011

Cited by 6 | Viewed by 1

Abstract

Even if the overall survival of children with cancer is significantly improved over these decades, the cure rate of high-risk pediatric solid tumors such as neuroblastoma, Ewing’s sarcoma family tumors or rhabdomiosarcoma remain challenging. Autologous hematopoietic stem cell transplantation (HSCT) allows chemotherapy dose [...] Read more.

Even if the overall survival of children with cancer is significantly improved over these decades, the cure rate of high-risk pediatric solid tumors such as neuroblastoma, Ewing’s sarcoma family tumors or rhabdomiosarcoma remain challenging. Autologous hematopoietic stem cell transplantation (HSCT) allows chemotherapy dose intensification beyond marrow tolerance and has become a fundamental tool in the multimodal therapeutical approach of these patients. Anyway this procedure does not allow to these children an eventfree survival approaching more than 50% at 5 years. New concepts of allogeneic HSCT and in particular HLA-mismatched HSCT for high risk solid tumors do not rely on escalation of chemo therapy intensity and tumor load reduction but rather on a graft-versus-tumor effect. We here report an experimental study design of HLA-mismatched HSCT for the treatment of pediatric solid tumors and the inherent preliminary results. Full article

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Open AccessArticle

Reduced Intensity Transplantation for Primary Immunodeficiency Disorders

by Paul Veys

Pediatr. Rep. 2011, 3(s2), e11; https://doi.org/10.4081/pr.2011.s2.e11 - 17 Jun 2011

Cited by 12 | Viewed by 1

Abstract

Studies so far indicate that reduced intensity transplantation (RIT) may have an important role in treating patients with primary immunodeficiency disease (PID). Unlike more standard approaches, such regimens can be used without severe toxicity in patients with severe pulmonary or hepatic disease. RIT [...] Read more.

Studies so far indicate that reduced intensity transplantation (RIT) may have an important role in treating patients with primary immunodeficiency disease (PID). Unlike more standard approaches, such regimens can be used without severe toxicity in patients with severe pulmonary or hepatic disease. RIT also offers the advantage that long-term sequelae such as infertility or growth retardation may be avoided or reduced. RIT appears to be most appropriate for those patients with significant co-morbidities (eg T cell deficiencies) and those undergoing unrelated donor haematopoietic cell transplantation. More studies are required using pharmacokinetic monitoring (eg busulphan, treosulfan and alemtuzumab) and varying stem cell sources to optimise graft vs marrow reactions and minimise graft vs host disease. In certain PID patients RIT will be the “first step” towards establishing donor cell engraftment; second infusions of donor stem cells, donor lymphocyte infusions, or a second myeloablative HCT, which appears to be well tolerated, may be required in some patients with low level donor chimerism or graft rejection. Full article

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Open AccessArticle

The Role of Haploinsufficiency of rps14 and p53 Activation in the Molecular Pathogenesis of the 5q- Syndrome

by Jacqueline Boultwood

Pediatr. Rep. 2011, 3(s2), e10; https://doi.org/10.4081/pr.2011.s2.e10 - 17 Jun 2011

Cited by 15 | Viewed by 1

Abstract

In recent years we have gained great insight into the molecular pathogenesis of the 5q- syndrome, a distinct subtype of myelodysplasia. The demonstration of haploinsufficiency of the ribosomal gene RPS14 (mapping to the commonly deleted region) and the finding that this is the [...] Read more.

In recent years we have gained great insight into the molecular pathogenesis of the 5q- syndrome, a distinct subtype of myelodysplasia. The demonstration of haploinsufficiency of the ribosomal gene RPS14 (mapping to the commonly deleted region) and the finding that this is the cause of the erythroid defect in the 5qsyndrome represent major advances. A mouse model of the human 5q- syndrome generated by large-scale deletion of the Cd74-Nid67 interval (containing RPS14) further supports a critical role for RPS14 haploinsufficiency. It is widely accepted that ribosomal deficiency results in p53 activation and defective erythropoiesis and the crossing of the ‘5q- mice’ with p53 deficient mice ameliorated the erythroid progenitor defect. Emerging data suggests that the p53 activation observed in the mouse model may also apply to the human 5q- syndrome. Full article

391 KiB

Open AccessArticle

Acute Lymphoblastic Leukemia in Adults

by Josep-Maria Ribera

Pediatr. Rep. 2011, 3(s2), e1; https://doi.org/10.4081/pr.2011.s2.e1 - 17 Jun 2011

Cited by 6 | Viewed by 2

Abstract

Acute lymphoblastic leukemia (ALL) is the most frequent neoplastic disease in children, being a rare disease in adults. Many of the advances in pediatric ALL have been through modifications in the doses and schedules of available agents as opposed to the introduction of [...] Read more.

Acute lymphoblastic leukemia (ALL) is the most frequent neoplastic disease in children, being a rare disease in adults. Many of the advances in pediatric ALL have been through modifications in the doses and schedules of available agents as opposed to the introduction of new compounds. In recent years some improvements in the outcome of ALL in adults have occurred. Application of pediatric regimens to young and middle-aged adults shows promise to improve outcome. Advances in the supportive care of patients undergoing allogeneic stem cell transplantation (SCT), the use of alternative sources of hematopoietic stem cells and the use of reduced-intensity conditioning regimens will expand the number of patients who can benefit from this therapeutic modality. The evaluation of minimal residual disease will further stratify risk classification and redefine the role of therapeutic modalities such as SCT or biologic agents. New drugs such as thyrosin kinase inhibitors or monoclonal antibodies have led to incremental improvements in outcome. Advances in the genetic and epigenetic mechanisms of the disease provide hope that targeted therapies can more effectively treat the disease with less toxicity. Full article

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Pediatr. Rep., Volume 3, Issue s2 (June 2011) – 15 articles

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