Publications by authors named "Luisa Strocchio"

30 Publications

  • Page 1 of 1

HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia.

Blood Adv 2021 Mar;5(5):1333-1339

Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS) Bambino Gesù Children's Hospital, Rome, Italy.

We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell-depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.
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http://dx.doi.org/10.1182/bloodadvances.2020003707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948273PMC
March 2021

Identification of New Soluble Factors Correlated With the Development of Graft Failure After Haploidentical Hematopoietic Stem Cell Transplantation.

Front Immunol 2020 29;11:613644. Epub 2021 Jan 29.

Department of Pediatric Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.

Graft failure is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). The mechanisms involved in this phenomenon are still not completely understood; data available suggest that recipient T lymphocytes surviving the conditioning regimen are the main mediators of immune-mediated graft failure. So far, no predictive marker or early detection method is available. In order to identify a non-invasive and efficient strategy to diagnose this complication, as well as to find possible targets to prevent/treat it, we performed a detailed analysis of serum of eight patients experiencing graft failure after T-cell depleted HLA-haploidentical HSCT. In this study, we confirm data describing graft failure to be a complex phenomenon involving different components of the immune system, mainly driven by the IFNγ pathway. We observed a significant modulation of IL7, IL8, IL18, IL27, CCL2, CCL5 (Rantes), CCL7, CCL20 (MIP3a), CCL24 (Eotaxin2), and CXCL11 in patients experiencing graft failure, as compared to matched patients not developing this complication. For some of these factors, the difference was already present at the time of infusion of the graft, thus allowing early risk stratification. Moreover, these cytokines/chemokines could represent possible targets, providing the rationale for exploring new therapeutic/preventive strategies.
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http://dx.doi.org/10.3389/fimmu.2020.613644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878541PMC
January 2021

The role of interferon-gamma and its signaling pathway in pediatric hematological disorders.

Pediatr Blood Cancer 2021 Apr 23;68(4):e28900. Epub 2021 Jan 23.

Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Interferon-gamma (IFN-γ) plays a key role in the pathophysiology of hemophagocytic lymphohistiocytosis (HLH), and available evidence also points to a role in other conditions, including aplastic anemia (AA) and graft failure following allogeneic hematopoietic stem cell transplantation. Recently, the therapeutic potential of IFN-γ inhibition has been documented; emapalumab, an anti-IFN-γ monoclonal antibody, has been approved in the United States for treatment of primary HLH that is refractory, recurrent or progressive, or in patients with intolerance to conventional therapy. Moreover, ruxolitinib, an inhibitor of JAK/STAT intracellular signaling, is currently being investigated for treating HLH. In AA, IFN-γ inhibits hematopoiesis by disrupting the interaction between thrombopoietin and its receptor, c-MPL. Eltrombopag, a small-molecule agonist of c-MPL, acts at a different binding site to IFN-γ and is thus able to circumvent its inhibitory effects. Ongoing trials will elucidate the role of IFN-γ neutralization in secondary HLH and future studies could explore this strategy in controlling hyperinflammation due to CAR T cells.
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http://dx.doi.org/10.1002/pbc.28900DOI Listing
April 2021

Acute Promyelocytic Leukemia in Children: A Model of Precision Medicine and Chemotherapy-Free Therapy.

Int J Mol Sci 2021 Jan 11;22(2). Epub 2021 Jan 11.

Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, 00165 Rome, Italy.

Acute promyelocytic leukemia (APL) represents a paradigm of precision medicine. Indeed, in the last decades, the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) completely revolutionized the therapeutic approach to this previously highly fatal disorder. This entirely chemotherapy-free treatment, which provided excellent survival rates, has been initially validated in adults and, recently, translated in the pediatric setting. This review summarizes currently available data on the use of ATRA and ATO combination in pediatric APL, providing a particular focus on peculiar issues and challenges, such as the occurrence of and death during induction (early death), as well as the advantage offered by the ATO/ATRA combination in sparing long-term .
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http://dx.doi.org/10.3390/ijms22020642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826974PMC
January 2021

Effects of Eltrombopag on In Vitro Macrophage Polarization in Pediatric Immune Thrombocytopenia.

Int J Mol Sci 2020 Dec 24;22(1). Epub 2020 Dec 24.

Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.

Immune Thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibodies-mediated platelet destruction, a prevalence of M1 pro-inflammatory macrophage phenotype and an elevated T helper 1 and T helper 2 lymphocytes (Th1/Th2) ratio, resulting in impairment of inflammatory profile and immune response. Macrophages are immune cells, present as pro-inflammatory classically activated macrophages (M1) or as anti-inflammatory alternatively activated macrophages (M2). They have a key role in ITP, acting both as effector cells, phagocytizing platelets, and, as antigen presenting cells, stimulating auto-antibodies against platelets production. Eltrombopag (ELT) is a thrombopoietin receptor agonist licensed for chronic ITP to stimulate platelet production. Moreover, it improves T and B regulatory cells functions, suppresses T-cells activity, and inhibits monocytes activation. We analyzed the effect of ELT on macrophage phenotype polarization, proposing a new possible mechanism of action. We suggest it as a mediator of macrophage phenotype switch from the M1 pro-inflammatory type to the M2 anti-inflammatory one in paediatric patients with ITP, in order to reduce inflammatory state and restore the immune system function. Our results provide new insights into the therapy and the management of ITP, suggesting ELT also as immune-modulating drug.
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http://dx.doi.org/10.3390/ijms22010097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796119PMC
December 2020

GATA2 Related Conditions and Predisposition to Pediatric Myelodysplastic Syndromes.

Cancers (Basel) 2020 Oct 13;12(10). Epub 2020 Oct 13.

Department of Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, 00165 Rome, Italy.

Myelodysplastic syndromes (MDS) are hematopoietic disorders rare in childhood, often occurring in patients with inherited bone marrow failure syndromes or germinal predisposition syndromes. Among the latter, one of the most frequent involves the gene GATA binding protein 2 (), coding for a transcriptional regulator of hematopoiesis. The genetic lesion as well as the clinical phenotype are extremely variable; many patients present hematological malignancies, especially MDS with the possibility to evolve into acute myeloid leukemia. Variable immune dysfunction, especially resulting in B- and NK-cell lymphopenia, lead to severe infections, including generalized warts and mycobacterial infection. Defects of alveolar macrophages lead to pulmonary alveolar proteinosis through inadequate clearance of surfactant proteins. Currently, there are no clear guidelines for the monitoring and treatment of patients with mutations. In patients with MDS, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT) that restores normal hematopoiesis preventing the progression to acute myeloid leukemia and clears long-standing infections. However, to date, the donor type, conditioning regimen, and the optimal time to proceed to HSCT, as well as the level of chimerism needed to reverse the phenotype, remain unclear highlighting the need for consensus guidelines.
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http://dx.doi.org/10.3390/cancers12102962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602110PMC
October 2020

Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition.

Cancers (Basel) 2020 Sep 20;12(9). Epub 2020 Sep 20.

Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, 00146 Rome, Italy.

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), and a predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved in the FA pathway are associated with the development of sporadic hematological and solid malignancies. The key function of the FA pathway is to orchestrate proteins involved in the repair of interstrand cross-links (ICLs), to prevent genomic instability and replication stress. Recently, many studies have highlighted the importance of FA genes in noncanonical pathways, such as mitochondria homeostasis, inflammation, and virophagy, which act, in some cases, independently of DNA repair processes. Thus, primary defects in DNA repair mechanisms of FA patients are typically exacerbated by an impairment of other cytoprotective pathways that contribute to the multifaceted clinical phenotype of this disease. In this review, we summarize recent advances in the understanding of the pathogenesis of FA, with a focus on the cytosolic noncanonical roles of FA genes, discussing how they may contribute to cancer development, thus suggesting opportunities to envisage novel therapeutic approaches.
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http://dx.doi.org/10.3390/cancers12092684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565043PMC
September 2020

QuantiFERON-TB Gold can help clinicians in the diagnosis of haemophagocytic lymphohistiocytosis.

Br J Haematol 2020 10 26;191(2):e64-e67. Epub 2020 Jul 26.

Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, Rome, Italy.

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http://dx.doi.org/10.1111/bjh.17001DOI Listing
October 2020

Oral Manifestations and Complications in Childhood Acute Myeloid Leukemia.

Cancers (Basel) 2020 06 19;12(6). Epub 2020 Jun 19.

Unit of Dentistry, Bambino Gesù Children's Hospital, 00165 Rome, Italy.

Acute myeloid leukemia (AML) is a heterogeneous group of diseases, whose classification is based on lineage-commitment and genetics. Although rare in childhood, it is the most common type of acute leukemia in adults, accounting for 80% of all cases in this age group. The prognosis of this disease remains poor (especially in childhood, as compared to acute lymphoblastic leukemia); however, overall survival has significantly improved over the past 30 years. The health of the oral cavity is a remarkable reflection of the systemic status of an individual. Identification of the signs and symptoms of oral lesions can act as a warning sign of hidden and serious systemic involvement. Moreover, they may be the presenting feature of acute leukemia and provide important diagnostic indicators. Primary oral alterations are identified in up to 90% of cases of acute myeloid leukemia and consist of petechiae, spontaneous bleeding, mucosal ulceration, gingival enlargement with or without necrosis, infections, hemorrhagic bullae on the tongue, and cracked lips. Poor oral hygiene is a well-known risk factor for local and systemic infectious complications. Oro-dental complications due to AML treatment can affect the teeth, oral mucosa, soft and bone tissue, and contribute to opportunistic infections, dental decay, and enamel discoloration. The treatment of acute myeloid leukemia is still associated with high mortality and morbidity. The management is multimodal, involving aggressive multidrug chemotherapy and, in most cases, allogenic bone marrow transplantation. Periodontal and dental treatment for patients with leukemia should always be planned and concerted with hematologists.
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http://dx.doi.org/10.3390/cancers12061634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352340PMC
June 2020

Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia.

Front Immunol 2020 12;11:699. Epub 2020 May 12.

Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.

TcRαβ/CD19-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a promising new platform for children affected by acute leukemia in need of an allograft and lacking a matched donor, disease recurrence being the main cause of treatment failure. The use of zoledronic acid to enhance TcRγδ+ lymphocyte function after TcRαβ/CD19-cell depleted haplo-HSCT was tested in an open-label, feasibility, proof-of-principle study. Forty-six children affected by high-risk acute leukemia underwent haplo-HSCT after removal of TcRαβ+ and CD19+ B lymphocytes. No post-transplant pharmacological graft-versus-host disease (GvHD) prophylaxis was given. Zoledronic acid was administered monthly at a dose of 0.05 mg/kg/dose (maximum dose 4 mg), starting from day +20 after transplantation. A total of 139 infusions were administered, with a mean of 3 infusions per patient. No severe adverse event was observed. Common side effects were represented by asymptomatic hypocalcemia and acute phase reactions (including fever, chills, malaise, and/or arthralgia) within 24-48 h from zoledronic acid infusion. The cumulative incidence of acute and chronic GvHD was 17.3% (all grade I-II) and 4.8% (all limited), respectively. Patients given 3 or more infusions of zoledronic acid had a lower incidence of both acute GvHD (8.8 vs. 41.6%, = 0.015) and chronic GvHD (0 vs. 22.2%, = 0.006). Transplant-related mortality (TRM) and relapse incidence at 3 years were 4.3 and 30.4%, respectively. Patients receiving repeated infusions of zoledronic acid had a lower TRM as compared to those receiving 1 or 2 administration of the drug (0 vs. 16.7%, = 0.01). Five-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 67.2 and 65.2%, respectively, with a trend toward a better OS for patients receiving 3 or more infusions (73.1 vs. 50.0%, = 0.05). The probability of GvHD/relapse-free survival was significantly worse in patients receiving 1-2 infusions of zoledonic acid than in those given ≥3 infusions (33.3 vs. 70.6%, respectively, = 0.006). Multivariable analysis showed an independent positive effect on outcome given by repeated infusions of zoledronic acid (HR 0.27, = 0.03). These data indicate that the use of zoledronic acid after TcRαβ/CD19-cell depleted haploHSCT is safe and may result in a lower incidence of acute GvHD, chronic GvHD, and TRM.
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http://dx.doi.org/10.3389/fimmu.2020.00699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235359PMC
March 2021

Role of interferon-γ in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation.

Haematologica 2019 11 21;104(11):2314-2323. Epub 2019 Feb 21.

Bambino Ges Children's Hospital, Department of Pediatric Hematology/Oncology, Cellular and Gene Therapy, Rome, Italy.

Pathophysiology of graft failure (GF) occurring after allogeneic hematopoietic stem cell transplantation (HSCT) still remains elusive. We measured serum levels of several different cytokines/chemokines in 15 children experiencing GF, comparing their values with those of 15 controls who had sustained donor cell engraftment. Already at day +3 after transplantation, patients developing GF had serum levels of interferon (IFN)-γ and CXCL9 (a chemokine specifically induced by IFNγ) significantly higher than those of controls (8859±7502 0 pg/mL, =0.03, and 1514.0±773 233.6±50.1 pg/mlL, =0.0006, respectively). The role played by IFNγ in HSCT-related GF was further supported by the observation that a rat anti-mouse IFNγ-neutralizing monoclonal antibody promotes donor cell engraftment in Ifngr1mice receiving an allograft. In comparison to controls, analysis of bone marrow-infiltrating T lymphocytes in patients experiencing GF documented a predominance of effector memory CD8 cells, which showed markers of activation (overexpression of CD95 and downregulation of CD127) and exhaustion (CD57, CD279, CD223 and CD366). Finally, we obtained successful donor engraftment in 2 out of 3 children with primary hemophagocytic lymphohistiocytosis who, after experiencing GF, were re-transplanted from the same HLA-haploidentical donor under the compassionate use coverage of emapalumab, an anti-IFNγ monoclonal antibody recently approved by the US Food and Drug Administration for treatment of patients with primary hemophagocytic lymphohistiocytosis. Altogether, these results suggest that the IFNγ pathway plays a major role in GF occurring after HSCT. Increased serum levels of IFNγ and CXCL9 represent potential biomarkers useful for early diagnosis of GF and provide the rationale for exploring the therapeutic/preventive role of targeted neutralization of IFNγ.
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http://dx.doi.org/10.3324/haematol.2019.216101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821635PMC
November 2019

Burkitt lymphoma in a patient with Kabuki syndrome carrying a novel KMT2D mutation.

Am J Med Genet A 2019 01 20;179(1):113-117. Epub 2018 Dec 20.

Department of Pediatric Hematology/Oncology and Cellular and Gene Therapy, Bambino Gesù Children's Hospital, Rome, Italy.

Kabuki syndrome (KS) is an extremely rare genetic disorder, mainly caused by germline mutations at specific epigenetic modifier genes, including KMT2D. Because the tumor suppressor gene KMT2D is also frequently altered in many cancer types, it has been suggested that KS may predispose to the development of cancer. However, KS being a rare disorder, few data are available on the incidence of cancer in KS patients. Here, we report the case of a 5-year-old boy affected by KS who developed Burkitt lymphoma (BL). Genetic analysis revealed the presence of a novel heterozygous mutation in the splice site of the intron 4 of KMT2D gene in both peripheral blood-extracted DNA and tumour cells. In addition, the tumour sample of the patient was positive for the classical somatic chromosomal translocation t(8;14) involving the c-MYC gene frequently identified in BL. We propose that the mutated KMT2D gene contributes to the development of both KS and BL observed in our patient and we suggest that strict surveillance must be performed in KS patients.
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http://dx.doi.org/10.1002/ajmg.a.60674DOI Listing
January 2019

Uncommon Presentation of Childhood Leukemia in Emergency Department: The Usefulness of an Early Multidisciplinary Approach.

Pediatr Emerg Care 2018 Nov 19. Epub 2018 Nov 19.

Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Leukemia is the most common childhood malignancy, and it is often characterized by pallor, fatigue, cytopenia, and organomegaly; sometimes musculoskeletal symptoms, mainly characterized by diffuse bone pain in the lower extremities, are the onset clinical characteristics of the disease. In these cases, the disease may initially be misdiagnosed as reactive arthritis, osteomyelitis, or juvenile idiopathic arthritis delaying appropriate diagnosis and management. Even if leukopenia, thrombocytopenia, and a history of nighttime pain are reported to be the most important predictive factors for a pediatric leukemia, blood examinations can sometimes be subtle or within normal limits, and this represents a further diagnostic difficulty. Radiological findings of leukemic bone involvement are described in patients with musculoskeletal symptoms of acute lymphoblastic leukemia and often appear before hematologic anomalies, but they are not specific for the disease. However, they could be helpful to get the right diagnosis if integrated with other features; thus, it is important knowing them, and it is mandatory for the multidisciplinary comparison to talk about dubious cases even in an emergency setting. We describe 4 patients visited in the emergency department for musculoskeletal complaints and having radiological lesions and a final diagnosis of acute lymphoblastic leukemia, in whom the onset of the manifestations could mimic orthopedic/rheumatologic diseases.
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http://dx.doi.org/10.1097/PEC.0000000000001694DOI Listing
November 2018

Arsenic trioxide and all-trans retinoic acid treatment for childhood acute promyelocytic leukaemia.

Br J Haematol 2019 04 20;185(2):360-363. Epub 2018 Jul 20.

Department of Paediatric Haematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

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http://dx.doi.org/10.1111/bjh.15507DOI Listing
April 2019

Hematopoietic Stem Cell Transplantation in Thalassemia.

Hematol Oncol Clin North Am 2018 04;32(2):317-328

Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Piazza S Onofrio, 4, Roma 00165, Italy; Department of Pediatric Science, University of Pavia, Viale Brambilla 74, Pavia, Italy. Electronic address:

Although recent advances in gene therapy are expected to increase the chance of disease cure in thalassemia major, at present hematopoietic stem cell transplantation (HSCT) remains the only consolidated curative approach for this disorder. The widest experience has been obtained in the HLA-matched family donor (MFD) setting, with probabilities of overall and thalassemia-free survival exceeding 90% and 85%, respectively. As for most patients a suitable MFD is not available, alternative donors (HLA-matched unrelated donor, unrelated cord blood, HLA-haploidentical relative) have been increasingly explored, translating into the expansion of the number of patients treatable with HSCT.
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http://dx.doi.org/10.1016/j.hoc.2017.11.011DOI Listing
April 2018

Che-1 is targeted by c-Myc to sustain proliferation in pre-B-cell acute lymphoblastic leukemia.

EMBO Rep 2018 03 24;19(3). Epub 2018 Jan 24.

SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy

Despite progress in treating B-cell precursor acute lymphoblastic leukemia (BCP-ALL), disease recurrence remains the main cause of treatment failure. New strategies to improve therapeutic outcomes are needed, particularly in high-risk relapsed patients. Che-1/AATF (Che-1) is an RNA polymerase II-binding protein involved in proliferation and tumor survival, but its role in hematological malignancies has not been clarified. Here, we show that Che-1 is overexpressed in pediatric BCP-ALL during disease onset and at relapse, and that its depletion inhibits the proliferation of BCP-ALL cells. Furthermore, we report that c-Myc regulates Che-1 expression by direct binding to its promoter and describe a strict correlation between Che-1 expression and c-Myc expression. RNA-seq analyses upon Che-1 or c-Myc depletion reveal a strong overlap of the respective controlled pathways. Genomewide ChIP-seq experiments suggest that Che-1 acts as a downstream effector of c-Myc. These results identify the pivotal role of Che-1 in the control of BCP-ALL proliferation and present the protein as a possible therapeutic target in children with relapsed BCP-ALL.
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http://dx.doi.org/10.15252/embr.201744871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835840PMC
March 2018

Novel approaches to diagnosis and treatment of Juvenile Myelomonocytic Leukemia.

Expert Rev Hematol 2018 02 3;11(2):129-143. Epub 2018 Jan 3.

a Department of Pediatric Hematology/Oncology , IRCCS Bambino Gesù Children's Hospital , Rome , Italy.

Introduction: Juvenile myelomonocytic leukemia (JMML) is a clonal hematopoietic disorder of infancy/early childhood, resulting from oncogenic mutations in genes involved in the Ras pathway. As JMML often exhibits an aggressive course, the timing of diagnosis and treatment is critical to outcome. Areas covered: This review summarizes current approaches to diagnosis and treatment of JMML, highlighting most recent insights into genetic and epigenetic mechanisms underlying the disease, and providing an overview of novel potential therapeutic strategies. Expert commentary: At present, allogeneic HSCT remains the only potentially effective therapy, being able to cure more than 50% of patients, relapse representing the main cause of treatment failure. Prompt HSCT is recommended for all children with NF1, somatic PTPN11 and KRAS mutations, and for most children with somatic NRAS mutations. Conversely, a 'watch and wait' strategy should be adopted in children with germline CBL mutations, specific somatic NRAS mutation, and in Noonan syndrome patients, since spontaneous resolution has been reported to occur. Novel drugs targeting relevant nodes of JMML leukemogenesis have been explored in pre-HSCT window or at relapse. The use of 5-azacytidine, a DNA-hypomethylating agent reported to induce hematologic and molecular remission in some JMML children, is currently being investigated in clinical trials.
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http://dx.doi.org/10.1080/17474086.2018.1421937DOI Listing
February 2018

Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion.

Blood 2017 08 6;130(5):677-685. Epub 2017 Jun 6.

Immunology Research Area, IRCCS Ospedale Bambino Gesù, Rome, Italy.

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of αβ T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after αβ T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120.
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http://dx.doi.org/10.1182/blood-2017-04-779769DOI Listing
August 2017

The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood.

Br J Haematol 2017 02 24;176(4):629-636. Epub 2017 Jan 24.

Department of Paediatric Haematology-Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Achieving complete remission (CR) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL) is a difficult task. Bortezomib, a proteasome inhibitor, has in vitro activity against ALL blasts. A phase I-II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2-3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B-cell precursor (BCP) and T-cell ALL, respectively. Bortezomib (1·3 mg/m /dose) was administered intravenously on days 1, 4, 8, and 11. Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Three patients (8·1%) died due to infections. Twenty-seven patients (72·9%) achieved CR or CR with incomplete platelet recovery (CRp). Fourteen had minimal residual disease (MRD) lower than 0·1%. Twenty-two of 30 BCP-ALL patients (73·3%) and 5/7 patients (71%) with T-cell ALL achieved CR/CRp. The 2-year overall survival (OS) is 31·3%; CR/CRp patients with an MRD response had a remarkable 2-year OS of 68·4%. These data confirm that the combination of bortezomib with chemotherapy is a suitable/effective option for childhood relapsed/refractory ALL.
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http://dx.doi.org/10.1111/bjh.14505DOI Listing
February 2017

Transplantation for thalassemia major: alternative donors.

Curr Opin Hematol 2016 11;23(6):515-523

aDipartimento di Oncoematologia Pediatrica, IRCCS, Ospedale Pediatrico Bambino Gesù, Roma bDipartimento di Scienze Pediatriche, Università degli Studi di Pavia, Pavia, Italy.

Purpose Of Review: Lack of a human leukocyte antigen (HLA)-matched family donor is a major obstacle limiting the use of allogeneic hematopoietic stem cell transplantation (HSCT) to cure thalassemia major. Use of alternative donors, if found well tolerated enough, may be a viable option for transplantation in this setting, allowing to expand the number of patients treatable by HSCT. This review will provide an overview of alternative HSCT approaches in thalassemia major.

Recent Findings: With the introduction of high-resolution molecular HLA-typing techniques, the outcome of matched unrelated donor HSCT recipients has become comparable with that of patients given matched family donor HSCT. On the contrary, the use of unrelated cord blood transplantation has been limited by the risk of graft failure and slow hematopoietic recovery, although novel techniques of ex vivo graft manipulation are emerging as promising strategies for overcoming these obstacles. Although experience with haploidentical HSCT in thalassemia major is still limited, currently explored platforms hold the potential to extend the access to HSCT to thalassemia major patients lacking an HLA-matched either related or unrelated donor.

Summary: The significant advances achieved in transplantation techniques, both in the matched unrelated and in the haploidentical setting, are expected to significantly broaden the applicability of HSCT to patients with thalassemia major.
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http://dx.doi.org/10.1097/MOH.0000000000000280DOI Listing
November 2016

Eltrombopag for treatment of thrombocytopenia-associated disorders.

Expert Opin Pharmacother 2015 ;16(14):2243-56

a 1 Department of Pediatric Hematology-Oncology, IRCCS, Bambino Gesù Children's Hospital , Rome, Italy +39 06 68 59 26 78 ; +39 06 68 59 22 92 ;

Introduction: Eltrombopag is an orally bioavailable, non-peptide thrombopoietin receptor agonist capable of stimulating platelet production through the differentiation of CD34+ hematopoietic progenitor cells into committed CD41+ megakaryocyte precursors and proliferation of megakaryocyte progenitor cells.

Areas Covered: This drug has been tested in several clinical trials in adult patients with chronic immune thrombocytopenia (ITP), demonstrating the ability of the drug to reduce the burden of thrombocytopenia and its associated side effects. Two multicenter trials on eltrombopag in chronic ITP of childhood have been recently completed, showing that the drug is effective also in pediatric patients. Recent studies have suggested a potential role of eltrombopag in the treatment of thrombocytopenia associated with hepatitis-C virus infection. These studies have documented that adjunct treatment with eltrombopag can help avoid either dose reductions or withdrawal of pegylated interferon due to development of thrombocytopenia. Eltrombopag has shown efficacy also in patients with acquired severe aplastic anemia and myelodysplastic syndromes.

Expert Opinion: Eltrombopag plays an important therapeutic role in many different conditions characterized by persistent thrombocytopenia. A more comprehensive definition of both long-term safety and benefits deriving from the use of eltrombopag will be obtained through prolonged observation of patients already enrolled in the different studies conducted so far and from future prospective controlled trials.
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http://dx.doi.org/10.1517/14656566.2015.1085512DOI Listing
December 2015

Characterization of medulloblastoma in Fanconi Anemia: a novel mutation in the BRCA2 gene and SHH molecular subgroup.

Biomark Res 2015 6;3:13. Epub 2015 Jun 6.

Department of Experimental Medicine, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.

Fanconi Anemia (FA) is an inherited disorder characterized by the variable presence of multiple congenital somatic abnormalities, bone marrow failure and cancer susceptibility. Medulloblastoma (MB) has been described only in few cases of FA with biallelic inactivation in the tumor suppressor gene BRCA2/FANCD1 or its associated gene PALB2/FANCN. We report the case of a patient affected by Fanconi Anemia with Wilms tumor and unusual presentation of two medulloblastomas (MB1 and MB2). We identified a new pathogenetic germline BRCA2 mutation: c.2944_2944delA. Molecular analysis of MBs allowed us to define new features of MB in FA. MBs were found to belong to the Sonic Hedgehog (SHH) molecular subgroup with some differences between MB1 and MB2. We highlighted that MB in FA could share molecular aspects and hemispheric localization with sporadic adult SHH-MB. Our report provides new findings that shed new light on the genetic and molecular pathogenesis of MB in FA patients with implications in the disease management.
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http://dx.doi.org/10.1186/s40364-015-0038-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462002PMC
June 2015

Comprehensive characterization of mesenchymal stromal cells from patients with Fanconi anaemia.

Br J Haematol 2015 Sep 26;170(6):826-36. Epub 2015 May 26.

Department of Paediatric Haematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Fanconi anaemia (FA) is an inherited disorder characterized by pancytopenia, congenital malformations and a predisposition to develop malignancies. Alterations in the haematopoietic microenvironment of FA patients have been reported, but little is known regarding the components of their bone marrow (BM) stroma. We characterized mesenchymal stromal cells (MSCs) isolated from BM of 18 FA patients both before and after allogeneic haematopoietic stem cell transplantation (HSCT). Morphology, fibroblast colony-forming unit (CFU-F) ability, proliferative capacity, immunophenotype, differentiation potential, ability to support long-term haematopoiesis and immunomodulatory properties of FA-MSCs were analysed and compared with those of MSCs expanded from 15 age-matched healthy donors (HD-MSCs). FA-MSCs were genetically characterized through conventional karyotyping, diepoxybutane-test and array-comparative genomic hybridization. FA-MSCs generated before and after HSCT were compared. Morphology, immunophenotype, differentiation potential, ability in vitro to inhibit mitogen-induced T-cell proliferation and to support long-term haematopoiesis did not differ between FA-MSCs and HD-MSCs. CFU-F ability and proliferative capacity of FA-MSCs isolated after HSCT were significantly lower than those of HD-MSCs. FA-MSCs reached senescence significantly earlier than HD-MSCs and showed spontaneous chromosome fragility. Our findings indicate that FA-MSCs are defective in their ability to survive in vitro and display spontaneous chromosome breakages; whether these defects are involved in pathophysiology of BM failure syndromes deserves further investigation.
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http://dx.doi.org/10.1111/bjh.13504DOI Listing
September 2015

Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in children with sickle cell disease.

Br J Haematol 2015 Jun 27;169(5):726-36. Epub 2015 Mar 27.

Dipartimento di Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy.

Although allogeneic haematopoietic stem cell transplantation (HSCT) still represents the only consolidated possibility of cure for sickle cell disease (SCD) patients, its use has been limited by the risk of morbidity and mortality associated with conventional myeloablative therapy. The introduction of treosulfan to replace busulfan in conditioning regimens has recently been explored by virtue of its lower toxicity profile. We report our experience with a treosulfan/thiotepa/fludarabine conditioning for human leucocyte antigen (HLA)-matched sibling or unrelated donor-HSCT in 15 children with SCD, and compare patient outcomes with those of a historical cohort (15 patients) given a busulfan-based regimen. Engraftment was achieved in 28 out of 30 patients (93%), with one case of graft failure in either group. The conditioning regimen was well tolerated in both groups, with no cases of grade III-IV regimen-related toxicity. The 7-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 100% and 93%, respectively, with a 93% DFS in both busulfan and treosulfan groups. No SCD-related adverse events occurred after engraftment in patients with complete or mixed donor chimerism. This retrospective analysis suggests that a treosulfan-based conditioning regimen is able to ensure engraftment with excellent OS/DFS and low regimen-related toxicity in patients with SCD.
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http://dx.doi.org/10.1111/bjh.13352DOI Listing
June 2015

Successful T-cell-depleted haploidentical hematopoietic stem cell transplantation in a child with dyskeratosis congenita after a fludarabine-based conditioning regimen.

J Pediatr Hematol Oncol 2015 May;37(4):322-6

*Oncoematologia Pediatrica ‡Struttura Complessa di Radioterapia Oncologica, Fondazione IRCCS Policlinico San Matteo †Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, Pavia §Clinica Pediatrica, Policlinico Sant'Orsola, Bologna, Italy.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure for marrow failure associated with dyskeratosis congenita (DC). Data on transplants from alternative donors are limited. We describe a boy with DC and severe aplastic anemia who underwent haploidentical T-cell depleted HSCT using a reduced-intensity conditioning regimen. He underwent engraftment without toxicity or GVHD. His posttransplant course was complicated by EBV reactivation, treated with rituximab and EBV-specific T lymphocytes. After 26 months, he is in complete chimerism, with normal blood count and no sign of GVHD or pulmonary dysfunction. To the best of our knowledge, this is the first report of DC successfully treated with allogeneic HSCT from a haploidentical family donor.
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http://dx.doi.org/10.1097/MPH.0000000000000283DOI Listing
May 2015

HLA-haploidentical T cell-depleted allogeneic hematopoietic stem cell transplantation in children with Fanconi anemia.

Biol Blood Marrow Transplant 2014 Apr 22;20(4):571-6. Epub 2014 Jan 22.

Dipartimento di Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy; Department of Pediatric Science, Università degli Studi di Pavia, Italy. Electronic address:

We report the outcome of 12 consecutive pediatric patients with Fanconi anemia (FA) who had neither an HLA-identical sibling nor an HLA-matched unrelated donor and who were given T cell-depleted, CD34(+) positively selected cells from a haploidentical related donor after a reduced-intensity, fludarabine-based conditioning regimen. Engraftment was achieved in 9 of 12 patients (75%), and the cumulative incidence of graft rejection was 17% (95% confidence interval [CI], 5% to 59%). Cumulative incidences of grades II to IV acute and chronic graft-versus-host disease were 17% (95% CI, 5% to 59%) and 35% (95% CI, 14% to 89%), respectively. The conditioning regimen was well tolerated, with no fatal regimen-related toxicity and 3 cases of grade III regimen-related toxicity. The cumulative incidence of transplant-related mortality was 17% (95% CI, 5% to 59%). The 5-year overall survival, event-free survival, and disease-free survival were 83% (95% CI, 62% to 100%), 67% (95% CI, 40% to 93%), and 83% (95% CI, 62% to 100%), respectively. These data demonstrate that a fludarabine-based conditioning regimen, followed by infusion of high doses of T cell-depleted stem cells, is able to ensure engraftment with good overall survival and disease-free survival, confirming the feasibility of haploidentical hematopoietic stem cell transplantation in FA. To the best of our knowledge, this is the largest series of hematopoietic stem cell transplantation from a haploidentical related donor in FA patients reported to date.
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http://dx.doi.org/10.1016/j.bbmt.2014.01.015DOI Listing
April 2014

Global perfusion assessment and tissue oxygen saturation in preterm infants: where are we?

Early Hum Dev 2013 Jun;89 Suppl 1:S44-6

Neonatal Intensive Care Unit, Fondazione IRCCS-Policlinico San Matteo, Pavia, Italy.

Near infrared spectroscopy (NIRS) monitoring is a new challenge for clinicians who deal with early detection of dangerous hypoperfusion in the brain, as well as in splanchnic and renal districts in critically ill preterm infants. Previous studies performed on infants and children with congenital heart disease, demonstrated the efficacy of this non-invasive method in managing hypoperfusive states pre, post and during cardiac surgery. Its use has improved post surgery outcome. NIRS monitoring has been used also to assess therapeutic intervention utility. Early identification of silent hypoperfusion has made NIRS use in preterm infants very interesting for neonatologists, especially where other techniques have failed. In this work, literature on this topic has been carefully examined, particularly the "two site NIRS" use in preterm infants, to evaluate how regional splanchnic oxygen saturation changes, both in physiological events, such as enteral feeding and in hemodynamic disorders, that occur in patients with significant patent ductus and in hypoperfusive states that lead to necrotizing enterocolitis.
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http://dx.doi.org/10.1016/S0378-3782(13)70014-8DOI Listing
June 2013

Viral outbreaks in neonatal intensive care units: what we do not know.

Am J Infect Control 2013 Oct 23;41(10):854-6. Epub 2013 Apr 23.

Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Background: Nosocomial infection is among the most important causes of morbidity, prolonged hospital stay, increased hospital costs, and mortality in neonates, particularly those born preterm. The vast majority of scientific articles dealing with nosocomial infections address bacterial or fungal infections, and viral agents are often disregarded. This analysis reviews the medical literature in an effort to establish the incidence, types of pathogens, and clinical features of noncongenital neonatal viral infections.

Methods: This analysis was performed using the worldwide database of health care-associated outbreaks (http://www.outbreak-database.com). Items analyzed included causative pathogens, types of infection, source of outbreaks, and measures taken to stop outbreaks.

Results: The outbreak database contained a total of 590 neonatal outbreaks, of which 64 were originated by viruses, 44 of which (68.75%) were reported from neonatal intensive care units (NICUs). The 5 most frequent viral agents were rotavirus (23.44%), respiratory syncytial virus (17.19%), enterovirus (15.63%), hepatitis A virus (10.94%), and adenovirus (9.38%).

Conclusion: Our analysis of the viral origins of nosocomial infections in NICUs can be a valuable tool in the investigation of neonatal infections. The mortality rates reported in this analysis demonstrate the significance of noncongenital viral infections in NICUs and the need for more effective outbreak prevention strategies.
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http://dx.doi.org/10.1016/j.ajic.2013.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132694PMC
October 2013

A rare cause of recurrent spontaneous pneumothorax.

Clin Pediatr (Phila) 2011 May;50(5):456-8

Fondazione IRCCS Policlinico San Matteo, viale Golgi 2, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1177/0009922810385571DOI Listing
May 2011