170 results on '"Sarah Marktel"'
Search Results
52. Predicting failure of hematopoietic stem cell mobilization before it starts: the Predicted Poor Mobilizer (pPM) score
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Nicola Piccirillo, Paolo Corradini, Domenico Pastore, Roberta Nuccorini, Giorgina Specchia, Francesco Saraceni, Massimo Martino, Massimo Pini, Sarah Marktel, Andrea Mengarelli, Pietro Pioltelli, Giuseppe Milone, Francesco Zallio, Monica Poiani, Elvira Di Nardo, Saveria Capria, Sara Pasquina Pascale, Tiziana Moscato, Gianluca Gaidano, Immacolata Attolico, Pellegrino Musto, Paolo Perseghin, Francesco Merli, Lucia Farina, Luca Nassi, Martina Chiarucci, Simona Sica, Giuseppe Mele, Jacopo Olivieri, Francesco Lanza, Attilio Olivieri, Fabio Ciceri, Katia Codeluppi, Olivieri, Jacopo, Attolico, Immacolata, Nuccorini, Roberta, Pascale, Sara Pasquina, Chiarucci, Martina, Poiani, Monica, Corradini, Paolo, Farina, Lucia, Gaidano, Gianluca, Nassi, Luca, Sica, Simona, Piccirillo, Nicola, Pioltelli, Pietro Enrico, Martino, Massimo, Moscato, Tiziana, Pini, Massimo, Zallio, Francesco, Ciceri, Fabio, Marktel, Sarah, Mengarelli, Andrea, Musto, Pellegrino, Capria, Saveria, Merli, Francesco, Codeluppi, Katia, Mele, Giuseppe, Lanza, Francesco, Specchia, Giorgina, Pastore, Domenico, Milone, Giuseppe, Saraceni, Francesco, Di Nardo, Elvira, Perseghin, Paolo, and Olivieri, Attilio
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Multivariate analysis ,Adolescent ,lymphoma ,Filgrastim ,Likelihood ratios in diagnostic testing ,NO ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,medicine ,Humans ,Child ,Hematopoietic Stem Cell Mobilization ,Aged ,Retrospective Studies ,Transplantation ,Mobilization ,Receiver operating characteristic ,business.industry ,Plerixafor ,Patient Selection ,Area under the curve ,poor mobiliser ,Hematology ,Middle Aged ,stem cell mobilization, lymphoma, myeloma, poor mobiliser, oredicting clinical score ,stem cell mobilization ,Settore MED/15 - MALATTIE DEL SANGUE ,myeloma ,oredicting clinical score ,030220 oncology & carcinogenesis ,Area Under Curve ,Child, Preschool ,Female ,business ,Multiple Myeloma ,030215 immunology ,medicine.drug - Abstract
Predicting mobilization failure before it starts may enable patient-tailored strategies. Although consensus criteria for predicted PM (pPM) are available, their predictive performance has never been measured on real data. We retrospectively collected and analyzed 1318 mobilization procedures performed for MM and lymphoma patients in the plerixafor era. In our sample, 180/1318 (13.7%) were PM. The score resulting from published pPM criteria had sufficient performance for predicting PM, as measured by AUC (0.67, 95%CI: 0.63â0.72). We developed a new prediction model from multivariate analysis whose score (pPM-score) resulted in better AUC (0.80, 95%CI: 0.76â0.84, p < 0001). pPM-score included as risk factors: increasing age, diagnosis of NHL, positive bone marrow biopsy or cytopenias before mobilization, previous mobilization failure, priming strategy with G-CSF alone, or without upfront plerixafor. A simplified version of pPM-score was categorized using a cut-off to maximize positive likelihood ratio (15.7, 95%CI: 9.9â24.8); specificity was 98% (95%CI: 97â98.7%), sensitivity 31.7% (95%CI: 24.9â39%); positive predictive value in our sample was 71.3% (95%CI: 60â80.8%). Simplified pPM-score can ârule inâ patients at very high risk for PM before starting mobilization, allowing changes in clinical management, such as choice of alternative priming strategies, to avoid highly likely mobilization failure.
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- 2018
53. Transfusion Therapy in a Multi-Ethnic Sickle Cell Population Real-World Practice. a Preliminary Data Analysis of Multicentre Survey
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Frédéric B. Piel, Saveria Campisi, A. Vassanelli, Gianluca Boscariol, Giovanni Palazzi, Aldo Filosa, Gianluca Lodi, Vincenzo Voi, Roberto Lisi, Paola Giordano, Luca Badalamenti, Alberto Piperno, Barbara Gianesin, Gian Luca Forni, Maria Grazia Bisconte, Massimo Allò, Rosamaria Rosso, Lucia Dora Notarangelo, Giovanna Russo, Alessandra Quota, Lucia De Franceschi, Silvia Macchi, Giovanna Graziadei, Maddalena Casale, Elena Facchini, Fiorina Giona, Donatella Venturelli, Mauro Murgia, Paolo Rigano, Nicoletta Masera, Francesco Arcioni, Federico Bonetti, Paola Maroni, Laura Sainati, Raffaella Origa, Antonella Sau, Domenico Giuseppe D'Ascola, Sarah Marktel, Gloria Colarusso, and Pietro Bonomo
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education.field_of_study ,Pediatrics ,medicine.medical_specialty ,Blood transfusion ,Anemia ,business.industry ,medicine.medical_treatment ,Immunology ,Population ,Transfusion medicine ,Cell Biology ,Hematology ,030204 cardiovascular system & hematology ,medicine.disease ,Biochemistry ,Acute chest syndrome ,Sickle cell anemia ,03 medical and health sciences ,Regimen ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine ,Transfusion therapy ,education ,business - Abstract
Introduction. Despite the increasing of number of patients with Sickle Cell Disease (SCD) in Italy, due to multi-ethnic migratory phenomena, a large percentage of Caucasian sickle population is already present in Italy mainly with b-thal/HbS genotype. Red cell transfusion is one effective treatment for both acute and chronic complications of SCD, while hydroxycarbamide (HC) is used to reduce the frequency of painful vaso-occlusive crises (VOCs) and decrease the need for blood transfusion. Through the National Comprehensive Reference Centers for SCD, the Italian Society of Thalassemia and Hemoglobinopathies (SITE), in collaboration with the Society Italian Transfusion Medicine and Immunohematology (SIMTI) and the Italian Association of Hematology and Pediatric Oncology (AIEOP) conducted a national survey to collect information on different therapeutic approaches used for SCD patients. Aim. To assess therapeutic approaches used a large Italian cohort of patients with SCD, accounting for age, genotype and ethnicity. Patients and Methods. Observational Longitudinal Systemic Multicentre Study (https://clinicaltrials.gov/ct2/show/NCT03397017). Data were collected from 2015 to 2018 through a standard web-based application (www.SITE-italia.org) encrypted by the Central Server. All the SCD patients, treated or not treated, were included in order to identify the overall number and all gave written informed consent. The study was approved by Ethics Committee of Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy. Results. Thirty-four centers were involved from 14 Italian regions and 1,579 patients were enrolled (802 male and 777 female; median age 23 years - IQR, 25th-75th 10-41 yrs). Genotype, age and ethnicity distribution are shown in Table 1A. As expected, the median age of non-Caucasian patients, mainly HbSS, is significantly lower than Caucasian ones (p Out of 1,579, 365 SCD patients (23%) did not receive any therapy. Acute transfusion regimen (ATR), Chronic transfusion regimen (CTR) and HC were given in monotherapy, respectively in 160, 226 and 197 patients, or in succession/combination in 631 (Table 1B), distributed throughout genotypes. The main reasons for ATR were acute anemia (384 events) and VOCs (352), followed by acute chest syndrome (ACS; 170), surgery (82), pregnancy (64), splenic sequestration (26), stroke (9); multi-organ failure (MOFs 6) and priapism (5). For CRT, it was acute anemia (306 events) and prevention of VOCs (371), ACS (107), primary stroke prevention (78) and secondary prevention stroke (55), pain HC-resistent (39) and leg ulcers (12). For 275 patients out of 631 it was possible to follow the timing of therapy switching (Table 1C). Of 275 patients, 67.6% switched from ATR/CRT to HC, 2.9% from HC to CRT and 6.5% stopped every therapy. Out of 275 patients, 104 were treated with overlapping therapeutic regimen. Discussion. The significant difference of age in Caucasian and non-Caucasian patients is probably due to the efficacy of the national prevention program of hemoglobinopathies, because the non-Caucasian patients are prevalently born out of Italy. The transfusional approach is similar in HbSS and b°-thal/HbS and b+-thal/HbS patients regarding both ATR and CTR. HbSC genotype needed less therapies(p Summary/Conclusion. The transfusional approach is similar in HbSS, b°-thal/HbS and b+-thal/HbS patients with similar indications, prevalently VOCs and anemia. The significant higher age in Caucasian cohort and the consequent long term follow up could be the cause of variable therapeutic approach observed, however Hydroxycarbamide seemed to be the therapy more frequently used and finally suggested to manage chronic manifestations. Figure. Figure. Disclosures Origa: Apopharma: Honoraria; Novartis: Honoraria; Bluebird Bio: Consultancy; Cerus Corporation: Research Funding. Forni:Apopharma: Other: DSM Board; Celgene: Research Funding; Novartis: Other: travel expenses, Research Funding; Shire: Research Funding; Roche: Consultancy.
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- 2018
54. Successful Treatment With Ledipasvir/Sofosbuvir in an Infant With Severe Combined Immunodeficiency Caused by Adenosine Deaminase Deficiency With HCV Allowed Gene Therapy with Strimvelis
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Francesca Ferrua, Maria Ester Bernardo, Maria Pia Cicalese, Francesca Tucci, Federica Barzaghi, Giulia Consiglieri, Jonathan Appleby, Daniele Canarutto, Francesco Calzatini, Michela Gabaldo, Silvia Darin, Francesca Dionisio, Caterina Lucano, Sarah Marktel, Maddalena Migliavacca, Enza Cestone, Miriam Casiraghi, Renato Finazzi, Giorgina Mieli-Vergani, Dalia Abd Elaziz, Salvatore Recupero, Valeria Calbi, Alessandro Aiuti, Fabio Ciceri, Enzo Boeri, Tucci, Francesca, Calbi, Valeria, Barzaghi, Federica, Migliavacca, Maddalena, Ferrua, Francesca, Bernardo, Maria Ester, Canarutto, Daniele, Consiglieri, Giulia, Recupero, Salvatore, Calzatini, Francesco, Gabaldo, Michela, Lucano, Caterina, Casiraghi, Miriam, Darin, Silvia, Dionisio, Francesca, Marktel, Sarah, Cestone, Enza, Finazzi, Renato, Mieli-Vergani, Giorgina, Boeri, Enzo, Appleby, Jonathan, Elaziz, Dalia Abd, Ciceri, Fabio, Aiuti, Alessandro, and Cicalese, Maria Pia
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0301 basic medicine ,Male ,Strimvelis ,Adenosine Deaminase ,Genetic enhancement ,Antiviral Agents ,Clinical Observations in Hepatology ,03 medical and health sciences ,0302 clinical medicine ,Agammaglobulinemia ,medicine ,Humans ,Severe combined immunodeficiency ,Fluorenes ,Hepatology ,business.industry ,Infant ,Genetic Therapy ,medicine.disease ,Virology ,Hepatitis C ,Adenosine deaminase deficiency ,030104 developmental biology ,LEDIPASVIR/SOFOSBUVIR ,030211 gastroenterology & hepatology ,Benzimidazoles ,Severe Combined Immunodeficiency ,Sofosbuvir ,business ,Uridine Monophosphate - Abstract
Patients with inborn error diseases can be candidates for autologous haematopoietic stem cells (HSC) gene therapies (GT) but may require negative viral screening, including Hepatitis C (HCV), to allow HSC manipulation in Good Manufacturing Practices areas. In case of HCV positivity, patients might be excluded from life-saving treatments. As HCV antibodies could be negative in young infant immunodeficient patients due to their immature/impaired immune system, or positive due to maternal-fetal antibody transmission, the risk is usually also evaluated on the basis of the HCV-RNA. This article is protected by copyright. All rights reserved.
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- 2018
55. Lung Ultrasound to Evaluate Invasive Fungal Diseases after Allogeneic Hematopoietic Stem Cell Transplantation
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Raffaella, Greco, primary, Lorenzo, Lazzari, additional, Elisabetta, Xue, additional, Andrea, Assanelli, additional, Sarah, Marktel, additional, Fabio, Giglio, additional, Daniela, Clerici, additional, Maria Teresa, Lupo Stanghellini, additional, Consuelo, Corti, additional, Massimo, Bernardi, additional, Fabio, Ciceri, additional, and Jacopo, Peccatori, additional
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- 2019
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56. Enteric Microbiome Markers as Early Predictors of Clinical Outcome in Allogeneic Hematopoietic Stem Cell Transplant: Results of a Prospective Study in Adult Patients
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Fabio Ciceri, Jacopo Peccatori, Fabio Giglio, Roberto Burioni, Consuelo Corti, Renée Pasciuta, Andrea Assanelli, Nicola Clementi, Luca Vago, Giacomo Pini, Maria Teresa Lupo Stanghellini, Nicasio Mancini, Matteo Carrabba, Alessandra Forcina, Olivia B. Morrow, Sarah Marktel, Mara Morelli, Raffaella Greco, Massimo Clementi, Laura Infurnari, Maria Chiara Barbanti, Giuseppe Banfi, Massimo Bernardi, Maria Pia Sormani, Mancini, Nicasio, Greco, Raffaella, Pasciuta, Renée, Barbanti, Maria Chiara, Pini, Giacomo, Morrow, Olivia Beatrice, Morelli, Mara, Vago, Luca, Clementi, Nicola, Giglio, Fabio, Lupo Stanghellini, Maria Teresa, Forcina, Alessandra, Infurnari, Laura, Marktel, Sarah, Assanelli, Andrea, Carrabba, Matteo, Bernardi, Massimo, Corti, Consuelo, Burioni, Roberto, Peccatori, Jacopo, Sormani, Maria Pia, Banfi, Giuseppe, Ciceri, Fabio, and Clementi, Massimo
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0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Disease ,graft-vs-host disease (GvHD) ,Sepsis ,03 medical and health sciences ,Internal medicine ,medicine ,Major Article ,microbiologically confirmed sepsis ,Microbiome ,Prospective cohort study ,severe sepsis and septic shock ,allogeneic hematopoietic stem cell transplant (allo-HSCT) ,enteric microbiome ,Univariate analysis ,business.industry ,medicine.disease ,Transplantation ,030104 developmental biology ,Infectious Diseases ,Graft-versus-host disease ,surgical procedures, operative ,Oncology ,microbiologically confirmed sepsi ,Immunology ,business - Abstract
Background Infections and graft-vs-host disease (GvHD) still represent major, not easily predictable complications in allogeneic hematopoietic stem cell transplant (allo-HSCT). Both conditions have been correlated to altered enteric microbiome profiles during the peritransplant period. The main objective of this study was to identify possible early microbiome-based markers useful in pretransplant risk stratification. Methods Stool samples were collected from 96 consecutive patients at the beginning of the pretransplant conditioning regimen (T0) and at 10 (T1) and 30 (T2) days following transplant. When significant in univariate analysis, the identified microbiome markers were used in multivariate regression analyses, together with other significant clinical variables for allo-HSCT-related risk stratification. Four main outcomes were addressed: (1) septic complications, (2) GvHD, (3) relapse of the underlying disease, and (4) mortality. Results The presence of >5% proinflammatory Enterobacteriaceae at T0 was the only significant marker for the risk of microbiologically confirmed sepsis. Moreover, ≤10% Lachnospiraceae at T0 was the only significant factor for increased risk of overall mortality, including death from both infectious and noninfectious causes. Finally, a low bacterial alpha-diversity (Shannon index ≤ 1.3) at T1 was the only variable significantly correlating with an increased risk of GvHD within 30 days. Conclusions Microbiome markers can be useful in the very early identification of patients at risk for major transplant-related complications, offering new tools for individualized preemptive or therapeutic strategies to improve allo-HSCT outcomes.
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- 2017
57. Plerixafor on demand in ten healthy family donors as a rescue strategy to achieve an adequate graft for stem cell transplantation
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Raffaella Milani, Fabio Ciceri, Simona Malato, Lucia Malabarba, Salvatore Gattillo, Tiago De Freitas, Consuelo Corti, Laura Bellio, Milena Coppola, Andrea Assanelli, Sarah Marktel, and Lorenzo Rizzo
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Oncology ,medicine.medical_specialty ,Myeloid ,business.industry ,Plerixafor ,Immunology ,CD34 ,Hematopoietic stem cell ,Hematology ,Leukapheresis ,Transplantation ,medicine.anatomical_structure ,Internal medicine ,medicine ,Immunology and Allergy ,Stem cell ,business ,Contraindication ,medicine.drug - Abstract
BACKGROUND In allogeneic hematopoietic stem cell (HSC) transplantation, the collection of an appropriate number of HSCs while maintaining a high level of safety for healthy donors is fundamental. Inadequate HSC mobilization can be seen with the standard use of granulocyte–colony-stimulating (G-CSF). Plerixafor (PL) is a chemokine receptor CXC Type 4–stromal-derived factor 1 inhibitor; its HSC-mobilizing properties are synergistic with G-CSF in poor mobilizing patients. The use of PL as adjuvant or alternative to G-CSF in healthy donors has shown a good safety profile but is so far off-label. STUDY DESIGN AND METHODS We report 10 healthy HSC donors treated with PL because of insufficient response to G-CSF alone or contraindication to G-CSF. Eight donors did not mobilize enough CD34+ cells with G-CSF alone because poor mobilizers or because insufficient HSCs were harvested according to the clinical need of the patient; in two cases G-CSF administration and marrow harvest were unfeasible or contraindicated in the donor. RESULTS The use of PL for mobilization increased the number of circulating CD34+ cells by 2.8-fold and the CD34+/kg collection by 3.0-fold. Only mild adverse events were reported (bone pain or discomfort) and not univocally attributable to PL. Rate of engraftment and graft-versus-host disease were similar to those seen in recipients of grafts from G-CSF only–mobilized donors. CONCLUSION We exposed 10 allogeneic donors to mobilization with PL. PL was well tolerated in all cases and ensured procurement of an adequate graft for transplantation resulting in a normal hematopoietic engraftment.
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- 2015
58. Treosulfan based reduced toxicity conditioning followed by allogeneic stem cell transplantation in patients with myelofibrosis
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Fabio Giglio, Andrea Assanelli, Simone Claudiani, Fabio Ciceri, Matteo Carrabba, Elena Guggiari, Maria Teresa Lupo-Stanghellini, Jacopo Peccatori, Massimo Bernardi, Francesca Lunghi, Magda Marcatti, Tiago De Freitas, Consuelo Corti, Simona Piemontese, and Sarah Marktel
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Oncology ,Cancer Research ,medicine.medical_specialty ,Allogeneic transplantation ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Treosulfan ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Cumulative incidence ,Myelofibrosis ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Surgery ,Fludarabine ,Transplantation ,030220 oncology & carcinogenesis ,Stem cell ,business ,030215 immunology ,medicine.drug - Abstract
Allogeneic transplantation is the only potentially curative strategy for myelofibrosis, even in the era of new drugs that so far only mitigate symptoms. The choice to proceed to allogeneic transplantation is based on several variables including age, disease phase, degree of splenomegaly, donor availability, comorbidities and iron overload. These factors, along with conditioning regimen and time to transplantation, may influence the outcome of ASCT. We report 14 patients affected by myelofibrosis with a median age of 57 years (range, 41–76) receiving a treosulfan-fludarabine based reduced toxicity conditioning. Patients (pts) received a stem cell transplantation from an HLA identical (n = 10) or matched unrelated donor (n = 4). All pts had a complete myeloablation followed by engraftment and in 12 out of 13 evaluated pts donor chimerism was 100% at 1 month. In most cases a reduction of splenomegaly and a reduction (or resolution) of bone marrow fibrosis was observed. After a median follow-up of 39 months (range, 3–106), the 3-year probability of overall survival and disease free survival was 54 +/− 14% and 46 +/− 14%, respectively. The cumulative incidence of non-relapse mortality at 2 years was 39 +/− 15%. Causes of non-relapse mortality were: infection (n = 2), GvHD (n = 2) and haemorrhage (n = 1). We can conclude that a treosulfan and fludarabine based conditioning has a potent myeloablative and anti-disease activity although non-relapse mortality remains high in this challenging clinical setting. Copyright © 2014 John Wiley & Sons, Ltd.
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- 2014
59. Plerixafor and G-CSF combination mobilizes hematopoietic stem and progenitors cells with a distinct transcriptional profile and a reduced in vivo homing capacity compared to Plerixafor alone
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Laura Bellio, Bernhard Gentner, Laura Zanaboni, Matilde Zambelli, Annamaria Aprile, Elena Cassinerio, Sarah Marktel, Ylenia Paleari, Cristina Parisi, Fabio Ciceri, Antonello E. Spinelli, Marta Claudia Frittoli, Maria Domenica Cappellini, Giacomo Mandelli, Giuliana Ferrari, Maria Rosa Lidonnici, Lidonnici, Maria Rosa, Aprile, Annamaria, Frittoli, Marta Claudia, Mandelli, Giacomo, Paleari, Ylenia, Spinelli, Antonello, Gentner, Bernhard, Zambelli, Matilde, Parisi, Cristina, Bellio, Laura, Cassinerio, Elena, Zanaboni, Laura, Cappellini, Maria Domenica, Ciceri, Fabio, Marktel, Sarah, and Ferrari, Giuliana
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0301 basic medicine ,medicine.medical_treatment ,Plerixafor ,Hematopoietic Stem Cell ,Hematology ,Hematopoietic stem cell transplantation ,Biology ,Transplantation ,03 medical and health sciences ,Haematopoiesis ,030104 developmental biology ,Immunophenotyping ,medicine.anatomical_structure ,Cancer research ,medicine ,Hematopoiesi ,Bone marrow ,Progenitor cell ,Homing (hematopoietic) ,medicine.drug ,Stem Cell Transplantation - Abstract
For decades, bone marrow (BM) has been the preferred source of hematopoietic stem and progenitor cells (HSPCs) for transplants following myeloablative conditioning. At present, mobilized peripheral blood stem cells are commonly used for transplantation, particularly in the autologous setting.[1][1
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- 2017
60. Bendamustine Combined with Donor Lymphocytes Infusion in Hodgkin's Lymphoma Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation
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Stefania Bramanti, Consuelo Corti, Armando Santoro, Elisa Sala, Sarah Marktel, Barbara Sarina, Sara Gandolfi, Jacopo Peccatori, Roberto Crocchiolo, Luca Castagna, Marta Bruno-Ventre, Fabio Ciceri, Sala, E, Crocchiolo, R, Gandolfi, S, Bruno Ventre, M, Bramanti, S, Peccatori, J, Sarina, B, Corti, C, Ciceri, Fabio, Santoro, A, Marktel, S, and Castagna, L.
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Bendamustine ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Neutropenia ,Gastroenterology ,Donor lymphocyte infusion ,Internal medicine ,medicine ,Bendamustine Hydrochloride ,Humans ,Lymphocytes ,Antineoplastic Agents, Alkylating ,Transplantation ,Hodgkin's lymphoma ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Donor Lymphocytes ,medicine.disease ,Hodgkin Disease ,Allogeneic stem cell transplantation ,Surgery ,Lymphoma ,Nitrogen Mustard Compounds ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
The management of Hodgkin's lymphoma (HL) recurring after allogeneic stem cell transplantation is challenging. We retrospectively describe 18 adults treated with bendamustine followed by escalated donor lymphocyte infusion. Hematological toxicity was manageable (39% grade III to IV neutropenia and 28% grade III to IV thrombocytopenia). The overall response rate was 55%, with 3 complete and 7 partial responses. Median overall and progression-free survival were 11 (range, 1 to 52) and 6 (range, 1 to 28) months, respectively. One-year overall survival of responders (complete or partial) was 70% (95% confidence interval, 42% to 98%), although it was only 16% for nonresponders (n = 8). Our data show that bendamustine followed by donor lymphocyte infusion is feasible and can be efficacious as salvage treatment in HL relapsing after an allograft. (C) 2014 American Society for Blood and Marrow Transplantation.
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- 2014
61. Plerixafor and G-CSF combination mobilizes hematopoietic stem and progenitors cells with a distinct transcriptional profile and a reduced
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Maria Rosa, Lidonnici, Annamaria, Aprile, Marta Claudia, Frittoli, Giacomo, Mandelli, Ylenia, Paleari, Antonello, Spinelli, Bernhard, Gentner, Matilde, Zambelli, Cristina, Parisi, Laura, Bellio, Elena, Cassinerio, Laura, Zanaboni, Maria Domenica, Cappellini, Fabio, Ciceri, Sarah, Marktel, and Giuliana, Ferrari
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Benzylamines ,Receptors, CXCR4 ,Antigens, CD34 ,Cell Cycle Proteins ,Cyclams ,Immunophenotyping ,Mice ,Heterocyclic Compounds ,Granulocyte Colony-Stimulating Factor ,Animals ,Humans ,Leukapheresis ,Stem Cell Niche ,Online Only Articles ,Gene Expression Profiling ,beta-Thalassemia ,Hematopoietic Stem Cell Transplantation ,Mesenchymal Stem Cells ,Endonucleases ,Hematopoietic Stem Cells ,Chemokine CXCL12 ,Hematopoietic Stem Cell Mobilization ,Drug Combinations ,Gene Expression Regulation ,Protein Binding ,Signal Transduction - Published
- 2016
62. Immune Reconstitution Is a Predictive Biomarker of Chronic Graft-Versus-Host Disease: Analysis of 307 Consecutive Patients
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Raffaella Greco, Francesca Lunghi, Raffaella Milani, Elena Guggiari, Magda Marcatti, Massimo Bernardi, Jacopo Peccatori, Francesca Lorentino, Matteo Carrabba, Chiara Bonini, Consuelo Corti, Sarah Marktel, Sara Mastaglio, Francesca Pavesi, Fabio Ciceri, Fabio Giglio, Fabio Serpenti, Francesca Farina, Andrea Assanelli, Carlo Messina, and Maria Teresa Lupo Stanghellini
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medicine.medical_specialty ,biology ,Proportional hazards model ,business.industry ,Surrogate endpoint ,Immunology ,Cell Biology ,Hematology ,Immune dysregulation ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Gastroenterology ,Transplantation ,Graft-versus-host disease ,Hypocellularity ,Immunoglobulin M ,Internal medicine ,medicine ,biology.protein ,Biomarker (medicine) ,business - Abstract
Introduction Allogeneic stem cell transplantation (HCT) survivors are at a relevant risk of developing long-term complications such as chronic GvHD (cGvHD), which importantly affects their quality of life and increases their morbidity and mortality. Being able to early identify high risk patients would enable us to tailor preventive strategies. Current approach on prophylaxis of GvHD is lacking of predictive biomarkers that could guide patient-tailoring of drugs choice, tapering and treatment schedules. Immune system is the cause of cGvHD but is also a target of it, and cGvHD patients are characterized by lymphoid hypocellularity. Moreover, immune reconstitution (IR) is a good candidate biomarker being it an easily-available and reproducible parameter. We investigated IR variables as predictive biomarker of cGvHD. Methods A standardized follow-up of HCT-survivors is applied at our center. We analyzed 307 adult patients consecutively undergoing first allogeneic HCT transplant between July 2012 and December 2016 at our Institution. A written consent was given for the use of medical records for research in accordance with the Declaration of Helsinki. Median follow-up for surviving patients was 2.8 years (range 1.1-5.5). We prospectively collected IR data of our entire cohort at specific time-points (+30, +60, +90, +180, +365 days) and followed patients up recording events. IR variables were CD3+, CD3+CD4+, CD3+CD8+, CD19+, CD56+ cell counts, measured by flow-citometry, and immunoglobulins IgG, IgA and IgM levels, measured by immunoturbidimetric assays. Time as a continuous parameter could not be studied since the number of events would have been too low for the analysis. For this reason, a series of landmark analyses were performed at 3, 6 and 12 months post-HCT in order to identify predictive factors of cGvHD, transplant-related mortality (TRM), progression-free survival (PFS) and overall survival (OS) for patients alive and in good conditions at the beginning of each time interval. Factors predicting cGvHD incidence and survival endpoints were studied using multivariate analysis by Cox regression model. Variables included in the model were patient and donor age and Sorror-Comorbidity Index (according to median values), disease-related index, type of donor, stem cell source, IR values at the timepoint according to landmark cut-off for cell counts and median values for immunoglobulin levels. A backward stepwise procedure was used for variable selection with a p-value Results Chronic-GvHD of any grade and severity was diagnosed in 111 patients. Immune recovery in our cohort was in line with the current knowledge: CD3+CD8+ and NK (CD56+) cells normalized first, followed by CD3+ and CD3+CD4+ cell. B cells (CD19+) took at least 1 year to normalize in terms of absolute counts. IgM levels were the first to rise among immunoglobulins, followed by IgG and then IgA which can also be subnormal for a long time after transplant. Results of multivariate analysis are shown in Table 1. Single lymphocyte subset counts did not prove to be associated to cGvHD onset significantly; conversely, immunoglobulins were strongly predictive of cGvHD in our multivariate model. Median time to GvHD onset was 198 days, thus the most important analysis was the one performed at +90 days as the majority of patients had still not developed cGvHD. IgG, IgA and IgM at +90 days from HCT below the median value were found before the onset of GvHD and could predict its onset. This data were confirmed on the analysis at later time-points in which low IgG levels predicted cGvHD diagnosis. Conclusions Day-90 low immunoglobulin levels predict cGvHD, confirming that subclinical immune dysregulation mechanisms could be already present before overt clinical onset of cGvHD symptoms. Early prediction of subsequent cGvHD will be operationally translated into patient-tailored preventive measures. Disclosures Bonini: Intellia Therapeutics: Research Funding.
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- 2018
63. Elderly patients 65 years of age with acute myeloid leukemia and normal karyotype benefit from intensive therapeutic programs
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Alessandra Forcina, Carlo Messina, Sarah Marktel, Consuelo Corti, Andrea Assanelli, Francesca Pavesi, Raffaella Milani, Bernhard Gentner, Matteo Carrabba, Fabio Ciceri, Jacopo Peccatori, Luca Vago, Elisa Sala, Massimo Bernardi, Bernardi, Massimo, Carrabba, Matteo, Messina, Carlo, Milani, Raffaella, Sala, Elisa, Pavesi, Francesca, Gentner, Bernhard, Peccatori, Jacopo, Assanelli, Andrea, Marktel, Sarah, Corti, Consuelo, Forcina, Alessandra, Vago, Luca, and Ciceri, Fabio
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0301 basic medicine ,Male ,medicine.medical_specialty ,Karyotype ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Age Factor ,Aged ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Age Factors ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,Middle Aged ,Combined Modality Therapy ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Immunology ,Female ,business ,Human - Published
- 2016
64. Low-dose antithymocyte globulin, post-transplant cyclophosphamide and sirolimus as graft-versus-host disease prophylaxis in unrelated donor transplants
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Maria Chiara Barbanti, Fabio Giglio, Matteo Carrabba, Maria Teresa Lupo Stanghellini, Carlo Messina, Raffaella Greco, Chiara Bonini, Jacopo Peccatori, Mara Morelli, Sarah Marktel, Raffaella Milani, Magda Marcatti, Nicoletta Cieri, Consuelo Corti, Lara Crucitti, Massimo Bernardi, Tommaso Perini, Luca Vago, Elisa Sala, Simona Piemontese, Francesca Pavesi, Fabio Ciceri, Andrea Assanelli, Greco, R, Crucitti, L, Vago, L, Cieri, N, Giglio, F, Stanghellini, Mtl, Morelli, M, Barbanti, Mc, Piemontese, S, Perini, T, Sala, E, Pavesi, F, Messina, C, Milani, R, Marcatti, M, Marktel, S, Carrabba, M, Bernardi, M, Corti, C, Assanelli, A, Bonini, C, Ciceri, F, Peccatori, J, and Carrabba, Mg
- Subjects
medicine.medical_specialty ,Globulin ,biology ,business.industry ,Immunology ,Congenital cytomegalovirus infection ,Cell Biology ,Hematology ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Gastroenterology ,BK virus ,Transplantation ,surgical procedures, operative ,Graft-versus-host disease ,Internal medicine ,Sirolimus ,medicine ,biology.protein ,Rituximab ,business ,medicine.drug ,Hemorrhagic cystitis - Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only cure for several patients with high-risk hematological malignancies. Recent advances in supportive therapies have significantly reduced the treatment-related mortality over the last decades. Nevertheless graft-versus-host disease (GvHD) still represents a major complication, and research is needed to achieve further progress in this area of transplantation. Moreover, although initial studies suggested relative equivalence, recent and large prospective studies showed higher rates of acute and chronic GvHD, and worse survival in allo-HSCT from unrelated donors (URD) compared with HLA-identical sibling donors. Following our encouraging results in haplodentical setting with the more recently post-transplantation cyclophosphamide (PTCy) and sirolimus as GvHD prophylaxis (Cieri et al, 2015), in this study we investigated whether the incorporation of low dose anti-thymocyte globulin (ATG) to PTCy and sirolimus GvHD prophylactic approach, may alleviate some of the increased alloreactivity associated with URD transplants. We retrospectively evaluated a cohort of 21 haematological patients receiving URD allo-HSCT in the San Raffaele Haematology and BMT Unit, from 2013 to 2015. All subjects had high-risk hematologic malignancies, with the most common diagnosis being myeloid diseases (52%). A total of 11 patients had active disease at HSCT, while 9 were in hematologic remission. Nine patients scored high according to disease risk index defined by Armand et al, 10 scored intermediate, while only 2 had a low disease score. Myeloablative conditioning consisted of treosulfan (14 g/m2/day) on days -6 to -4, fludarabine (30 mg/m2/day) on days -6 to -2, and melphalan (70 mg/m2/day) on days -2 and -1, followed by T-replete G-CSF-mobilized PBSCs (n=19) or BM grafts (n=2). Whether 12 patients received stem cells from HLA- matched URD (fully 10/10 HLA matched), the remaining 9 had one-locus HLA-mismatched from their donors. During conditioning patients received ATG-Fresenius 5 mg/kg per day IV on day -4 to -2. In vivo B-cell depletion was obtained by rituximab (i.v. 375mg/m2 given as a single dose on day -1). Postgrafting immunosuppression consisted of PTCy (50 mg/kg/day) on days 3 and 4. Sirolimus was given orally from day 5, and monitored to maintain a target therapeutic plasma level of 5-14 ng/ml. According to chimeric status and evidence of GVHD, the dosage of sirolimus was tapered during the second month post-transplantation, ending in complete withdrawal within the sixth month after HSCT. Mycophenolate mofetil (MMF) was initiated orally at 10 mg/kg t.i.d. on day 5 after HSCT, and withdrawn on day 30. Median follow up was 247 days (range 29-486) from HSCT. All patients were engrafted in a median time of 17 days (range, 14-51 days), with full donor chimerism achieved by day 30. Poor graft function was observed in 11 patients. Post-HSCT recovery of lymphocyte subsets was lengthy as compared to other unmanipulated HSCT, with a median time to CD3>100/ml of 41 days (range, 22-389 days) by flow-cytometry, while 5 patients never reached immune reconstitution. All except one developed febrile neutropenia during aplasia. We observed a high rate of serious infections: severe pneumonia in 7 cases (5 required NIV, 4 were admitted to ICU), CMV reactivation in 13 (3 CMV disease), HHV6 reactivation in 10, BK virus haemorrhagic cystitis in 2 patients. Although the overall mortality associated with these complications was limited, as evidenced by a favourable NRM, it caused significant morbidity in patients and often required aggressive therapies, potentially contributing to poor graft function. The incidences of acute and chronic GVHD were low. A grade II-IV acute GvHD was reported in 10% patients, while five patients developed chronic GvHD (mild in 4 cases, only one moderate). Non-relapse mortality (NRM) at 100 days and 1 year was 4.8% and 20.7%, respectively. The estimated 1-year overall survival (OS) and relapse incidence were 51% and 22.5% respectively. Although limited by a small number of patients with relatively short follow-up, our study suggests that URD allo-HSCT with ATG, PTCy and sirolimus-based GvHD prophylaxis, can be very effective in preventing GvHD, but at the expense of delayed immune reconstitution and high rate of infectious complications, while warranting acceptable NRM and relapse incidence. Disclosures Bonini: MolMed S.p.A: Consultancy.
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- 2016
65. Coadministration of posaconazole and sirolimus in allogeneic hematopoietic stem cell transplant recipients
- Author
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Luca Vago, Jacopo Peccatori, Alessandra Forcina, Maria Chiara Barbanti, Massimo Bernardi, Fabio Ciceri, Chiara Messina, Sarah Marktel, Matteo Carrabba, Paolo Scarpellini, Fabio Giglio, Chiara Oltolini, Raffaella Greco, Mara Morelli, M. T. Lupo Stranghellini, Consuelo Corti, Simona Piemontese, Andrea Assanelli, Greco, R, Barbanti, M. C., Lupo Stanghellini, M. T., Giglio, F., Morelli, M., Messina, C., Forcina, A., Oltolini, C., Piemontese, S., Scarpellini, P., Marktel, S., Assanelli, A., Carrabba, M., Vago, L., Corti, C., Bernardi, M., Peccatori, J., and Ciceri, Fabio
- Subjects
Adult ,Male ,Risk ,0301 basic medicine ,Posaconazole ,Transplantation Conditioning ,Adolescent ,medicine.medical_treatment ,030106 microbiology ,Hematopoietic stem cell transplantation ,Young Adult ,03 medical and health sciences ,medicine ,Humans ,Transplantation, Homologous ,cardiovascular diseases ,Progenitor cell ,Multiple myeloma ,Aged ,Sirolimus ,Transplantation ,business.industry ,Lymphoma, Non-Hodgkin ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Triazoles ,equipment and supplies ,medicine.disease ,Hodgkin Disease ,Leukemia, Myeloid, Acute ,Treatment Outcome ,surgical procedures, operative ,Graft-versus-host disease ,Immunology ,cardiovascular system ,Female ,Stem cell ,Multiple Myeloma ,business ,Follow-Up Studies ,medicine.drug - Abstract
Coadministration of posaconazole and sirolimus in allogeneic hematopoietic stem cell transplant recipients
- Published
- 2016
66. When diagnostics meets translational research: detection of hemoglobin fractions in cellular lysates from in vitro erythroid cultures by Capillarys2 Flex Piercing® analyzer (Sebia)
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Maria Domenica Cappellini, Ferruccio Ceriotti, Gabriella Passerini, Fabio Ciceri, Annamaria Aprile, Sarah Marktel, Giuliana Ferrari, Aprile, A, Passerini, G, Cappellini M., D, Marktel, S, Ciceri, Fabio, Ferrari, Giuliana, and Ceriotti, F.
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0301 basic medicine ,Spectrum analyzer ,Erythrocytes ,Coefficient of variation ,Translational Research, Biomedical ,Hemoglobins ,03 medical and health sciences ,0302 clinical medicine ,Capillary electrophoresis ,Limit of Detection ,Physiology (medical) ,Humans ,Medicine ,Cells, Cultured ,Detection limit ,Chromatography ,business.industry ,Biochemistry (medical) ,Public Health, Environmental and Occupational Health ,Electrophoresis, Capillary ,Reproducibility of Results ,General Medicine ,In vitro ,Peripheral blood ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,Hemoglobin ,business ,Automated method - Abstract
Detection of hemoglobin (Hb) variants represents an important issue for diagnosis and adequate treatment of hemoglobinopathies. The Capillarys 2 Flex Piercing analyzer (Capillarys) by Sebia is routinely used in our clinical laboratories to detect Hb variants in peripheral blood (PB). This automated method separates Hb fractions by capillary electrophoresis, giving a spectrophotometric measure of their relative proportion. The scientific research in the field of hemoglobinopathies needs robust procedures to evaluate the efficacy of experimental therapies, as gene therapy. We investigated for the first time the feasibility to use Capillarys on cellular lysates from in vitro erythroid cultures. Because total Hb concentration in erythroid lysates is up to 20-fold lower than in hemolysates from PB, we analyzed diluted blood samples, thanks to the manual mode included in the Capillarys setting. We compared analytical precision, accuracy, sensitivity, and specificity of this procedure to the automatic method, routinely used in diagnostics. For instance, adult Hb intra- and interassay precision were estimated as coefficient of variation 0.2% and 0.3%, respectively. The manual mode is less robust for detection of fractions
- Published
- 2016
67. Genotypes and haplotypes in the 3′ untranslated region of the HLA-G gene and their association with clinical outcome of hematopoietic stem cell transplantation for beta-thalassemia
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Antonio Amoroso, Benedetta Mazzi, Federico Sizzano, M Torchio, C Pultrone, Fabio Ciceri, Maria Troiano, Robert Chiesa, Sarah Marktel, Katharina Fleischhauer, M. G. Roncarolo, Laura Zito, Javid Gaziev, Roberto Crocchiolo, Silvia Gregori, Guido Lucarelli, Manuela Testi, G Turchiano, Pietro Sodani, Marco Andreani, Sizzano, F, Testi, M, Zito, L, Crocchiolo, R, Troiano, M, Mazzi, B, Turchiano, G, Torchio, M, Pultrone, C, Gregori, S, Chiesa, R, Gaziev, J, Sodani, P, Marktel, S, Amoroso, A, Roncarolo, MARIA GRAZIA, Lucarelli, G, Ciceri, Fabio, Andreani, M, and Fleischhauer, K.
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Adult ,Male ,Linkage disequilibrium ,Adolescent ,Genotype ,medicine.medical_treatment ,Immunology ,Graft vs Host Disease ,Single-nucleotide polymorphism ,Hematopoietic stem cell transplantation ,Human leukocyte antigen ,Biology ,Biochemistry ,Linkage Disequilibrium ,Immune Tolerance ,Genetics ,medicine ,Humans ,Transplantation, Homologous ,Immunology and Allergy ,Child ,3' Untranslated Regions ,Sequence Deletion ,HLA-G Antigens ,Polymorphism, Genetic ,Siblings ,beta-Thalassemia ,Haplotype ,Hematopoietic Stem Cell Transplantation ,Beta thalassemia ,General Medicine ,medicine.disease ,Transplantation ,Mutagenesis, Insertional ,Treatment Outcome ,Haplotypes ,Italy ,Case-Control Studies ,Child, Preschool ,Female - Abstract
Polymorphisms in the 3' untranslated region (3'UTR) of HLA-G, an important player in immunological tolerance, could be involved in post-transcriptional expression control, and their association with different clinical immune-related conditions including autoimmunity and transplantation is of mounting interest. Most studies have focused on a 14 base pair (bp) insertion/deletion (ins/del), while additional single-nucleotide polymorphisms (SNPs) in the HLA-G 3'UTR have been described but not extensively investigated for their clinical relevance. Here we have comparatively studied the association between 3'UTR haplotypes of HLA-G, or the 14 bp ins/del, with clinical outcome of HLA-identical sibling hematopoietic stem cell transplantation (HSCT) in 147 Middle Eastern beta-thalassemia patients. Sequence based typing of 3'UTR HLA-G polymorphisms in the patients and in 102 healthy Italian blood donors showed strong linkage disequilibrium between the 14 bp ins/del and five 3'UTR SNPs, which together could be arranged into eight distinct haplotypes based on expectation-maximization studies, with four predominant haplotypes (UTRs1-4). After HSCT, we found a moderate though not significant association between the presence of UTR-2 in double dose and protection from acute graft versus host disease (hazard ratio (HR) 0.45, 95% confidence intervals (CI): 0.14-1.45; P = 0.18), an effect that was also seen when the corresponding 14 bp ins/ins genotype was considered alone (HR 0.42, 95% CI: 0.16-1.06; P = 0.07). No association was found with rejection or survival. Taken together, our data show that there is no apparent added value of considering entire 3'UTR HLA-G haplotypes for risk prediction after allogeneic HSCT for beta-thalassemia.
- Published
- 2012
68. Platelet-lysate-Expanded Mesenchymal Stromal Cells as a Salvage Therapy for Severe Resistant Graft-versus-Host Disease in a Pediatric Population
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Giovanna D'Amico, Maria Grazia Orofino, J. Golay, Daniela Belotti, Ettore Biagi, Martino Introna, Giuseppe Gaipa, Paolo Perseghin, Attilio Rovelli, Andrea Biondi, Giovanna Lucchini, Sonia Bonanomi, Sarah Marktel, Patrizia Chiusolo, Paola Vinci, Edoardo Lanino, Erica Dander, Alessandro Rambaldi, Agnese Salvadè, Chiara Capelli, Adriana Balduzzi, Lucchini, G, Introna, M, Dander, E, Rovelli, A, Balduzzi, A, Bonanomi, S, Salvadè, A, Capelli, C, Belotti, D, Gaipa, G, Perseghin, P, Vinci, P, Lanino, E, Chiusolo, P, Orofino, M, Marktel, S, Golay, J, Rambaldi, A, Biondi, A, D'Amico, G, and Biagi, E
- Subjects
Blood Platelets ,Compassionate Use Trials ,Male ,medicine.medical_specialty ,Adolescent ,Bone marrow transplantation ,medicine.medical_treatment ,Mesenchymal stromal cells ,GVHD ,Graft vs Host Disease ,Salvage therapy ,Mesenchymal Stem Cell Transplantation ,Gastroenterology ,Cell therapy ,immune system diseases ,Internal medicine ,medicine ,Humans ,Child ,Salvage Therapy ,Transplantation ,Mesenchymal stromal cell ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Immunosuppression ,Hematology ,medicine.disease ,Surgery ,surgical procedures, operative ,Graft-versus-host disease ,Child, Preschool ,Cord blood ,Female ,Platelet lysate ,Stromal Cells ,business - Abstract
Despite advances in graft-versus-host-disease (GVHD) treatment, it is estimated that overall survival (OS) at 2 years for hematopoietic cell transplantation (HCT) recipients who experience steroid-resistant GVHD is 10%. Among recent therapeutic approaches for GVHD treatment, mesenchymal stromal cells (MSCs) hold a key position. We describe a multicenter experience of 11 pediatric patients diagnosed with acute or chronic GVHD (aGVHD, cGVHD) treated for compassionate use with GMP-grade unrelated HLA-disparate donors' bone marrow-derived MSCs, expanded in platelet-lysate (PL)-containing medium. Eleven patients (aged 4-15 years) received intravenous (i.v.) MSCs for aGVHD or cGVHD, which was resistant to multiple lines of immunosuppression. The median dose was 1.2 x 10(6)/kg (range: 0.7-3.7 x 10(6)/kg). No acute side effects were observed, and no late side effects were reported at a median follow-up of 8 months (range: 4-18 months). Overall response was obtained in 71.4% of patients, with complete response in 23.8% of cases. None of our patients presented GVHD progression upon MSC administration, but 4 patients presented GVHD recurrence 2 to 5 months after infusion. Two patients developed chronic limited GVHD. This study underlines the safety of PL-expanded MSC use in children. MSC efficacy seems to be greater in aGVHD than in cGVHD, even after failure of multiple lines of immunosuppression.
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- 2010
69. Impairment in the Mesenchymal Bone-Marrow Niche of Beta-Thalassemia Patients and Association with Prolonged Iron Exposure
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Marco Zecca, Samantha Scaramuzza, Maria Ester Bernardo, Valeria Rossella, Annamaria Aprile, Stefania Crippa, Sarah Marktel, Silvia Rivis, Fabio Ciceri, Laura Silvestri, Alessandro Aiuti, Maria Antonietta Avanzini, and Giuliana Ferrari
- Subjects
Blood transfusion ,biology ,business.industry ,medicine.medical_treatment ,Genetic enhancement ,Immunology ,Mesenchymal stem cell ,Beta thalassemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,biology.protein ,medicine ,Cancer research ,Doubling time ,Stromal cell-derived factor 1 ,Bone marrow ,Stem cell ,business - Abstract
Bone marrow (BM) contains a population of mesenchymal stromal cells (MSC) that, together with endothelial cells and osteoblasts, provide a specific microenvironment to support hematopoietic stem cell homeostasis. Beta-thalassemia (BT) is an hereditary blood disorder characterized by reduced or absent synthesis of hemoglobin beta-chains. Data on the mesenchymal compartment in BT patients are scarce. We isolated and characterized MSCs from BT and healthy donor (HD) BM samples. BT-MSCs showed a reduced clonogenic capacity, delay in colony formation, lower numbers of CFU-Fs and longer population doubling time. Similarly, we observed an altered differentiation capacity into adipocytes and osteoblasts. Both HD- and BT-MSCs express the canonical mesenchymal markers. On the contrary, the expression of CD146 and CD271 was extremely reduced in BT-MSCs, indicating a pauperization of the most primitive stem cell pool. We analyzed the expression of genes involved in the crosstalk between MSCs and HSCs and found a reduced expression of Cxcl12, SCF and Angp1 in BT-MSCs. Several genes relevant for MSC functionality were also downregulated in BT-MSCs. We demonstrated that MSCs are able to uptake and store iron. ROS levels were increased in BT-MSCs possibly due to altered anti-oxidant response and iron overload associated with blood transfusions. Importantly, higher level of ROS and reduced expression of primitive markers were observed in HD-MSCs cultured in presence of iron, underlying the importance of iron level for normal MSC function. In conclusion, we showed an impairment in the mesenchymal niche of BT-BM possibly associated with prolonged iron exposure. Disclosures Marktel: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Ciceri: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding.
- Published
- 2017
70. Antitumor effects of HSV-TK–engineered donor lymphocytes after allogeneic stem-cell transplantation
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Catia Traversari, Chiara Bonini, Zulma Magnani, Claudio Bordignon, Monica Salomoni, Sarah Marktel, Paolo Corradini, Elisabetta Zappone, Fabio Ciceri, Jacopo Peccatori, Luciano Callegaro, Attilio Bondanza, Alessandra Pescarollo, Maurilio Ponzoni, Silvano Rossini, Massimo Bernardi, Claudia Benati, Paolo Servida, Marco Bregni, Ciceri, Fabio, Bonini, MARIA CHIARA, Marktel, S, Zappone, E, Servida, P, Bernardi, M, Pescarollo, A, Bondanza, Attilio, Peccatori, J, Rossini, S, Magnani, Z, Salomoni, M, Benati, C, Ponzoni, Maurilio, Callegaro, L, Corradini, P, Bregni, M, Traversari, C, and Bordignon, Claudio
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Adult ,Male ,Ganciclovir ,Adolescent ,Lymphocyte ,Immunology ,Graft vs Host Disease ,Context (language use) ,Biology ,Antiviral Agents ,Thymidine Kinase ,Biochemistry ,Neoplasms ,medicine ,Humans ,Simplexvirus ,Transplantation, Homologous ,Lymphocytes ,Genetic Therapy ,Cell Biology ,Hematology ,Middle Aged ,Suicide gene ,Donor Lymphocytes ,Transplantation ,surgical procedures, operative ,medicine.anatomical_structure ,Thymidine kinase ,Female ,Immunotherapy ,Stem cell ,Stem Cell Transplantation ,medicine.drug - Abstract
The extensive exploitation of the antitumor effect of donor lymphocytes infused after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is limited by the risk of graft-versus-host disease (GvHD). To overcome this limitation, we investigated the therapeutic potential of donor lymphocytes engineered with the suicide gene thymidine kinase of herpes simplex virus (TK) in 23 patients experiencing recurrence of hematologic malignancies after allo-HSCT. Long-term follow-up of infused patients included analysis of engraftment of genetically engineered lymphocytes, in vivo assessment of antitumor effect, and control of GvHD by ganciclovir. All 17 patients evaluable for engraftment and graft-versus-leukemia (GvL) had circulating TK+ cells detectable beginning at a median time of 18 days. Eleven patients (65%) experienced a substantial clinical benefit resulting in 6 (35%) complete remissions and 5 (29%) partial responses. The antitumor effect tightly correlated with the in vivo received ganciclovir, resulting in elimination of TK+ cells and effective and selective treatment of GvHD. Immunization against HSV-TK was observed in 7 patients but did not preclude an effective GvL. These data validate the feasibility, safety, and efficacy of TK+ cells in the context of allografting and represent the basis for a broader application of this technology. The extensive exploitation of the antitumor effect of donor lymphocytes infused after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is limited by the risk of graft-versus-host disease (GvHD). To overcome this limitation, we investigated the therapeutic potential of donor lymphocytes engineered with the suicide gene thymidine kinase of herpes simplex virus (TK) in 23 patients experiencing recurrence of hematologic malignancies after allo-HSCT. Long-term follow-up of infused patients included analysis of engraftment of genetically engineered lymphocytes, in vivo assessment of antitumor effect, and control of GvHD by ganciclovir. All 17 patients evaluable for engraftment and graft-versus-leukemia (GvL) had circulating TK+ cells detectable beginning at a median time of 18 days. Eleven patients (65%) experienced a substantial clinical benefit resulting in 6 (35%) complete remissions and 5 (29%) partial responses. The antitumor effect tightly correlated with the in vivo received ganciclovir, resulting in elimination of TK+ cells and effective and selective treatment of GvHD. Immunization against HSV-TK was observed in 7 patients but did not preclude an effective GvL. These data validate the feasibility, safety, and efficacy of TK+ cells in the context of allografting and represent the basis for a broader application of this technology.
- Published
- 2007
71. Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy
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Edward Kanfer, E. Nadal, Richard Szydlo, Eduardo Olavarria, Marco Bua, Maria Paola Simula, David Marin, Jane F. Apperley, Francesco Dazzi, Jaspal Kaeda, John M. Goldman, Sarah Marktel, Amin Rahemtulla, and Claudio Fozza
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Lymphocyte ,medicine.medical_treatment ,Graft vs Host Disease ,Donor lymphocyte infusion ,Recurrence ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,Humans ,Medicine ,Hematology ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Immunotherapy ,Effective dose (pharmacology) ,Histocompatibility ,Regimen ,medicine.anatomical_structure ,Lymphocyte Transfusion ,Acute Disease ,Immunology ,business - Abstract
Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3(+) cell doseor =10(7)/kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility.
- Published
- 2007
72. Post-transplantation Cyclophosphamide and Sirolimus after Haploidentical Hematopoietic Stem Cell Transplantation Using a Treosulfan-based Myeloablative Conditioning and Peripheral Blood Stem Cells
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Giorgia Levati, Matteo Carrabba, Chiara Bonini, Luca Vago, Fabio Giglio, Fabio Ciceri, Lara Crucitti, Francesca Lorentino, Andrea Assanelli, Laura Bellio, Raffaella Milani, Sarah Marktel, Massimo Bernardi, Maria Teresa Lupo Stanghellini, Consuelo Corti, Raffaella Greco, Tiago De Freitas, Nicoletta Cieri, Jacopo Peccatori, Mara Morelli, Cieri, N, Greco, R, Crucitti, L, Morelli, M, Giglio, F, Levati, G, Assanelli, A, Carrabba, Mg, Bellio, L, Milani, R, Lorentino, F, Lupo Stanghellini, Mt, De Freitas, T, Marktel, S, Bernardi, M, Corti, C, Vago, L, Bonini, MARIA CHIARA, Ciceri, Fabio, and Peccatori, J.
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,Cyclophosphamide ,Haploidentical transplantation ,Post transplantation cyclophosphamide ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Treosulfan ,Peripheral Blood Stem Cells ,Disease-Free Survival ,Cohort Studies ,Young Adult ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Transplantation, Homologous ,Post-transplantation cyclophosphamide ,Busulfan ,Aged ,Aged, 80 and over ,Sirolimus ,Peripheral Blood Stem Cell Transplantation ,Transplantation ,Antibiotics, Antineoplastic ,business.industry ,Myeloablative conditioning ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Myeloablative Agonists ,Allogeneic stem cell transplantation ,Treatment Outcome ,surgical procedures, operative ,medicine.anatomical_structure ,Immunology ,Female ,Bone marrow ,business ,medicine.drug - Abstract
Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) grafts and post-transplantation cyclophosphamide (PTCy) has gained much interest for the excellent toxicity profile after both reduced-intensity and myeloablative conditioning. We investigated, in a cohort of 40 high-risk hematological patients, the feasibility of peripheral blood stem cells grafts after a treosulfan-melphalan myeloablative conditioning, followed by a PTCy and sirolimus-based graft-versus-host disease (GVHD) prophylaxis (Sir-PTCy). Donor engraftment occurred in all patients, with full donor chimerism achieved by day 30. Post-HSCT recovery of lymphocyte subsets was broad and fast, with a median time to CD4 > 200/mu L of 41 days. Cumulative incidences of grade II to IV and III-IV acute GVHD were 15% and 7.5%, respectively, and were associated with a significant early increase in circulating regulatory T cells at day 15 after HSCT, with values < 5% being predictive of subsequent GVHD occurrence. The 1-year cumulative incidence of chronic GVHD was 20%. Nonrelapse mortality (NRM) at 100 days and 1 year were 12% and 17%, respectively. With a median follow-up for living patients of 15 months, the estimated 1-year overall and disease-free survival (DFS) was 56% and 48%, respectively. Outcomes were more favorable in patients who underwent transplantation in complete remission (1-year DFS 71%) versus patients who underwent transplantation with active disease (DFS, 34%; P = .01). Overall, myeloablative haploidentical HSCT with peripheral blood stem cells (PBSC) and Sir-PTCy is a feasible treatment option: the low rates of GVHD and NRM as well as the favorable immune reconstitution profile pave the way for a prospective comparative trial comparing BM and PBSC in this specific transplantation setting. (C) 2015 American Society for Blood and Marrow Transplantation.
- Published
- 2015
73. Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors
- Author
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Jacopo Peccatori, Sven Olek, Luca Vago, A Lorusso, Lara Crucitti, Francesco Locatelli, Massimo Bernardi, Consuelo Corti, Maddalena Noviello, M. Tassara, Giacomo Oliveira, Sarah Marktel, Andrea Assanelli, Daniela Clerici, Fabio Giglio, Matteo Carrabba, Alessandra Forcina, Elena Guggiari, Maria Grazia Roncarolo, Francesca Patriarca, Katharina Fleischhauer, Marco Zecca, Alessandro Crotta, Sara Mastaglio, Alessandra Ferraro, Chiara Messina, Chiara Bonini, Fabio Ciceri, Roberto Crocchiolo, Manuela Battaglia, Attilio Bondanza, Maria Rosaria Carbone, Claudio Bordignon, Francesca Lunghi, Magda Marcatti, Silvano Rossini, Maria Teresa Lupo Stanghellini, Peccatori, J, Forcina, A, Clerici, D, Crocchiolo, R, Vago, L, Stanghellini, Mt, Noviello, M, Messina, C, Crotta, A, Assanelli, A, Marktel, S, Olek, S, Mastaglio, S, Giglio, F, Crucitti, L, Lorusso, A, Guggiari, E, Lunghi, F, Carrabba, M, Tassara, M, Battaglia, MARCO MARIA, Ferraro, A, Carbone, Mr, Oliveira, G, Roncarolo, Mg, Rossini, S, Bernardi, M, Corti, C, Marcatti, M, Patriarca, F, Zecca, M, Locatelli, F, Bordignon, Claudio, Fleischhauer, K, Bondanza, Attilio, Bonini, MARIA CHIARA, and Ciceri, Fabio
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Male ,Cancer Research ,Transplantation Conditioning ,Neutrophils ,medicine.medical_treatment ,T-Lymphocytes ,Medizin ,Administration, Oral ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,T-Lymphocytes, Regulatory ,Antibodies, Monoclonal, Murine-Derived ,immune system diseases ,HLA Antigens ,Prospective Studies ,Child ,Hematology ,Middle Aged ,Tissue Donors ,Fludarabine ,surgical procedures, operative ,medicine.anatomical_structure ,sirolimus ,Treatment Outcome ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Oncology ,Female ,Rituximab ,Immunosuppressive Agents ,Vidarabine ,medicine.drug ,Adult ,Blood Platelets ,Platelet Engraftment ,Adolescent ,T cells ,graft-versus-host ,chemical and pharmacologic phenomena ,Treosulfan ,Young Adult ,medicine ,Humans ,Busulfan ,Aged ,Antilymphocyte Serum ,Sirolimus ,Peripheral Blood Stem Cell Transplantation ,business.industry ,Mycophenolic Acid ,medicine.disease ,Graft-versus-host disease ,Immunology ,Bone marrow ,business - Abstract
Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts. Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients’ bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II–IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transplant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus– mycophenolate–ATG-F–rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.
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- 2015
74. Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation
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Chiara Bonini, Raffaella Greco, Francesca Lunghi, Maddalena Noviello, Beatrice Claudia Cianciotti, Sarah Marktel, Giacomo Oliveira, Fabio Ciceri, Veronica Valtolina, Jacopo Peccatori, Nicoletta Cieri, Luca Vago, Attilio Bondanza, Laura Bellio, Mattia Forcato, Cristian Taccioli, Claudio Bordignon, Silvio Bicciato, Cieri, N., Oliveira, G., Greco, R., Forcato, M., Taccioli, C., Cianciotti, B., Valtolina, V., Noviello, M., Vago, L., Bondanza, Attilio, Lunghi, F., Marktel, S., Bellio, L., Bordignon, Claudio, Bicciato, S., Peccatori, J., Ciceri, Fabio, and Bonini, MARIA CHIARA
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Homologous ,Adult ,medicine.medical_treatment ,Cellular differentiation ,T-Lymphocytes ,Immunology ,Blood Donors ,T-Cell Antigen Receptor Specificity ,Hematopoietic stem cell transplantation ,Biology ,Biochemistry ,Immune system ,Antigen ,medicine ,Humans ,Transplantation, Homologous ,Lymphopoiesis ,Antigens ,Cell Proliferation ,Transplantation ,Medicine (all) ,T-cell receptor ,Hematopoietic Stem Cell Transplantation ,Interleukin ,Cell Differentiation ,Hematology ,Cell Biology ,Antigens, CD31 ,Haplotypes ,Immunologic Memory ,Platelet Endothelial Cell Adhesion Molecule-1 ,hematopoietic stem cell transplantation ,CD31 ,memory stem T cell - Abstract
Memory stem T cells (TSCM) have been proposed as key determinants of immunologic memory. However, their exact contribution to a mounting immune response, as well as the mechanisms and timing of their in vivo generation, are poorly understood. We longitudinally tracked TSCM dynamics in patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), thereby providing novel hints on the contribution of this subset to posttransplant immune reconstitution in humans. We found that donor-derived TSCM are highly enriched early after HSCT. We showed at the antigen-specific and clonal level that TSCM lymphocytes can differentiate directly from naive precursors infused within the graft and that the extent of TSCM generation might correlate with interleukin 7 serum levels. In vivo fate mapping through T-cell receptor sequencing allowed defining the in vivo differentiation landscapes of human naive T cells, supporting the notion that progenies of single naive cells embrace disparate fates in vivo and highlighting TSCM as relevant novel players in the diversification of immunological memory after allogeneic HSCT. Memory stem T cells (TSCM) have been proposed as key determinants of immunologic memory. However, their exact contribution to a mounting immune response, as well as the mechanisms and timing of their in vivo generation, are poorly understood. We longitudinally tracked TSCM dynamics in patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), thereby providing novel hints on the contribution of this subset to post transplant immune reconstitution in humans. We found that donor-derived TSCM are highly enriched early after HSCT. We showed at the antigen specific and clonal level that TSCM lymphocytes can differentiate directly from naïve precursors infused within the graft and that the extent of TSCM generation might correlate with interleukin 7 serum levels. In vivo fate mapping through T-cell receptor sequencing allowed defining the in vivo differentiation landscapes of human naïve T cells, supporting the notion that progenies of single naive cells embrace disparate fates in vivo and highlighting TSCM as relevant novel players in the diversification of immunological memory after allogeneic HSCT.
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- 2015
75. Plerixafor on demand in ten healthy family donors as a rescue strategy to achieve an adequate graft for stem cell transplantation
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Salvatore, Gattillo, Sarah, Marktel, Lorenzo, Rizzo, Simona, Malato, Lucia, Malabarba, Milena, Coppola, Andrea, Assanelli, Raffaella, Milani, Tiago, De Freitas, Consuelo, Corti, Laura, Bellio, and Fabio, Ciceri
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Adult ,Male ,Parents ,Benzylamines ,Graft vs Host Disease ,Pain ,Antigens, CD34 ,Cyclams ,Lenograstim ,Colony-Forming Units Assay ,Heterocyclic Compounds ,Granulocyte Colony-Stimulating Factor ,Living Donors ,Humans ,Leukapheresis ,Carcinoma, Renal Cell ,Aged ,Peripheral Blood Stem Cell Transplantation ,Siblings ,Graft Survival ,Drug Synergism ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Allografts ,Hematopoietic Stem Cells ,Hematopoietic Stem Cell Mobilization ,Kidney Neoplasms ,Recombinant Proteins ,Blood Cell Count ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Female - Abstract
In allogeneic hematopoietic stem cell (HSC) transplantation, the collection of an appropriate number of HSCs while maintaining a high level of safety for healthy donors is fundamental. Inadequate HSC mobilization can be seen with the standard use of granulocyte-colony-stimulating (G-CSF). Plerixafor (PL) is a chemokine receptor CXC Type 4-stromal-derived factor 1 inhibitor; its HSC-mobilizing properties are synergistic with G-CSF in poor mobilizing patients. The use of PL as adjuvant or alternative to G-CSF in healthy donors has shown a good safety profile but is so far off-label.We report 10 healthy HSC donors treated with PL because of insufficient response to G-CSF alone or contraindication to G-CSF. Eight donors did not mobilize enough CD34+ cells with G-CSF alone because poor mobilizers or because insufficient HSCs were harvested according to the clinical need of the patient; in two cases G-CSF administration and marrow harvest were unfeasible or contraindicated in the donor.The use of PL for mobilization increased the number of circulating CD34+ cells by 2.8-fold and the CD34+/kg collection by 3.0-fold. Only mild adverse events were reported (bone pain or discomfort) and not univocally attributable to PL. Rate of engraftment and graft-versus-host disease were similar to those seen in recipients of grafts from G-CSF only-mobilized donors.We exposed 10 allogeneic donors to mobilization with PL. PL was well tolerated in all cases and ensured procurement of an adequate graft for transplantation resulting in a normal hematopoietic engraftment.
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- 2014
76. Secondary SOLID Tumors after Allogeneic STEM CELL Transplantation: A CROSS-Sectional Evaluation in 260 Adults at 1-Year Follow-up
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Margherita Brambilla, Francesca Lorentino, Serena Dalto, Sara Mastaglio, Massimo Bernardi, Jacopo Peccatori, Francesca Lunghi, Sarah Marktel, Daniele Mannina, Elisa Sala, Fabio Giglio, Ambra Malerba, Luca Vago, Mara Morelli, Matteo Carrabba, Magda Marcatti, Maria Chiara Bonini, Francesca Pavesi, Fabio Ciceri, Simon Piemontese, Raffaella Greco, Consuelo Corti, Andrea Assanelli, Maria Teresa Lupo-Stanghellini, Carlo Messina, Elena Guggiari, Lupo-Stanghellini, Mt, Assanelli, A, Greco, R, Giglio, F, Mastaglio, S, Morelli, M, Pavesi, F, Sala, E, Brambilla, M, Piemontese, S, Vago, L, Messina, C, Dalto, Sc, Lorentino, F, Mannina, D, Malerba, A, Marcatti, M, Guggiari, E, Marktel, S, Carrabba, Mg, Lunghi, F, Bernardi, M, Bonini, Mc, Corti, C, Peccatori, J, and Ciceri, F
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Transplantation ,medicine.medical_specialty ,business.industry ,medicine ,1 year follow up ,Hematology ,Stem cell ,business ,Surgery - Published
- 2016
77. Treosulfan based reduced toxicity conditioning followed by allogeneic stem cell transplantation in patients with myelofibrosis
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Simone, Claudiani, Sarah, Marktel, Simona, Piemontese, Andrea, Assanelli, Maria Teresa, Lupo-Stanghellini, Matteo, Carrabba, Elena, Guggiari, Fabio, Giglio, Tiago, De Freitas, Magda, Marcatti, Massimo, Bernardi, Consuelo, Corti, Jacopo, Peccatori, Francesca, Lunghi, and Fabio, Ciceri
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Male ,Transplantation Conditioning ,Middle Aged ,Allografts ,Disease-Free Survival ,Survival Rate ,Primary Myelofibrosis ,Humans ,Female ,Unrelated Donors ,Busulfan ,Vidarabine ,Aged ,Stem Cell Transplantation - Abstract
Allogeneic transplantation is the only potentially curative strategy for myelofibrosis, even in the era of new drugs that so far only mitigate symptoms. The choice to proceed to allogeneic transplantation is based on several variables including age, disease phase, degree of splenomegaly, donor availability, comorbidities and iron overload. These factors, along with conditioning regimen and time to transplantation, may influence the outcome of ASCT. We report 14 patients affected by myelofibrosis with a median age of 57 years (range, 41-76) receiving a treosulfan-fludarabine based reduced toxicity conditioning. Patients (pts) received a stem cell transplantation from an HLA identical (n = 10) or matched unrelated donor (n = 4). All pts had a complete myeloablation followed by engraftment and in 12 out of 13 evaluated pts donor chimerism was 100% at 1 month. In most cases a reduction of splenomegaly and a reduction (or resolution) of bone marrow fibrosis was observed. After a median follow-up of 39 months (range, 3-106), the 3-year probability of overall survival and disease free survival was 54 +/- 14% and 46 +/- 14%, respectively. The cumulative incidence of non-relapse mortality at 2 years was 39 +/- 15%. Causes of non-relapse mortality were: infection (n = 2), GvHD (n = 2) and haemorrhage (n = 1). We can conclude that a treosulfan and fludarabine based conditioning has a potent myeloablative and anti-disease activity although non-relapse mortality remains high in this challenging clinical setting. Copyright © 2014 John WileySons, Ltd.
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- 2014
78. Inflammation Converts Human Mesoangioblasts Into Targets of Alloreactive Immune Responses: Implications for Allogeneic Cell Therapy of DMD
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Fabio Ciceri, Chiara Bonini, Mattia F. M. Gerli, Giuseppe M. Peretti, Maria Pia Cicalese, Giulio Cossu, Maddalena Noviello, Sarah Marktel, Rossana Tonlorenzi, Attilio Bondanza, Maria Rosaria Carbone, Francesco Tedesco, Sara Napolitano, Noviello, M, Tedesco, F, Bondanza, Attilio, Tonlorenzi, R, Carbone, Mr, Gerli, Mfm, Marktel, S, Napolitano, S, Cicalese, Mp, Ciceri, Fabio, Peretti, G, Cossu, G, and Bonini, MARIA CHIARA
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Stromal cell ,medicine.medical_treatment ,Cellular differentiation ,Cell- and Tissue-Based Therapy ,Biology ,Cell therapy ,Interferon-gamma ,Immune system ,Drug Discovery ,Genetics ,medicine ,Humans ,Molecular Biology ,Cells, Cultured ,Pharmacology ,Stem Cells ,Mesenchymal stem cell ,Cell Differentiation ,Stem-cell therapy ,3. Good health ,Cell biology ,Transplantation ,Muscular Dystrophy, Duchenne ,Immunology ,Molecular Medicine ,Original Article ,Stem cell - Abstract
Stem cell therapy is a promising approach to regenerate healthy tissues starting from a limited amount of self-renewing cells. Immunological rejection of cell therapy products might represent a major limitation. In this study, we investigated the immunological functional profile of mesoangioblasts, vessel-associated myogenic stem cells, currently tested in a phase 1-2a trial, active in our Institute, for the treatment of Duchenne muscular dystrophy. We report that in resting conditions, human mesoangioblasts are poorly immunogenic, inefficient in promoting the expansion of alloreactive T cells and intrinsically resistant to T-cell killing. However, upon exposure to interferon-gamma or differentiation into myotubes, mesoangioblasts acquire the ability to promote the expansion of alloreactive T cells and acquire sensitivity to T-cell killing. Resistance of mesoangioblasts to T-cell killing is largely due to the expression of the intracellular serine protease inhibitor-9 and represents a relevant mechanism of stem cell immune evasion. Stem cell therapy is a promising approach to regenerate healthy tissues starting from a limited amount of self-renewing cells. Immunological rejection of cell therapy products might represent a major limitation. In this study, we investigated the immunological functional profile of mesoangioblasts, vessel-associated myogenic stem cells, currently tested in a phase 1-2a trial, active in our Institute, for the treatment of Duchenne muscular dystrophy. We report that in resting conditions, human mesoangioblasts are poorly immunogenic, inefficient in promoting the expansion of alloreactive T cells and intrinsically resistant to T-cell killing. However, upon exposure to interferon-γ or differentiation into myotubes, mesoangioblasts acquire the ability to promote the expansion of alloreactive T cells and acquire sensitivity to T-cell killing. Resistance of mesoangioblasts to T-cell killing is largely due to the expression of the intracellular serine protease inhibitor-9 and represents a relevant mechanism of stem cell immune evasion.
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- 2014
79. A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease
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Chiara Bonini, Tim Clackson, Catia Traversari, Michael Z. Gilman, Daniel C. Thomis, Claudio Bordignon, Sarah Marktel, Thomis, Dc, Marktel, S, Bonini, C, Traversari, C, Gilman, M, Bordignon, C, and Clackson, T
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Time Factors ,Recombinant Fusion Proteins ,T-Lymphocytes ,Genetic enhancement ,Immunology ,Graft vs Host Disease ,Apoptosis ,Biology ,Lymphocyte Activation ,Biochemistry ,Tacrolimus Binding Proteins ,Immune system ,Transduction, Genetic ,medicine ,Humans ,Transgenes ,fas Receptor ,Organic Chemicals ,Bone Marrow Transplantation ,Gene Rearrangement ,Dose-Response Relationship, Drug ,Immunomagnetic Separation ,Cell Biology ,Hematology ,T lymphocyte ,Suicide gene ,medicine.disease ,Cross-Linking Reagents ,Retroviridae ,medicine.anatomical_structure ,Graft-versus-host disease ,Cancer research ,Bone marrow ,Stem cell - Abstract
Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. One strategy to treat GVHD is to equip donor T cells with a conditional suicide mechanism that can be triggered when GVHD occurs. The herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir system used clinically has several limitations, Including immunogenicity and cell cycle dependence. An alternative switch based on chemically inducible apoptosis was designed and evaluated, A chimeric human protein was expressed comprising an extracellular marker (Delta LNGFR), the Pas intracellular domain, and 2 copies of an FK506-binding protein (FKBP), Primary human T lymphocytes retrovirally transduced with this construct could be purified to homogeneity using immunomagnetic beads. Genetic integrity of the construct was ensured by redesigning repetitive sequences. Transduced T cells behaved indistinguishably from untransduced cells, retaining the ability to mount a specific; antiallogeneic immune response, However, they rapidly underwent apoptosis with the addition of subnanomolar concentrations of AP1903, a bivalent "dimerizer" drug that binds FKBP and induces Pas cross-linking, A single P-hour treatment eliminated approximately 80% of T cells, and multiple exposures induced further apoptosis. T cells were eliminated regardless of their proliferation state, suggesting that the AP1903/Fas system, which contains only human components, is a promising alternative to HSV-fk for treating GVHD, (Blood, 2001; 97:1249-1257) (C) 2001 by The American Society of Hematology.
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- 2001
80. Biomarkers Predicting Acute GvHD and Transplant Outcomes in 120 Consecutive Allogeneic HSCT Recipients
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Alessandra Forcina, Maria Teresa Lupo Stanghellini, Raffaella Greco, Sarah Marktel, Consuelo Corti, Jacopo Peccatori, Daniele Mannina, Francesca Lorentino, Tommaso Perini, Linda Cheyenne Vaccari, Fabio Giglio, Mara Morelli, Matteo Carrabba, Andrea Assanelli, Fabio Ciceri, Sara Mastaglio, Rosamaria Nitti, Simona Piemontese, Maria Chiara Barbanti, Massimo Bernardi, and Luca Vago
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medicine.medical_specialty ,Myeloid ,Multivariate analysis ,Receiver operating characteristic ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Logistic regression ,Biochemistry ,Gastroenterology ,Surgery ,Transplantation ,medicine.anatomical_structure ,Graft-versus-host disease ,Internal medicine ,Cord blood ,medicine ,Biomarker (medicine) ,business - Abstract
Background: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for many haematological diseases. Despite advances in supportive therapies, acute Graft-versus-Host Disease (aGvHD) remains the leading cause of early morbidity and mortality. There are shortcomings in the prediction of aGVHD, indicating the urgent need for non-invasive and reliable laboratory tests to allow a precision-medicine tailored prophylactic approach. Aims: We conducted a prospective observational study to ascertain the potential usefulness of the levels of eleven biomarkers, measured pre- and at +7 days post-alloHSCT, in predicting the development and severity of aGvHD in allo-HSCT patients. These time-points were chosen as early risk stratification may provide a window for additional prophylactic measures. Methods: We collected data from 120 consecutive patients (41 female and 79 male; median age 52, range 19-77 years) who underwent allo-HSCT at our institute between 2014 and 2015. Most patients were affected by myeloid malignancies (AML=52%, MDS=11%, MPN=5%) while 32% were of lymphoid origin (ALL, MM and lymphomas). Revised disease-risk index (DRI, Armand et al.) was low or intermediate for 41% of pts, high for 44% and very high for 15% of them. Most patients (n=101) received peripheral blood stem cells (PBSC). Stem cell donors were unrelated (n=39, HLA matching 9/10 in 14 and 10/10 in 25), family haploidentical (n=56), HLA-identical sibling (n=21), or cord blood (n=4). Post-transplant GvHD prophylaxis was PT-Cy-bases in 65 patients, ATG-bases in 28 patients, both agents in 18 cases whilst 9 patients received neither. Additionally, sirolimus and MMF were used as additional GvHD prophylaxis according to institutional guidelines. The following biomarkers were measured 7 days pre- and post-transplant: interleukin-6 (IL6), Ceruloplasmin(CER), Cholinesterase (CHE), Albumin, Immunoglobulin A, Gammaglutamyl-transferase (GGT), White Blood Cells, Neutrophils, Haemoglobin,Platelets and Glycaemia. ROC curves were used to define optimal cut-offs of the biochemical variables to predict 100-day severe aGvHD and 100-days TRM by logistic regression. Then cumulative incidences curves (CI) for aGvHD and TRM and overall-survival (OS) curves were computed comparing patients under and over the identified cut offs for the variables with the best reported sensitivity and specificity. Multivariate Cox proportional hazard regression was finally applied. Results: The 100-days CI of grade III-IV aGvHD was 13.5%, with a 100-days CI of TRM of 12%. The 1-year OS was 64%. Death was reported in 49 of the total 120 patients: 5/49 deaths were attributable to aGvHD. At baseline, IL6 threshold value of 2.5 pg/ml was significantly associated with the prediction of 100-days severe aGVHD (sens 65%, spec 61%) and TRM (sens 75%, spec 61%). Patients with IL-6 concentration equal or superior to 2.5 pg/ml had higher 100-days CI of severe aGvHD (16% Vs 6%, p 0,03) and TRM (12% Vs 3%, p 0,06). Interestingly, higher IL6 concentrations were associated to worse 1-year OS (42% Vs 82%, p= 129 U/l levels had higher 100-days CI of severe aGVHD (15% vs 7%, p 0,16) and TRM (13% vs 4%, p 0,01), in addition to worse OS (53% vs 71% at 1y, p 0,03). By multivariate analysis (adjusting for age, DRI, Sorror comorbidity index, type of donor, source of stem cells, and backbone of GvHD prophylaxis) pre-transplant IL6 concentrations were significantly associated to severe aGvHD (HR 3, p 0.04), TRM (HR 3, p 0.06), and OS (HR 2.6, p 0,004). Conclusion: In our series, baseline IL6 levels are predictors of aGvHD, especially with regards to grade III/IV aGvHD and translate in a higher risk of TRM and worse OS. This biomarker could be incorporated in a treatment algorithm to increase primary GvHD prophylaxis in patients at risk of severe aGVHD, potentially improving the final outcome of allo-HSCT. Disclosures Ciceri: MolMed SpA: Consultancy.
- Published
- 2016
81. Longitudinal Microbiome Profile in Allogeneic Hematopoietic Stem Cell Transplantation: Results of a Prospective Study in 100 Patients
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Alessandra Forcina, Renée Pasciuta, Mara Morelli, Massimo Clementi, Nicasio Mancini, Massimo Bernardi, Luca Vago, Andrea Assanelli, Consuelo Corti, Laura Infurnari, Jacopo Peccatori, Maria Teresa Lupo Stanghellini, Raffaella Greco, Fabio Giglio, Fabio Ciceri, Sarah Marktel, Matteo Carrabba, and Maria Chiara Barbanti
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Acute leukemia ,medicine.medical_treatment ,Immunology ,Lachnospiraceae ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biology ,medicine.disease ,Biochemistry ,Transplantation ,Sepsis ,Graft-versus-host disease ,medicine ,Microbiome ,Prospective cohort study - Abstract
BACKGROUND: Allogeneic HSCT (allo-HSCT) is the only cure for several patients with hematological malignancies. Recent advances in therapies have significantly reduced transplant-related mortality (TRM); nevertheless infections and graft-versus-host disease (GvHD) still represent major complications. Recent studies indicate that patients undergo dramatic alterations of intestinal microbiota during allo-HSCT, potentially affecting the outcome. An alarming emergence of gram-negative multi-drug-resistant (GN-MDR) pathogens has been increasingly reported from various cancer centers, and the primary site of colonization is mainly the gut. Moreover, GvHD was associated with major shifts in the composition of intestinal microbiota, able to modulate the severity of intestinal inflammation. METHODS: Between October 2014 and March 2016, we have conducted a prospective observational study to examine the intestinal microbiota by NGS techniques in 100 consecutive adult patients, who received allo-HSCT for high-risk hematological malignancies (63.5% acute leukemia). Stem cell donors were family haploidentical (n=45), HLA identical sibling (n=15), unrelated volunteer (n=35), cord blood (n=5). Stem cell source was mainly T-cell replete PBSCs. Fecal specimens have been collected before conditioning (T0), during aplasia (T10) and after engraftment (T30). The fecal microbiome have been analyzed using the 454 GS Junior System, and QIIME software. We defined a threshold of normality for the main phyla on the basis of the control. RESULTS: We observed an important difference in relative percentages of phyla populating the gut between our pts and control. Our patients showed a progressive reduction of the intestinal microbial diversity (alpha diversity) during the transplant process, with a specific decrease of anaerobic species belonging to both Bacteroidetes and Firmicutes phyla, and a relative increase of facultative anaerobic gram-positive families such as Enterococcaceae and Staphylococcaceae. A great variation was observed, particularly between T0 and T30, where we found a significant decrease in alpha diversity (p < 0.001). A significantly different distribution in the baseline microbiome was reported in patients who will experience different clinical outcomes. Patients (n=23) who developed a microbiologically-confirmed sepsis show an increase of Proteobacteria phylum (cut-off 5%; p We identified by multivariate analysis some associations between the relative increase of a specific phylum and clinical variables at baseline. Previous allo-HSCT and prior infections represented strong risk factors for developing colonization by Proteobacteria (exceeding 5%). Sepsis by GN-MDR bacteria was associated to increase in Enterobacteriaceae(exceeding 5%; p 0.011). Interestingly, significant microbioma changes were observed at 10 days after transplant, in patients who developed a subsequent acute GvHD, with a predominant role played by gram-positive bacteria belonging to Firmicutes. More in details, the presence of Lachnospiraceae was associated to a decreased risk of developing acute GvHD (p=0.04 and RR= 4.35), whereas dominance of Enterococcaceae (p CONCLUSIONS: Longitudinal study of microbioma profile allows early identification of patients at risk for major transplant-related complications such as sepsis by GN-MDR or acute GvHD, offering a new tool for individualized pre-emptive or therapeutical strategies to improve the outcome of allo-HSCT. Disclosures Ciceri: MolMed SpA: Consultancy.
- Published
- 2016
82. Haploidentical Peripheral Blood Stem Cell Transplantation after Treosulfan-Based Conditioning and Rapamycin GvHD Prophylaxis in Hodgkin Lymphoma
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Jacopo Peccatori, Mara Morelli, Serena Dalto, Chiara Bonini, Fabio Ciceri, Lorenzo Lazzari, Francesca Lorentino, Andrea Assanelli, Magda Marcatti, Maria Teresa Lupo Stanghellini, Raffaella Greco, Raffaella Milani, Michela Tassara, Sarah Marktel, and Fabio Giglio
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Oncology ,Melphalan ,medicine.medical_specialty ,business.industry ,Umbilical Cord Blood Transplantation ,Immunology ,Cell Biology ,Hematology ,Treosulfan ,medicine.disease ,Peripheral Blood Stem Cells ,Biochemistry ,Graft-versus-host disease ,Internal medicine ,medicine ,Peripheral Blood Stem Cell Transplantation ,Hodgkin lymphoma ,Gvhd prophylaxis ,business ,medicine.drug - Abstract
Patients with advanced refractory Hodgkin Lymphoma (HL) may obtain long-term cure from haploidentical SCT. We experienced a package of haploidentical peripheral blood stem cell transplantation after Treosulfan-based conditioning and Rapamycin GvHD prophylaxis. Between July 1999 and June 2016, 57 patients with classical relapsed/refractory Hodgkin Lymphoma underwent an allogeneic stem cell transplantation (alloSCT) at san Raffaele Scientific Institute in Milan (Italy). Eleven patients received a matched related donor alloSCT, 7 patients received a matched unrelated donor alloSCT, one patient underwent a double cord blood transplant and 38 patients, lacking identical related or unrelated donor, received an haploidentical transplant (haploSCT); 32 out of 38 patients underwent an unmanipulated peripheral blood stem cell transplant. This retrospective study analyzes the outcome of these 32 patients allografted after a Treosulfan based conditioning and a backbone GvHD prophylaxis with the mTOR inhibitor Rapamycin. Median age at alloSCT was 30 years; twenty patients (62,5%) had a primary refractory disease. Median number of previous lines before haploSCT was 4 (range 2-8); thirty patients (94%) received at least one or more autologous stem cell transplant and 12 of them were considered in an auto-allo program. Median time from diagnosis to haploSCT were 30 months (range 8-146). At haploSCT after receiving the last salvage treatment, 10 patients were in complete remission (CR), 6 were in partial remission (PR) and 16 patients had progressive disease (PD). A combination of Melfalan or Thiotepa or TBI4Gy to Treosulfan mieloablative conditioning regimens (MAC) were used in 16 (50%) patients; the others received a Treosulfan-alone based reduced intensity conditioning regimen (RIC). GvHD prophylaxis consisted of in vivo T cell depletion with pre transplant anti-Thymocyte Globulin (ATG) in 19 patient and of post transplant Cyclophosphamide (PT-Cy) in 13 patients; all patients received also Mycophenolate Mofetil till day + 30 and Rapamycin till day + 90. Median numbers of infused CD34+/Kg were 5,4 x 10^6 (range 5-5,8) and median numbers of infused CD3+/Kg were 2.34 x 10^8 (range 1.00-4.76). Median follow up was 46 months (range 1-109); two and 4 years Overall survival (OS) was 52% and 48% respectively, Progression Free Survival (PFS) and Relapse Incidence (RI) were 29% and 59% at both two and four years. Transplant related mortality was 9.5% at 100 days, 13% at 1 year and for the entire follow-up. The 100-day Cumulative Incidence (CI) of grade ≥ 2 and grade ≥ 3 aGvHD were 31% and 19% respectively; CI of cGvHD was 38% and CI of moderate-severe cGvHD was 27% at both a 2 and 4 years. No difference in OS, PFS, RI were found if patients were stratified according to disease status at transplant or according to the use of ATG or PT-Cy. CI of cGvHD and CI of moderate-severe cGvHD were significantly better after RIC regimens vs MAC ones (p value 0.01 and 0.001 respectively), but no difference were found between the two groups in term of OS, PFS and RI. Twelve out of twenty-two patients with active disease at haploSCT achieved a CR after transplantation and median time from aploSCT to CR was 3 months (range 2-6); six of them (4 PD and 2 PR at transplant) achieved and maintained a CR for the entire follow-up without the need for other post transplant treatment. Unmanipulated peripheral blood haploSCT after Treosulfan based conditioning regimen and GvHD prophylaxis with Rapamycin is feasible, even in heavily pretreated patients and with active disease, with acceptable toxicities. Intensification of conditioning increased the toxicities. Disease relapse or progression was the major cause of treatment failure in our series, but 22 patients (69%) had detectable disease at the time of transplant. Six out of those very poor prognosis patients (28%) achieved a long term CR. Hodgkin Lymphoma is characterized by high mTOR activity, and Rapamycin is known to inhibit in vitro and in vivo cell proliferation and to induce apoptosis in Lymphoma cells. Rapamycin in these patients could have played an important role in disease control in immediate post transplant phase by increasing the apoptotic effect of chemotherapeutic agents, until the onset of the Graft versus Lymphoma effect. Disclosures Bonini: Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Ciceri:MolMed SpA: Consultancy.
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- 2016
83. Voriconazole and Non-Melanoma Skin Cancer after Allogeneic HSCT: Results of a Prospective Dedicated Follow-up Program in 302 Patients
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Sarah Marktel, Francesca Lunghi, Fabio Ciceri, Mara Morelli, Elena Guggiari, Magda Marcatti, Sara Mastaglio, Chiara Bonini, Serena Dalto, Fabio Giglio, Elisa Sala, Matteo Carrabba, Massimo Bernardi, Jacopo Peccatori, Andrea Assanelli, Francesca Pavesi, Luca Vago, Raffaella Greco, Tommaso Perini, Simona Piemontese, Francesca Lorentino, Consuelo Corti, Stefania Girlanda, Gabriele Antonarelli, Carlo Messina, and Maria Teresa Lupo-Stanghellini
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Voriconazole ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Actinic keratosis ,Retrospective cohort study ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Surgery ,Transplantation ,Internal medicine ,medicine ,Basal cell carcinoma ,Cumulative incidence ,Skin cancer ,business ,medicine.drug - Abstract
Introduction Voriconazoleis a second-generationtriazolebroad-spectrum antifungal agent indicated in adults and children aged 2 years and above as treatment of invasive aspergillosis, treatment ofcandidaemiain non-neutropenic patients (pts), treatment of fluconazole-resistant serious invasive Candida infections, treatment of serious fungal infections caused byScedosporiumspp. and Fusarium spp. Voriconazoleis associated with a broad spectrum of dermatologically adverse reactions: it seems to be responsible for a multistep process beginning with acute and chronicphototoxicity, followed by actinic keratosis (AK), and finally skin squamous cell carcinoma (SCC), especially if therapy is maintained. Strictphotoprotectionis mandatory; drug replacement by anothertriazolemust be discussed in case of acutephototoxicity.Voriconazolemust be stopped in pts with chronicphototoxicity, and a long-term dermatologic follow-up of skin lesions is required even after withdrawal. It is now established thatvoriconazoleis an independent risk factor for the development of cutaneous malignancy in lung transplant recipients. Recently, a retrospective study from the Mayo Clinic (WojenskiDJ et al, Transplant Infectious Disease 2015, 17, 250-58) confirmed the association betweenvoriconazoleand SCC also after allo-HSCT (allogeneic hematopoietic stem cell transplantation) and identified cumulative days ofvoriconazoleas a risk factor for SCC. Methods The current study seeks to analyze the correlation betweenvoriconazoleexposure and non-melanoma skin cancer (NMSC) in our Center, where it is available an intensive dedicated follow-up after allo-HSCT to prevent and early detect second solid tumors. Results We analyze data prospectively collected at our Long-Term Follow-Up clinic between 2011 and 2016 including 302 adult pts with a minimum follow-up of 24 months. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Baseline characteristics of the 302 pts are outlined in table 1. In total, 25 pts developed NMSC - median time from allo-HSCT 42 months (range, 9 months - 20 years) - median follow-up after NMSC diagnosis 2 years (range, 2 months - 12 years). The estimated cumulative incidence of NMSC at 3 years was 3.2% and at 5 years 6.2%. At the dermatological annual evaluation 3 pts were presenting AK, only one progress to basal cell carcinoma (BCC), the 2 pts with AK are under dermatological follow-up. All pts were treated withvoriconazolefor more than 180 days. In total 19 pts were diagnosed with BCC and 6 pts with SCC. Five pts with SCC and 17 with BCC were treated withvoriconazole, overall 16/22 (4 SCC) for more than 180 days. All pts were treated according to standard practice for NMSC, unfortunately 1 pts deceased due to SCC progression. Only 2 pts were diagnosed and treated for NMSC before transplantation. Six pts had antecedent acute GvHD and 8 pts had antecedent moderate to severe chronic GvHD. History ofvoriconazoleexposure, cumulative days ofvoriconazoleuse, gender, age at transplant, TBI based conditioning regimen, acute/chronic GvHD and skin cancer pre-transplant were considered for analysis. Age at transplant above 48 years (p Conclusions Our experience confirms the correlation betweenvoriconazoleand occurrence of NMSC after allo-HSCT. Incidence of NMSC is higher than previously reported in registry reports, and the occurrence of NMSC in pts exposed tovoriconazoleseems to be precocious. This observation confirms the relevance of counseling and prevention of NMSC in patients benefiting fromvoriconazoleas a crucialmold-active antifungal prophylaxis and treatment. Disclosures Bonini: Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Ciceri:MolMed SpA: Consultancy.
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- 2016
84. Post-Transplant Treatment with Ponatinib for Patients with High-Risk Philadelphia Chromosome Positive Leukemia
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Massimo Bernardi, Luca Vago, Tommaso Perini, Chiara Bonini, Serena Dalto, Fabio Ciceri, Elisa Sala, Maria Teresa Lupo-Stanghellini, Raffaella Greco, Francesca Pavesi, Carlo Messina, Francesca Lunghi, Andrea Assanelli, Matteo Carrabba, Magda Marcatti, Elena Guggiari, Francesca Lorentino, Sarah Marktel, Fabio Giglio, Sara Mastaglio, Jacopo Peccatori, Daniele Mannina, Mara Morelli, Simona Piemontese, and Consuelo Corti
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Oncology ,Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Ponatinib ,Imatinib ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Treosulfan ,medicine.disease ,Biochemistry ,Surgery ,Transplantation ,Dasatinib ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,business ,Progressive disease ,medicine.drug - Abstract
Introduction Tyrosine kinase inhibitor (TKi) has become the standard of care in patients (pts) with chronic myeloid leukemia (CML) and an unavoidable tool in the combined therapy for pts with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Nevertheless, because of resistance to TKI and side-effects, allogeneic stem cell transplantation (HSCT) remains the standard therapy of ALL Ph+ and of CML pts failing 1st line therapy with TKi, with failure or insufficient response or intolerance or mutations resistant to 2nd generation TKI, or in the advanced phase at diagnosis (accelerated phase and blast crisis). Unfortunately, despite greater remission with the use of TKi pre-transplant, HSCT transplant outcome have not improved largely due to high incidence of relapse after transplant. In the past decade several multi-institutional studies confirmed the feasibility and safety of post-HSCT imatinib administration as prophylactic or therapeutic strategy. Second and 3rd generation TKi administration after HSCT - targeting mutational status and according to pre-HSCT activity - is today under investigation. Methods Here we are reporting our experience in post-HSCT treatment with the 3rd generation TKi ponatinib in 5 pts (4 CML, 1 ALL Ph+) treated between 2011 and 2016 at our Institution. Pts data and information were collected from Institutional database and chapters revision. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Results Pts and diseases features are reported in table 1. Stem cell source was peripheral blood in all cases, 3 pts were transplanted from a family mismatched donor (haplo), 1 from a family matched donor, 1 from a matched unrelated donor (MUD). The 3 haplo-transplanted pts previously underwent a MUD HSCT. All pts received a treosulfan based conditioning regimen and GvHD prophylaxis consisted on co-administration of MMF and rapamycin. Pre-transplant treatment for the ALL Ph+ consisted of chemotherapy combined with dasatinib, followed by a first MUD HSCT and dasatinib in maintenance. The patient relapsed 1 year after HSCT with documentation of mutation V299L. Ponatinib was introduced as salvage treatment to bridge second haplo HSCT. Pre-transplant treatment for the CML patients consisted of TKi therapy with combination of chemotherapy in case of uncontrolled progression of disease. Two pts received a first MUD HSCT but relapsed respectively 5 months and 4 years later. Four pts received ponatinib 45 mg daily before the last HSCT: one patient achieved sustained major molecular response, 3 pts obtained transient response. All pts were presenting 2nd generation TKi resistant mutation (ref table 1). Ponatinib was started at a median time of 157 days after HSCT (range, 117-583): in 3 cases as salvage treatment in overt relapse, while in one case as prophylaxis and one case as preemptive therapy. Acute GvHD was diagnosed in 4 pts before ponatinib administration, 2 of them also experienced chronic GvHD. No new cases of GvHD were observed after initiation of ponatinib. Immunosuppressive treatment and azoles treatment were discontinued before ponatinib in all but one patient who was under combined treatment for chronic GvHD: therapeutic drug monitoring was closely performed without evidence drug-drug interaction. Pts were regularly evaluated for toxicities. No serious adverse events were reported in our experience: we administered ponatinib at a median maximum dosage of 30 mg daily (range, 15-45 mg), for a median of 24 weeks (range, 4 - 116 weeks). Two pts required anti hypertension drugs. One patient was closely monitored for multifactorial liver cholestasis never requiring ponatinib discontinuation. At last evaluation one patient maintained the status of molecularly undetectable leukemia (follow-up post HSCT 30 months) and two pts obtained molecular response (follow-up post HSCT 25 months and 5 months). Two patients who received therapeutic ponatinib in overt relapse didn't respond and died for progressive disease. Conclusions Ponatinib is safe and well tolerated as bridge to HSCT and to maintain the disease control after transplant. Prophylaxis targeted therapy and pre-emptive therapy with ponatinib may lead the reduction of disease relapse for high-risk Ph+ leukemia. Disclosures Bonini: Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Ciceri:MolMed SpA: Consultancy.
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- 2016
85. Disease Risk Index (DRI) Score Stratification and Composite End-Point GvHD-Free Relapse-Free Survival (GRFS) May Optimize Transplant Decision-Making Process in Haploidentical Stem Cell Transplantation
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Francesca Pavesi, Serena Dalto, Matteo Carrabba, Francesca Lorentino, Sarah Marktel, Fabio Giglio, Jacopo Peccatori, Fabio Ciceri, Gabriele Antonarelli, Tommaso Perini, Alessandra Forcina, Elisa Sala, Andrea Assanelli, Consuelo Corti, Massimo Bernardi, Sara Mastaglio, Luca Vago, Simona Piemontese, Elena Guggiari, Mara Morelli, Raffaella Greco, Francesca Lunghi, Magda Marcatti, and Maria Teresa Lupo-Stanghellini
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Oncology ,medicine.medical_specialty ,Allogeneic transplantation ,Cyclophosphamide ,Proportional hazards model ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Transplant-Related Mortality ,Hematopoietic stem cell transplantation ,Biochemistry ,Transplantation ,Internal medicine ,medicine ,Cumulative incidence ,Risk assessment ,business ,medicine.drug - Abstract
Introduction Pre-transplant risk assessment is a crucial issue to improve the HCT decision-making process. Several transplant-related models have been designed to optimize decision-making about suitable candidates for allogeneic HCT. The refined Disease Risk Index (DRI) was developed to stratify disease risk acrosshistologiesand HCT regimens. However, few recipients of haploidentical HCT were originally included in the DRI study cohorts. In 2015 a first large cohort of non-myeloablativehaploidentical HCT with post-transplant cyclophosphamide (PTCy) confirmed the validity of DRI also in this setting. Beside this, in the past few years the novel composite end point of GVHD-free, relapse-free survival (GRFS) after HCT spreads out. GRFS acknowledge that both survival and rates of grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death are clinically meaningful. GRFS therefore represents ideal recovery from HCT and a measure of cure without ongoing morbidity. Methods We analyzed risk-stratified GRFS according to the refined DRI in haploidentical HCT at our Center, where it was exploited - since 2006 - asirolimus-based,calcineurininhibitor-free prophylaxis of GvHD to allow the safe infusion of unmanipulated haploidentical HCT. We analyze data collected between 2006 and 2014 including 207 adult pts. Data were prospectively collected in Institutional database. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. All consecutive pts receiving a haplo HCT as 1st allogeneic transplantation were included - pts receiving haplo HCT as 2nd or 3rd HCT were excluded from the present analysis. Results Baseline characteristics of the 207 pts are outlined in table 1. With 4-year median follow-up, 4-year probabilities of transplant related mortality (TRM),relapse, progression-free survival (PFS), and overall survival (OS) were 25,8%, 42,5%, 31,7%, and 34,4%, respectively. Day-100 cumulative incidence of grade II-IV and III-IV acute graft-versus-host-disease (GvHD) were 30,1% and 15,5% respectively. The 4-year cumulative incidence of chronic GvHD was 33,5% (moderate-severe chronic GvHD 26,2%). Considering the composite end point of GRFS, for the entire population the 4-year GRFS was 17,8%. By refined DRI group, low-intermediate (n 69), high (n 105), and very high (n 33) risk groups had 4-year GRFS estimates of 31,1%, 13,7%, and 3,0% (p < .0001), with corresponding 4-year OS estimates of 56,7%, 28,9%, and 6,1% (p < .0001). On a multivariable Cox model we considered as covariates age, host/donor sex mismatch, host/donor CMV status, stem cell source, conditioning intensity, GvHD prophylaxis ATG-based versusPTCy-based, DRI stratification, HCT Comorbidity Index Score (HCT-CI). On multivariable analyses, the DRI was statistically significantly associated with GRFS, OS, PFS, relapse, TRM and grade II to IV acute GvHD (ref table 2). HCT-CI was statistically significantly associated with GRFS, OS, PFS and TRM. Conditioning intensity was associated with PFS and relapse, while GvHD prophylaxis (PTCyvs ATG) was only associated with OS. Interestingly no risk factors were clearly emerging for chronic GvHD. Conclusions The combination of a refined DRI and GRFS provide a valid tool to improve the HCT decision-making process and will help optimize patient outcomes. Disclosures Ciceri: MolMed SpA: Consultancy.
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- 2016
86. HHV6 Specific T-Cells Are Predictive Biomarker of Active HHV6 Infection after Allogeneic Hematopoietic Stem Cell Transplantation: Results of a Prospective Study in 213 Patients
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Mara Morelli, Massimo Bernardi, Veronica Valtolina, Luca Vago, Lara Crucitti, Massimo Clementi, Jacopo Peccatori, Maddalena Noviello, Sarah Marktel, Fabio Giglio, Daniele Mannina, Mattia Pozzato, Chiara Bonini, Andrea Assanelli, Alessandra Forcina, Serena Rolla, Matteo Carrabba, Sara Racca, Maria Chiara Barbanti, Consuelo Corti, Fabio Ciceri, Maria Teresa Lupo Stanghellini, and Raffaella Greco
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Acute leukemia ,Univariate analysis ,biology ,business.industry ,ELISPOT ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,biology.organism_classification ,medicine.disease ,Biochemistry ,Graft-versus-host disease ,Cord blood ,Medicine ,Human herpesvirus 6 ,business ,Viral load - Abstract
BACKGROUND: Although Human herpesvirus 6 (HHV6) reactivation in healthy individuals usually occurs without significant morbidity, in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with severe clinical manifestations and increased transplant-related mortality (TRM). The role of HHV6 in transplant-related complications remains in question, considering that both latent and active viral infection can occur. Moreover, only limited experiences are reported on HHV6-specific immune responses after HSCT, and their correlation with clinical outcome is largely unexplored. METHODS: From February 2013 to October 2015, we conducted a prospective observational study to investigate HHV6 reactivation in 213 consecutive adult patients (median age 52 years) who received allo-HSCT for high-risk hematological malignancies (57% acute leukemia) in our institute. Stem cell donors were family haploidentical (104), HLA identical sibling (39), unrelated (63), cord blood (7). Stem cell source was mainly T-cell replete PBSCs (87%). Viral load was weekly monitored by quantitative PCR in plasma within the first month after HSCT. Numbers of IFNγ-producing HHV6-T-cells were determined by enzyme-linked immunospot assay (ELISPOT). We challenged patients PBMC against a library of overlapping peptides covering the entire sequence of the immunodominant virus protein U54, expressed during the lytic cycle of virus replication. Patients were evaluated at a median of 34 days after HSCT (HHV6-; 57 patients) for controls or by the 4th day after the first HHV6 DNAemia (median 32 days) for reactivating patients (HHV-6+; 54 patients). RESULTS: HHV6-reactivation occurred in 56% of patients at 100 days, with a median time of 28 days after HSCT. HHV6 was detected in plasma for 86% of patients, while 33% resulted positive in other materials: 9 BM aspirates, 39 gut biopsies, 3 BAL, 5 CSF. All patients received acyclovir as prophylaxis. Only 41% of reactivating patients presented a clinically relevant HHV6 infection (HHV6 positivity in presence of HHV6-related clinical symptoms and/or HHV6-disease). Clinical manifestations were: fever (25), skin rash (37), hepatitis (19), diarrhoea (28), encephalitis (5), BM suppression (30). According to center guidelines, antiviral treatment was given in 23% of reactivating patients, for uncontrolled clinically relevant HHV6 infection. Overall survival (OS) was not different in HHV6 reactivating patients compared to controls (p=0,2). Relapse incidence and TRM were not affected by HHV6. All HSCT recipients showed a better OS with CD3+ cells≥200/mcl at 30 days (p The number of IFNγ-producing HHV6-specific T-cells was significantly higher in HHV6 reactivating patients (p= 0.0149; mean number of specific T-cells 43.48 per 10^5 PBMC) than in non-reactivating patients (specific T-cells 12.57 per 10^5 PBMC), especially in the presence of active and clinically relevant HHV6 infection (p CONCLUSIONS: In this study, we observed that active disease status before HSCT, haploidentical donors, especially using PT-Cy, CMV reactivation, GvHD and lower CD3+ counts at 30 days, are strong predictors of HHV6 reactivation. HHV6-specific T-cells, detectable by ELISPOT assay despite extremely low T-cell numbers and immunosuppressive therapy, are significantly associated with active and clinically relevant HHV6 infections, representing a new and promising tool to unravel the role of HHV6 positivity in allo-HSCT recipients. Disclosures Ciceri: MolMed SpA: Consultancy. Bonini:TxCell: Membership on an entity's Board of Directors or advisory committees; Molmed SpA: Consultancy.
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- 2016
87. Human CD34+ Cells from Different Sources Disclose a Specific Stemness Signature
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Maria Rosa Lidonnici, Marta Claudia Frittoli, Matilde Zambelli, Giuliana Ferrari, Giacomo Mandelli, Annamaria Aprile, Bernhard Gentner, Fabio Ciceri, Maria Domenica Cappellini, Ylenia Paleari, Sarah Marktel, Antonello E. Spinelli, Laura Zanaboni, Elena Cassinerio, Cristina Parisi, and Laura Bellio
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0301 basic medicine ,biology ,Plerixafor ,Immunology ,Hematopoietic stem cell ,Cell Biology ,Hematology ,Biochemistry ,CXCR4 ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,medicine ,biology.protein ,Stromal cell-derived factor 1 ,Bone marrow ,Progenitor cell ,Stem cell ,Homing (hematopoietic) ,medicine.drug - Abstract
Over the past decades outcomes of clinical hematopoietic stem cell transplants have established a clear relationship between the sources of hematopoietic stem cells (HSCs) infused and their differential homing and engraftment properties. For a long time, bone marrow (BM) harvest has been the preferred source of hematopoietic stem and progenitor cells (HSPCs) for hematopoietic reconstitution following myeloablative conditioning regimen. At present, mobilized peripheral blood (PB) is commonly used for hematopoietic cells transplantation in both adults and children, particularly in the autologous setting, and it has progressively replaced BM as the source of HSCs.HSCs are maintained in their niche by binding to cellular determinants through adhesion molecules and diverse strategies are currently used to promote their egress from BM to PB. Traditionally, the growth factor granulocyte-colony stimulating factor (G-CSF) represents the gold standard agent to mobilize HSPCs for transplantation. Nevertheless, other compounds have been recently tested. One of the most successful mobilizing agents is Plerixafor (AMD3100, Mozobil™), a bicyclam molecule that selectively and reversibly antagonizes the binding of stromal cell derived factor-1 (SDF-1), located on the surface of BM stromal cells and osteoclasts, to chemokine CXC-receptor-4 (CXCR4), located on the surface of HSPCs, with the subsequent mobilization in the blood. The use of this drug is currently approved by FDA and EMA in combination with G-CSF, in patients affected by lymphoma or multiple myeloma whose cells mobilize poorly with G-CSF alone. Clinical trials demonstrated that Plerixafor alone safely and rapidly mobilizes HSCs also in healthy donors, beta-thalassemia patients and pediatric patients affected by malignancies. Previous characterization studies on non-human primates and human samples of Plerixafor mobilized cells in comparison to cells mobilized by G-CSF alone or in combination with Plerixafor showed a different expression profile, cell composition and engrafting potential in a xenotransplant model. From these studies remains unsolved whether Plerixafor, G-CSF, or their combination mobilizes different primitive HSC populations, defined both by multimarker immunophenotype and in vivo functional analysis. In the present study we investigated by controlled comparative analysis the functional and molecular hallmarks of human HSCs collected from BM, G-CSF and/or Plerixafor mobilized peripheral blood. We show that Plerixafor alone mobilizes preferentially long-term hematopoietic stem cells (LT-HSCs), defined as CD34+CD38/lowCD90+CD45RA-CD49f+ cells and primitive populations of HSCs. These cells possess higher ability to home to hematopoietic niches and engraft in NOD/SCID/IL2rγnull (NSG) mice, resulting in enriched scid-repopulating cell frequency, in comparison to other sources. The higher content of CXCR4+ and CD49f+ cells correlates with this feature. Furthermore, global gene expression profiling highlights the superior in vivo reconstitution activity of Plerixafor mobilized cells. The "stemness" signature of cells dislodged from their niche by the drug is attenuated by the combined use with G-CSF, which emphasizes the gene expression profile induced by G-CSF treatment. These data indicate that a qualitative advantage accounts for the superior performance of Plerixafor mobilized cells. These findings provide the rationale for using a suboptimal dose of more primitive HSCs when target cell number for transplantation is limited, or when G-CSF mobilization is too risky like in sickle cell anemia patients. Moreover, CD34+ cells mobilized by Plerixafor alone or with the combination of G-CSF are efficiently transduced by a lentiviral vector encoding for human ß-globin gene (GLOBE LV) and are able to engraft and differentiate in vivo, supporting their use for gene therapy applications. Disclosures Ciceri: MolMed SpA: Consultancy.
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- 2016
88. Incremental Innovation of Ex Vivo Hematopoietic Stem Cell Engineering to Expand Clinical Gene Therapy Applications
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Giuliana Ferrari, Carolina Petrillo, Maria Rosa Lidonnici, Sarah Marktel, Fabio Ciceri, Anna Kajaste-Rudnitski, Oriana Meo, Samantha Scaramuzza, Erika Zonari, Luigi Naldini, Bernhard Gentner, Giacomo Desantis, and Alessandro Aiuti
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Immunology ,CD34 ,Hematopoietic stem cell ,Cell Biology ,Hematology ,CD38 ,Biology ,Biochemistry ,Haematopoiesis ,medicine.anatomical_structure ,NSG mouse ,medicine ,Cancer research ,Stem cell ,Progenitor cell ,Ex vivo - Abstract
Transplantation of genetically engineered, autologous hematopoietic stem and progenitor cells (HSPC) is becoming a promising alternative to allogeneic stem cell transplantation for curing genetic diseases, avoiding the risks of graft versus host disease and prolonged immunosuppression. Most clinical gene therapy protocols are based on CD34+ HSPC engineered during >2 days of ex vivo culture. By xenotransplanting mobilized peripheral blood (mPB) CD34+ HSPC, which were lentivirally (LV) marked with different fluorescent proteins according to CD38/CD90 expression levels allowing quantitative assessment of the contribution of CD38/CD90 subpopulations to hematopoietic reconstitution (n=48 NSG mice, 3 experiments), we identified 2 distinct waves of reconstitution: (1) short term repopulation (up to 2 months) mostly driven by CD34+CD38intCD90+/- cells and (2) long-term repopulation driven by CD34+CD38-CD90+ (70%) and CD34+CD38-CD90- cells (30%). Notably, an intermediate wave extending from 2 to 4 months driven by CD34+CD38low cells was selectively eliminated by prolonged ex vivo culture and could be rescued when culture time was reduced to 1 day. We therefore developed a novel LV transduction protocol able to provide curative levels of gene transfer during a single day of ex vivo culture. Stimulating CD34+ cells or CD34+CD38- cells with Prostaglandin E2 (PGE2) increased gene transfer with VSVg-pseudotyped LVs by 1.5-2 fold acting on early steps of transduction, an effect that was further potentiated by the late-acting compound Cyclosporin A. Using large-scale vector preparations for gene therapy of mucopolysaccharidosis type 1, chronic granulomatous disease or beta-thalassemia, we show by in vitro and xenotransplantation assays that a 1-day PGE2 protocol achieved similar transduction efficiencies into BM or MPB HSPC from healthy donors and patients as our 62h benchmark protocol. PGE2 treatment did not result in toxicity or skewed multi-lineage differentiation. However, shortening ex vivo culture increased engraftment levels in the NSG mouse model. To entirely avoid culturing progenitor cells, we explored the feasibility to limit ex vivo manipulation to HSC-enriched CD34+CD38- cells that may be co-transplanted with unmanipulated CD34+ progenitor cells devoid of long-term engraftment potential. This could further improve hematopoietic reconstitution, increase safety by reducing the LV integration load infused into the patient and downscale ex vivo manipulation making the process more efficient and economically sustainable. To this end, we optimized a sequential bead-based, GMP-compatible selection procedure to separate mPB into a CD34+CD38- stem and CD38+ progenitor cell fraction. We reached high purity (87+/-6.6% CD34+) and recovery of CD34+CD38- cells (37.3+/-8.7%), making their isolation clinically viable. Bead-selected CD34+CD38- cells showed higher engraftment potential than equivalent numbers of FACS-sorted cells. Co-infusion of unmanipulated (culture-sensitive) CD38+ supporter cells with genetically-engineered CD34+CD38- cells into NSG mice resulted in rapid engraftment followed by near-complete replacement of untransduced short-term repopulating progenitors by gene-marked HSPC deriving from CD34+CD38- cells after the 3rd month post-transplant. Finally, we explored ex vivo expansion of mPB CD34+CD38- cells with arylhydrocarbon receptor antagonists and/or pyrimido-indole-derivatives. These cells expanded 3-10 fold in a 7-14 d time-window, far less than seen for total CD34+ cells, thereby facilitating culture handling and reducing cost. Unlike CD34+ cells, expanded mPB CD34+CD38- cells largely maintained their SCID-repopulating potential providing proof-of-concept for the expansion of gene-modified HSC. This clinically applicable platform will improve the efficacy, safety and sustainability of ex vivo gene addition and open up new opportunities in the field of gene editing. Disclosures Ciceri: MolMed SpA: Consultancy.
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- 2016
89. BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related SCT
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Guido Lucarelli, Ignazio S. Piras, G. La Nasa, Alessandro Bulfone, Silvia Gregori, Rosa Bacchetta, Sarah Marktel, Maria Grazia Roncarolo, Marco Andreani, Manuela Testi, Katharina Fleischhauer, Andrea Angius, Matteo Floris, Fabio Ciceri, Piras, I, Angius, A, Andreani, M, Testi, M, Lucarelli, G, Floris, M, Marktel, S, Ciceri, Fabio, La Nasa, G, Fleischhauer, K, Roncarolo, Mg, Bulfone, A, Gregori, S, and Bacchetta, R.
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Adult ,Graft Rejection ,Male ,Risk ,Adolescent ,medicine.medical_treatment ,Genome-wide association study ,Human leukocyte antigen ,Hematopoietic stem cell transplantation ,Polymorphism, Single Nucleotide ,whole genome analysis ,Article ,immune system diseases ,HLA Antigens ,Risk Factors ,hemic and lymphatic diseases ,BAT3 ,medicine ,BAT2 ,Humans ,Genetic risk ,Child ,Allogeneic hematopoietic stem transplantation ,Transplantation ,Graft rejection ,business.industry ,beta-Thalassemia ,Hematopoietic Stem Cell Transplantation ,Beta thalassemia ,Proteins ,Hematology ,medicine.disease ,Allografts ,surgical procedures, operative ,Graft-versus-host disease ,Child, Preschool ,Immunology ,Female ,business ,therapeutics ,human activities ,Genome-Wide Association Study ,Molecular Chaperones - Abstract
The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We applied a whole genome analysis to investigate genetic variants - other than HLA class I and II - associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single nucleotide polymorphisms in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong Linkage Disequilibrium between each other (R2=0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P < 0.00001 for BAT2 SNP rs11538264, and P < 0.0001 for BAT3 SNP rs10484558). Whereas, the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs. 2.6%, nominal P = 1.15×10−8; and adjusted P = 0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT.
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- 2013
90. Potential of Gene Therapy in Bone Marrow Transplantation
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Chiara Bonini, Claudio Bordignon, Sarah Marktel, Marktel, S, Bonini, MARIA CHIARA, and Bordignon, Claudio
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Pharmacology ,Ganciclovir ,business.industry ,Genetic enhancement ,General Medicine ,Enzyme replacement therapy ,Suicide gene ,medicine.disease ,Donor Lymphocytes ,Molecular medicine ,Adenosine deaminase deficiency ,surgical procedures, operative ,Pharmacotherapy ,Immunology ,medicine ,Pharmacology (medical) ,business ,Biotechnology ,medicine.drug - Abstract
Gene therapy, initiated as a treatment for inherited disorders such as adenosine deaminase deficiency, is now a promising therapeutic strategy for malignancies and other acquired diseases. In particular, in the field of bone marrow transplantation (BMT) for haematological malignancies, the gene transfer of the suicide gene HSV-TK into donor lymphocytes allows control of the severe complication graft-versus-host disease (GvHD). The transfer of the HSV-TK suicide gene confers selective sensitivity to the drug ganciclovir, allowing in vivo elimination of the donor T-cells if severe GvHD occurs. In Italy, the first pilot study on delayed infusion of genetically engineered donor lymphocytes after T-depleted allogeneic BMT documented efficacy of engineered donor lymphocytes in terms of anti-tumour activity and efficiency of the suicide system. GvHD developed in 3 out of 8 patients and was successfully treated by ganciclovir administration.
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- 1999
91. Herpes Simplex Virus Thymidine Kinase Gene Transfer for Controlled Graft-versus-Host Disease and Graft-versus-Leukemia: Clinical Follow-up and Improved New Vectors
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Chiara Bonini, Sarah Marktel, Catia Traversari, Simona Verzeletti, Nadia Nobili, Claudio Bordignon, Fabio Ciceri, Verzeletti, S, Bonini, MARIA CHIARA, Marktel, S, Nobili, N, Ciceri, Fabio, Traversari, C, and Bordignon, Claudio
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Ganciclovir ,Immunogen ,Proliferation index ,viruses ,Genetic Vectors ,Graft vs Host Disease ,Biology ,Lymphocyte Activation ,medicine.disease_cause ,Antiviral Agents ,Thymidine Kinase ,Proviruses ,Genetics ,medicine ,Humans ,Simplexvirus ,Lymphocytes ,Vector (molecular biology) ,Molecular Biology ,Graft vs Tumor Effect ,Gene Transfer Techniques ,Drug Resistance, Microbial ,Neomycin ,Genetic Therapy ,Suicide gene ,Flow Cytometry ,Donor Lymphocytes ,Virology ,Anti-Bacterial Agents ,Blotting, Southern ,Retroviridae ,Herpes simplex virus ,Thymidine kinase ,Molecular Medicine ,medicine.drug - Abstract
We previously demonstrated that severe graft-versus-host disease (GVHD), associated with the therapeutic infusion of donor lymphocytes after allogeneic marrow transplantation (BMT), can be efficiently controlled by the SFCMM-2-mediated expression of the herpes simplex virus thymidine kinase (HSV-tk) suicide gene into the allogeneic lymphocytes. This was achieved by selective elimination of transduced lymphocytes by ganciclovir (GCV) infusion. Despite the positive results of the pilot clinical trial, two vector-related limitations were observed. The induction of a strong immune response against genetically modified cells was observed in two patients. In addition, the only patient who developed chronic GvHD showed only partial response to ganciclovir treatment. In an attempt to overcome these limitations, we developed a new generation of vectors. The neomycin resistance (neo(R)) gene was removed from the SPCMM-3 and SFCMM-4 retroviral vectors. These vectors are less immunogenic and able to confer higher ganciclovir sensitivity to transduced human lymphocytes. All the vectors carry a modified form of the low-affinity nerve growth factor receptor cDNA, as cell surface selectable marker (Delta LNGFR). The vectors were compared in terms of gene transfer efficiency, and ability to confer high and specific sensitivity to ganciclovir. The SFCMM-3 vector, carrying the entire HSV-tk gene driven by the LTR promoter, allows efficient transduction of human T lymphocytes and confers the highest GCV sensitivity to transduced lymphocytes with a high and a low proliferation index. The expression of the Delta LNGFR marker allows an easier in vitro manipulation and a faster immune selection of transduced cells compared with neo(R) selection. Finally, the elimination of the neo(R) gene removes a potent immunogen from transduced lymphocytes.
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- 1998
92. Haploidentical Transplantation Outcome is Not Inferior to Standard Matched Related - Unrelated Donor Transplantation: An Intention-to-Treat Analysis of 611 Patients in 8-Years Experience at San Raffaele Scientific Institute
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Claudio Bordignon, Katharina Fleischhauer, Milena Coppola, Maria Teresa Lupo Stanghellini, Carlo Messina, Elisa Sala, Massimo Bernardi, Andrea Assanelli, Fabio Ciceri, Iacopo Peccatori, Consuelo Corti, Sarah Marktel, Salvatore Gattillo, Francesca Lunghi, Magda Marcatti, Michela Tassara, Matteo Carrabba, Maria Chiara Bonini, Sara Mastaglio, Laura Bellio, Elena Guggiari, Stanghellini, Mtl, Mastaglio, S, Carrabba, M, Sala, E, Marcatti, M, Assanelli, A, Tassara, M, Messina, C, Fleischhauer, K, Guggiari, E, Marktel, S, Lunghi, F, Gattillo, S, Bellio, L, Coppola, M, Bonini, Mc, Bordignon, Claudio, Corti, C, Peccatori, I, Bernardi, M, and Ciceri, Fabio
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Transplantation ,medicine.medical_specialty ,surgical procedures, operative ,Intention-to-treat analysis ,Haploidentical transplantation ,Unrelated Donor ,business.industry ,medicine ,Hematology ,Intensive care medicine ,business ,Outcome (game theory) - Published
- 2013
93. Safety of retroviral gene marking with a truncated NGF receptor
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Hans-Jochem Kolb, Fabio Ciceri, Claudio Bordignon, Phil Greenberg, J H F Falkenburg, Mohammed A. Sadat, Marco Bregni, Eva M. Weissinger, M. Lamana, Manuel Grez, Timothy W. Austin, Alexis Grande, Mirjam H.M. Heemskerk, Zulma Magnani, Sabrina Cazzaniga, Alessandro Aiuti, Anton Hagenbeek, Saskia B. Ebeling, Steven M. Kornblau, Claudia Benati, Fulvio Mavilio, Sara Deola, Francesco Lotti, Catia Traversari, Mary C. Dinauer, Anton C.M. Martens, Giuliana Ferrari, Shimon Slavin, M. Weber, J. F. Apperley, Frank C. Marini, Chiara Bonini, Sarah Marktel, Corrado Gallo-Stampino, Salvatore Toma, Marina Radrizzani, Juan A. Bueren, Martino Introna, University of Groningen, Bonini, MARIA CHIARA, Grez, M, Traversari, C, Ciceri, Fabio, Marktel, S, Ferrari, Giuliana, Dinauer, M, Sadat, M, Aiuti, Alessandro, Deola, S, Radrizzani, M, Hagenbeek, A, Apperley, J, Ebeling, S, Martens, A, Kolb, Hj, Weber, M, Lotti, F, Grande, A, Weissinger, E, Bueren, Ja, Lamana, M, Falkenburg, Jh, Heemskerk, Mh, Austin, T, Kornblau, S, Marini, F, Benati, C, Magnani, Z, Cazzaniga, S, Toma, S, GALLO STAMPINO, C, Introna, M, Slavin, S, Greenberg, Pd, Bregni, M, Mavilio, F, Bordignon, Claudio, and Clinical Haematology
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NGF Receptor ,gene therapy ,viral vectors ,NGF receptor ,Bone marrow transplantation ,Genetic enhancement ,General Medicine ,Biology ,Molecular biology ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,Viral vector ,Transduction (genetics) ,Multicenter study ,Receptor ,Gene - Published
- 2003
94. Health related quality of life in Middle Eastern children with beta-thalassemia
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Francesca Ciotti, Maria Grazia Roncarolo, Sarah Marktel, Eugenia Piras, Fabio Ciceri, Fabio Efficace, Adriana Vacca, Franco Mandelli, Roberto Littera, Giovanni Caocci, Raji Suleiman Dawood Markous, Giorgio La Nasa, and Gary S. Collins
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Quality of life ,Pediatrics ,medicine.medical_specialty ,Multivariate analysis ,Thalassemia ,Developing country ,PEDsQL 4.0 ,Middle East ,medicine ,Molecular Biology ,Health related quality of life ,lcsh:RC633-647.5 ,business.industry ,Incidence (epidemiology) ,Beta thalassemia ,Paediatrics ,lcsh:Diseases of the blood and blood-forming organs ,Hematology ,medicine.disease ,humanities ,business ,Psychosocial ,Haematology ,Research Article - Abstract
Background Thalassemia is a common disorder worldwide with a predominant incidence in Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia. Whilst substantial progress has been made towards the improvement of Health related quality of life (HRQoL) in western countries, scarce evidence-based data exists on HRQol of thalassemia children and adolescents living in developing countries. Methods We studied 60 thalassemia children from Middle Eastern countries with a median age of 10 years (range 5 to 17 years). HRQoL was assessed with the Pediatric Quality of Life Inventory (PedsQL) 4.0. The Questionnaire was completed at baseline by all patients and their parents. The agreement between child-self and parent-proxy HRQoL reports and the relationship between HRQoL profiles and socio-demographic and clinical factors were investigated. Results The scores of parents were generally lower than those of their children for Emotional Functioning (mean 75 vs 85; p = 0.002), Psychosocial Health Summary (mean 70.3 vs 79.1; p = 0.015) and the Total Summary Score (mean 74.3 vs 77.7 p = 0.047). HRQoL was not associated with ferritin levels, hepatomegaly or frequency of transfusions or iron chelation therapy. Multivariate analysis showed that a delayed start of iron chelation had a negative impact on total PedsQL scores of both children (p = 0.046) and their parents (p = 0.007). Conclusions The PedsQL 4.0 is a useful tool for the measurement of HRQoL in pediatric thalassemia patients. This study shows that delayed start of iron chelation has a negative impact on children’s HRQoL.
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- 2012
95. Risk of complications during hematopoietic stem cell collection in pediatric sibling donors: A prospective European Group for Blood and Marrow Transplantation Pediatric Diseases Working Party study
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Miguel Angel Diaz, Franca Fagioli, Giorgio Dini, Jolanta Gozdzik, Adriana Balduzzi, Jacek Wachowiak, Chiara Messina, Jean-Hugues Dalle, Jelena Rascon, Matthias Eyrich, Myriam Labopin, Karoline Ehlert, Lidia Gil, Christina Peters, Christiane Vermylen, Rose-Marie Hamladji, Sarah Marktel, Maurizio Miano, M. Akif Yesilipek, Isabel Badell, Daphna Hutt, Martina Matulova, Jan Styczyński, Peter Dreger, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique, Styczynski, J, Balduzzi, A, Gil, L, Labopin, M, Hamladji, R, Marktel, S, Yesilipek M., A, Fagioli, F, Ehlert, K, Matulova, M, Dalle, J, Wachowiak, J, Miano, M, Messina, C, Diaz Miguel, A, Vermylen, C, Eyrich, M, Badell, I, Dreger, P, Gozdzik, J, Hutt, D, Rascon, J, Dini, G, and Peters, C
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Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Immunology ,Blood Specimen Collection ,Bone Marrow Transplantation ,Child ,Child, Preschool ,Female ,Humans ,Infant ,Infant, Newborn ,Peripheral Blood Stem Cell Transplantation ,Siblings ,Hematopoietic Stem Cell Transplantation ,Tissue Donors ,Hematology ,Biochemistry ,Cell Biology ,Hematopoietic stem cell transplantation ,medicine ,Adverse effect ,Preschool ,hematopoietic stem cell transplantation, sibling, complications, stem cell donor, pediatric ,business.industry ,Hematopoietic stem cell ,medicine.disease ,Newborn ,medicine.anatomical_structure ,Apheresis ,Pneumothorax ,Donation ,Hydrothorax ,business ,Central venous catheter - Abstract
We investigated prospectively factors influencing the safety of hematopoietic stem cell (HSC) collection in 453 pediatric donors. The children in the study donated either BM or peripheral blood stem cells (PBSCs) according to center policy. A large variability in approach to donor issues was observed between the participating centers. Significant differences were observed between BM and PBSC donors regarding pain, blood allotransfusion, duration of hospital stay, and iron supplementation; however, differences between the groups undergoing BM vs PBSC donation preclude direct risk comparisons between the 2 procedures. The most common adverse event was pain, reported mainly by older children after BM harvest, but also observed after central venous catheter (CVC) placement for PBSC collection. With regard to severe adverse events, one patient (0.7%) developed a pneumothorax with hydrothorax after CVC placement for PBSC collection. The risk of allotransfusion after BM harvest was associated with a donor age of < 4 years and a BM harvest volume of > 20 mL/kg. Children < 4 years were at higher risk than older children for allotransfusion after BM harvest and there was a higher risk of complications from CVC placement before apheresis. We conclude that PBSC and BM collection are safe procedures in children. (Blood. 2012;119(12):2935-2942) We investigated prospectively factors influencing the safety of hematopoietic stem cell (HSC) collection in 453 pediatric donors. The children in the study donated either BM or peripheral blood stem cells (PBSCs) according to center policy. A large variability in approach to donor issues was observed between the participating centers. Significant differences were observed between BM and PBSC donors regarding pain, blood allotransfusion, duration of hospital stay, and iron supplementation; however, differences between the groups undergoing BM vs PBSC donation preclude direct risk comparisons between the 2 procedures. The most common adverse event was pain, reported mainly by older children after BM harvest, but also observed after central venous catheter (CVC) placement for PBSC collection. With regard to severe adverse events, one patient (0.7%) developed a pneumothorax with hydrothorax after CVC placement for PBSC collection. The risk of allotransfusion after BM harvest was associated with a donor age of < 4 years and a BM harvest volume of > 20 mL/kg. Children < 4 years were at higher risk than older children for allotransfusion after BM harvest and there was a higher risk of complications from CVC placement before apheresis.We conclude that PBSC and BM collection are safe procedures in children. © 2012 by The American Society of Hematology.
- Published
- 2012
96. Facing the Rising Tide of Multidrug Resistant Gram-Negative Pathogens in Allogeneic HSCT with Nanosphere's Verigene® System
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Renée Pasciuta, Massimo Bernardi, Maria Chiara Barbanti, Maria Teresa Lupo Stanghellini, Massimo Clementi, Raffaella Greco, Laura Infurnari, Sarah Marktel, Carlo Messina, Fabio Giglio, Andrea Assanelli, Fabio Ciceri, Stefania Girlanda, Mara Morelli, Tommaso Perini, Matteo Carrabba, Jacopo Peccatori, Alessandra Forcina, Nicasio Mancini, Luca Vago, and Consuelo Corti
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medicine.medical_specialty ,Hematology ,medicine.diagnostic_test ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Immunology ,Antibiotics ,Cell Biology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Multiple drug resistance ,Sepsis ,Antibiotic resistance ,Internal medicine ,Medicine ,Infection control ,Blood culture ,business - Abstract
Infections are the major cause of treatment-related morbidity and mortality in hematological patients, mostly after allogeneic hematopoietic stem cell transplantation (HSCT). Although the proportion of infection-related deaths has decreased in the past two decades, the alarming emergence of multidrug resistant (MDR) gram-negative pathogens, increasingly reported from various cancer treatment centers, represents a significant challenge. Dramatic infection-related mortality (64.4%) have been observed in allogeneic HSCT, due to carbapenem-resistant Klebsiella pneumoniae (CRKp). Timely microbiological diagnosis, active surveillance and early therapeutic strategies represent critical aspects for the management of MDR infections after allogeneic HSCT. In this study, we investigated whether a new molecular tool could be clinically relevant in the management of high-risk hematological patients, particularly in allogeneic HSCT. At San Raffaele Hematology and BMT Unit, all blood cultures positive for gram-negative bacteria in the last year, were prospectively collected and in parallel tested with Verigene® Gram-negative blood culture (BC-GN) test (Nanosphere, Northbrook, IL, USA), a microarray-based system allowing a rapid identification of genus, species, and genetic resistance determinants for a broad panel of gram-negative bacteria directly from positive blood cultures. Initially, we evaluated the reliability of the BC-GN test on 50 consecutive patients undergoing chemotherapy (n=16), autologous (n=4) or allogeneic (n=30) HSCT. The concordance with the standard blood culture was 100% considering the bacteria detectable by the system. Resistance genes (CTX-M or carbapenemases, as KPC and VIM) were detected in 15% of the isolates, and 100% were associated to the same phenotypic antibiotic resistance. We observed only 8% of phenotypic resistances not detected by the test, belonging to other kinds of resistance mechanisms not related to the genes included in the panel. Overall, Verigene BC-GN assay correctly identified 40/50 of all the gram-negative pathogens (3 Klebsiella pneumonia, 25 Escherichia coli, 5 Pseudomonas aeruginosa, 4 Acinetobacter spp, 1 Enterobacter spp, 2 Citrobacter spp), yielding a general sensitivity of 80%, which increased to 100% if only the genera and species included in the panel were considered. Then, we examined the potential clinical impact of this molecular approach in allogeneic HSCT recipients (n=30), either in an inpatient (n=24) or outpatient (n=6) management. As far as transplanted patients' care is concerned, the BC-GN test strongly influenced clinical practice. In the majority of cases we were able to early start targeted antibiotic therapy (78%), sparing or interrupting non-specific antimicrobial therapy (56%), thus reducing useless and/or potentially more toxic antibiotics and their potential impact in favouring antimicrobial resistance. Moreover, in 5/8 cases the 'triple therapy', recommended at fever onset for all CRKp-colonized patients, was spared thanks to BC-GN test results, showing the absence of resistance markers. In 95% of patients immunosuppressive prophylaxis was not reduced, thanks to a rapid control of sepsis, avoiding the risk of undesired GVHD. Early contact isolation was possible in 32% of patients, preventing the spread of infections from a patient to the others and allowing infection control. Infection-related mortality was reported only in one patient. An outpatient management was continued in 3/6 haemodynamically stable patients, avoiding unnecessary hospitalization. While conventional microbiological methods required 2-4 days, BC-GN test provided detailed results within 2 hours from blood culture positivity. The mean gain in time comparing BC-GN test to fast blood cultures was reported to be about 20 hours. In our experience, this new microarray test has provided highly accurate identification results and earlier potentially important information on antibiotic susceptibility, both confirming and excluding the presence of an MDR phenotype. The contribution to a rapid diagnosis and an earlier targeted antimicrobial therapy of Verigene BC-GN test is of high clinical relevance for the infections by MDR bacteria, a significant public health challenge worldwide, particularly in allogeneic HSCT recipients. Disclosures No relevant conflicts of interest to declare.
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- 2015
97. Antifungal Prophylaxis with Posaconazole in Allogeneic Hematopoietic Stem Cell Transplantation Using Sirolimus for Prevention of Graft-Versus-Host Disease
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Fabio Giglio, Maria Chiara Barbanti, Maria Teresa Lupo Stanghellini, Francesca Pavesi, Fabio Ciceri, Elisa Sala, Raffaella Greco, Sarah Marktel, Carlo Messina, Andrea Assanelli, Alessandra Forcina, Mara Morelli, Massimo Bernardi, Matteo Carrabba, Luca Vago, Jacopo Peccatori, Consuelo Corti, and Simona Piemontese
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medicine.medical_specialty ,Posaconazole ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Immunology ,Antifungal drug ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Pharmacology ,medicine.disease ,Biochemistry ,Gastroenterology ,Tacrolimus ,surgical procedures, operative ,Graft-versus-host disease ,Therapeutic drug monitoring ,Internal medicine ,Sirolimus ,medicine ,Adverse effect ,business ,medicine.drug - Abstract
Invasive fungal infections (IFI) have emerged as a leading cause of morbidity and infection-related mortality among allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients over the past two decades. Several new drugs have recently been introduced as antifungal prophylaxis, supported by results of prospective randomized trials. In agreement with the international guidelines, a mold-active antifungal prophylaxis is strongly recommended in high-risk patients receiving allo-HSCT, considering efficacy, different pharmacokinetic, drug-drug interactions, and toxicity profile of the various antifungal drugs. Posaconazole, a triazole with broad-spectrum antifungal activity and a favorable toxicity profile, is the drug of choice for patients with graft versus host disease (GVHD). Consequently, posaconazole prophylaxis in allo-HSCT recipients is administered in combination with immunosuppressive drugs for GVHD prophylaxis and/or treatment, most commonly cyclosporine (CsA) or tacrolimus. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR), largely used for GVHD prevention and treatment, but extensively metabolized by CYP3A4. As posaconazole strongly inhibits CYP3A4 its coadministration with sirolimus is contraindicated by the manufacturer of posaconazole, and up to now poorly described in literature. In the San Raffaele Haematology and Bone Marrow Transplantation Unit, from 2010 to 2015, we retrospectively identified sixty-six patients that received posaconazole oral suspension as primary (n=43) or secondary (n=23) antifungal prophylaxis after allo-HSCT. The majority of patients were affected by acute leukaemia (67%), not in remission at time of allo-HSCT (55%), and with a previous allo-HSCT reported for 50% of them, carrying an high risk for developing a post-transplant IFI. Median follow up was 357 days (range 43-1884) after HSCT. Posaconazole administration was given for a median of 221 days (range 13-966). Thirty-two patients (49%) received posaconazole during engraftment phase, while 28 (42%) and 19 (29%) patients for IFI prophylaxis in the setting of acute or chronic GvHD respectively. A concomitant administration of sirolimus was performed in 49 patients (74%). Sirolimus concentrations were monitored two times a week, while posaconazole was controlled in patients' serum on a weekly basis, during the first two months of treatment. We observed a 55-70% steady-state dose reduction of sirolimus in 19 patients, after posaconazole introduction. Alternatively, patients with ongoing posaconazole prophylaxis received an initial empiric sirolimus dose reduction at 1 mg/day. The co-administration of posaconazole and sirolimus resulted safe. Discontinuation was reported mainly in patients with documented IFI, who required a change of the antifungal drug. No adverse events potentially associated with sirolimus overexposure (i.e. sinusoidal obstructive syndrome, sirolimus-related thrombotic microangiopathy) were reported, although one-third of the patients experienced a transient and moderate elevation of sirolimus serum levels in the first week of coadministration. In this analysis post-transplant IFI occurred in 14 cases. The risk of developing IFI was influenced by type of prophylaxis, resulting in 12% and 39% of IFI during primary and secondary prophylaxis respectively (p value 0.013; OR 4.89, CI 1.39-17.11). However the most significant and strong association was reported in concomitant with insufficient posaconazole serum levels ( In patients with adequate posaconazole serum levels (>0.5 ml/L) the incidence of IFI was 5%, supporting the utility of therapeutic drug monitoring (TDM) in such conditions and generating interest for the use of the upcoming posaconazole tablets with improved bioavailability in allo-HSCT recipients. In our experience concurrent sirolimus and posaconazole use was well tolerated, with a 55% to 70% sirolimus dose reduction at posaconazole initiation and close monitoring of serum sirolimus and posaconazole trough levels in the first months of co-administration. Disclosures No relevant conflicts of interest to declare.
- Published
- 2015
98. Standardized Long-Term Follow-up after Allogeneic Stem Cell Transplantation: A Cross-Sectional 1-Year Evaluation in 260 Adults
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Francesca Pavesi, Fabio Ciceri, Massimo Bernardi, Elisa Sala, Serena Dalto, Simona Piemontese, Andrea Assanelli, Elisabetta Xue, Lucia Malabarba, Matteo Carrabba, Francesca Lunghi, Sarah Marktel, Consuelo Corti, Luca Vago, Margherita Brambilla, Magda Marcatti, Chiara Bonini, Francesca Lorentino, Elena Guggiari, Fabio Giglio, Raffaella Greco, Sara Mastaglio, Mara Morelli, Maria Teresa Lupo-Stanghellini, Alessia Orsini, Carlo Messina, Ambra Malerba, Jacopo Peccatori, Lupo-Stanghellini, Mt, Assanelli, A, Orsini, A, Greco, R, Giglio, F, Mastaglio, S, Morelli, M, Pavesi, F, Sala, E, Brambilla, M, Piemontese, S, Xue, E, Vago, L, Messina, C, Dalto, Sc, Lorentino, F, Malabarba, L, Malerba, A, Marcatti, M, Guggiari, E, Marktel, S, Carrabba, Mg, Lunghi, F, Bernardi, M, Bonini, C, Corti, C, Peccatori, J, and Ciceri, F
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Cervical cancer ,medicine.medical_specialty ,education.field_of_study ,business.industry ,medicine.medical_treatment ,Incidence (epidemiology) ,Immunology ,Population ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Surgery ,Transplantation ,Concomitant ,Internal medicine ,medicine ,education ,Complication ,business ,Lung cancer - Abstract
Introduction Allogeneic hematopoietic cell transplantation (HCT) is an effective therapeutic option for high-risk hematological malignancies; 80% of those who survive the first 2 years are expected to become long-term survivors. The prevalence of chronic health conditions approaches 75% among HCT survivors and that for severe or life-threatening conditions exceeds 20%. Patients and Methods A standardized follow-up of HCT survivors is applied at our Center, according to Jacie Standards. Here we report the analysis of data collected between July 2014 and July 2015 in 260 adult patients (pts) who underwent an HCT between 1992 and 2014. Data on 7 items - selected to monitor relevant comorbidities - were prospectively collected in our Institutional database. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Results Pts characteristics are reported in table 1, median time of follow-up 4.4y (r1-22), cumulative follow-up 1404y; 13 pts deceased during the time of observation (6 due to disease relapse, 2 to late major infection, 2 to second cancer, 1 to GvHD, 1 to myocardial infarction, 1 unknown). - chronic Graft-versus-Host-Disease (c-GvHD): at a median follow-up of 43 months (r 16 months - 21 years) 84 (32%) pts are presenting c-GvHD features. According to NIH 2014 consensus criteria 23 cases were classified as mild, 32 moderate, 29 severe. Median number of involved organs 2 (r1-5), 39 pts were experiencing skin lesions, 55 eyes, 28 mouth, 19 joint and fascia, 18 lungs. Topical therapy was the treatment of choice for mild cases, while moderate and severe were treated with systemic therapy. The partnership with the lung specialist and the ophthalmologist was crucial for the management of lung and eyes GvHD. - Late infectious manifestation: 38 (15%) pts present late infection, 2 pts deceased due to major events. Of note pneumonia was reported in 12 pts, Varicella Zoster virus reactivation in 7, CMV late reactivation in 4 pts. - Second cancer screening was performed according to international guidelines. The incidence of new cases is 10% (26 pts) and 11 pts are actually under work-up for suspicious lesions. Non-melanoma skin cancer was the most frequent diagnosis (13 cases); 3 pts were diagnosed with cervix cancer, 2 with lung cancer. The prevalence of second cancer in our population is 18% (47 cases). All pts were treated according to standard for general population, 45/47 are alive. - Cardiovascular diseases were frequently observed in our setting: hypertension was documented in 36 pts, arterial diseases in 10 pts, cardiomyopathy in 28 pts. Overall 27% of pts were diagnosed with cardiovascular comorbidities. - Metabolic syndrome (MS) is reported as a very common complication in long-term survivors: 65 (25%) pts were presenting features of MS (3/5 among hypertension, dyslipidemia, raised fasting glucose, and central obesity). A concomitant thyroid dysfunction - requiring hormonal replacement - was present in 27/65 pts. - Secondary hemosiderosis was documented (with MRI and blood parameters) and treated in 39 pts (15%) - 8 pts received deferasirox while phlebotomy was used in 31. - Osteoporosis and bone loss were evaluated measuring bone mineral density using dual-energy X-ray absorptiometry; osteopenia was detected in 81 pts and osteoporosis in 42 (47%). Pts were evaluated in conjunction with the endocrinologist and treated according to the fracture risk score. According to donor source no difference were observed (Chi-square test - p ns) except for higher incidence of moderate/severe GvHD incidence in HLA identical sibling (p 0.0097) as compared to alternative donors. Discussion HCT survivors are at a defined relevant risk of developing long-term complications that have a direct impact on the morbidity and mortality.A multidisciplinary active screening within routine HCT long-term follow-up care is mandatory to enhance early diagnosis/treatment and overall outcome. The next challenge will be to enhance the primary prevention to reduce the incidence of preventable comorbidities. Table 1. patients characteristics N (range) Pts 260 Age At transplant 48y (10 - 76) At follow-up 54y (20 - 82) Male / Female 169 / 91 Diagnosis AML / ALL 106 / 33 MDS 27 HD / NHL 23 / 29 MM 14 CML 8 CLL 5 SAA / EPN 4 / 1 Others 10 Status at transplant CR / PD 169 / 91 Donor Haploidentical 100 HLA identical Sibling 76 Match Unrelated Donor 82 Cord Blood 2 Disclosures Bonini: MolMed S.p.A: Consultancy.
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- 2015
99. Refined Disease Risk Index (DRI) and Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) Predict Survival after Haploidentical Stem Cell Transplantation: A Comparative Study with EBMT Risk Score in 220 Consecutive Patients
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Mara Morelli, Sarah Marktel, Massimo Bernardi, Raffaella Greco, Maria Teresa Lupo-Stanghellini, Fabio Giglio, Luca Vago, Sara Mastaglio, Carlo Messina, Forcina Alessandra, Jacopo Peccatori, Francesca Lunghi, Matteo Carrabba, Magda Marcatti, Elisa Sala, Simona Piemontese, Andrea Assanelli, Consuelo Corti, Malato Simona, Francesca Pavesi, Fabio Ciceri, Francesca Lorentino, Elena Guggiari, Lupo-Stanghellini, Mt, Sala, E, Piemontese, S, Morelli, M, Greco, R, Marcatti, M, Assanelli, A, Carrabba, Mg, Alessandra, F, Mastaglio, S, Marktel, S, Lorentino, F, Lunghi, F, Guggiari, E, Giglio, F, Simona, M, Pavesi, F, Messina, C, Vago, L, Corti, C, Bernardi, M, Peccatori, J, and Ciceri, F
- Subjects
medicine.medical_specialty ,Framingham Risk Score ,business.industry ,Immunology ,Context (language use) ,Retrospective cohort study ,Cell Biology ,Hematology ,Total body irradiation ,Treosulfan ,Biochemistry ,Surgery ,Transplantation ,Clinical trial ,surgical procedures, operative ,Internal medicine ,medicine ,business ,Risk assessment ,medicine.drug - Abstract
Background Optimization of pre-transplant risk assessment is a crucial issue to improve the allo-HSCT decision making process. Actually 3 major algorithms are in use in clinical practice: the EBMT risk score, the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and - more recently introduced - the refined Disease Risk Index (DRI). DRI was defined to calibrate HSCT outcome across studies and centers. It was developed as a tool to assign patients into risk groups based on disease type and status at the time of transplantation. The aim of the DRI is to provide a robust tool that can be used for prognostication, for the analysis and interpretation of retrospective data, whether conducted in single-center, multicenter, or registry settings, or within the context of the federally mandated center outcome reporting. The DRI can also be used for the stratification of patients entering prospective HCT clinical trials. DRI is not a fixed tool but instead it was conceived to be refined by the transplant community as new information becomes available. Here we are presenting the results of a retrospective study designed to evaluate the 3 aforementioned score in stratification and prognostication of transplant outcome after a haploidentical HSCT (haplo-HSCT). Patients and Methods We included 220 adult patients (pts - 138 male, 82 female) who underwent a haplo-HSCT for hematologic malignancies, between 2006 and 2014 and were reported to our Institutional database. Risk assessment score and outcome analysis included all consecutive pts receiving an haplo-HSCT as 1st allogeneic transplantation. Pts receiving haplo-HSCT as 2nd or 3rd HSCT were excluded from the present analysis. Median age was 49 years (range, 15-77). The cohort included a broad representation of diseases (138/220 acute leukemia, 30 Hodgkin lymphoma); 62 pts were in complete remission at transplant, 158 were presenting active disease. Conditioning regimens mostly rely upon the combination of treosulfan plus fludarabine (201/220) and total body irradiation (range 200 - 400 cGy) was utilized in 52 patients. GVHD prophylaxis consisted mostly of an mTor inhibitor (rapamycin) combined with mycophenolate mofetil. The majority of patients received peripheral blood stem cells from a family haploidentical donor as stem cell source, while only 4 patients received bone marrow transplant. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Results The median follow-up for survivors was 37 months (r 6-107). The overall survival (OS) at 2-y was 35% and the transplant related mortality at 100-days 23%. The 2y OS according to EBMT / HCT-CI / DRI risk score are reported in table 1.a and figure 1. The evaluation of the HCT-CI impact after DRI stratification was able to show a significant difference in outcome showing better survival for pts with low DRI score and low HCT-CI score as expected (table 1.b). Discussion Refined DRI score and HCT-CI score predict survival after haplo-HSCT. The integrated application of refined DRI and HCT-CI may improve the definition of transplant eligibility for pts candidate to allogeneic HSCT form alternative donors including family haploidentical source. Table 1a. EBMT score 0-3 % pts 4-5 %pts > 5 %pts p 51% 17 34% 51 27% 32 0.07 HCT-CI score 0-2 3-4 >/= 5 48% 59 36% 31 0% 10 0.0001 DRI score Low-Intermediate High Very-High 61% 32 27% 51 5% 17 0.0001 Table 1b. HCT-CI 0-4 HCT-CI >/=5 p DRILow-Intermediate 64% 0% 0.0001 DRIHigh-Very High 29% 0% Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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- 2015
100. Intrinsic Molecular Features of Human Hematopoietic Stem Cells from Different Sources Define Their Specific Functional Properties
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Bernhard Gentner, Annamaria Aprile, Sarah Marktel, Laura Bellio, Ylenia Paleari, Marta Claudia Frittoli, Elena Cassinerio, Fabio Ciceri, Giacomo Mandelli, Laura Zanaboni, Maria Domenica Cappellini, Giuliana Ferrari, and Maria Rosa Lidonnici
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Plerixafor ,Immunology ,Hematopoietic stem cell ,Cell Biology ,Hematology ,Biology ,Biochemistry ,CXCR4 ,medicine.anatomical_structure ,medicine ,Cancer research ,Autologous transplantation ,Bone marrow ,Stem cell ,Progenitor cell ,Homing (hematopoietic) ,medicine.drug - Abstract
Over the past decades outcomes of clinical hematopoietic stem cell transplants have established a clear relationship between the sources of hematopoietic stem cells (HSCs) infused and their differential homing and engraftment properties. For a long time, bone marrow (BM) harvest has been the preferred source of hematopoietic stem and progenitor cells (HSPCs) for hematopoietic reconstitution following myeloablative conditioning regimen. At present, mobilized peripheral blood (PB) is commonly used for hematopoietic cells transplantation in both adults and children, particularly in the autologous setting, and it has progressively replaced BM as the source of HSCs. So far, the intrinsic molecular features of human primitive HSCs from different sources have not been investigated in comparative studies to unravel their variable reconstitution potential. Diverse strategies are currently used to disengage HSCs from the niche, promoting egress from BM to PB. Traditionally the growth factor granulocyte-colony stimulating factor (G-CSF) represents the gold standard agent to mobilize HSPCs for transplantation. Nevertheless, many other compounds have been tested to this regard. One of the most successful mobilizing agents is Plerixafor (AMD3100, Mozobil™), a bicyclam molecule that selectively and reversibly antagonizes the binding of stromal cell derived factor-1 (SDF-1), located on the surface of BM stromal cells and osteoclasts, to chemokine CXC-receptor-4 (CXCR4), located on the surface of HSPCs, with the subsequent mobilization in the PB. This drug, which was shown in preclinical combination studies with G-CSF to enhance mobilization compared to G-CSF alone, is currently approved by FDA and EMA "in combination with G-CSF to enhance the mobilization of HSCs into the peripheral blood for collection and autologous transplantation of patients affected by lymphoma or multiple myeloma whose cells mobilize poorly" We investigated functional and molecular hallmarks of human HSCs from different sources, i.e. BM and PB following mobilization by G-CSF and/or Plerixafor. We show that Plerixafor alone mobilizes preferentially long-term hematopoietic stem cells (LT-HSCs), defined as CD34+ CD38/low CD90+ CD45RA- CD49f+ cells and primitive populations of HSCs. These cells are able to provide stable long-term hematopoietic engraftment in NOD/SCID/IL2rγnull (NSG) mice, resulting in enriched scid-repopulating cell frequency, in comparison to other sources. The quiescence status of these cells correlates with the enriched scid-repopulating cell frequency. Noteworthy, the combined use of G-CSF and Plerixafor mobilizes a CD34+ population enriched in immature cells and with a lower engraftment capacity respect to cells mobilized by Plerixafor alone. Since the signaling provided by the interaction of SDF-1 with CXCR4, plays an essential role in maintaining HSC quiescence and regulating homing, we analyzed the CXCR4 expression. Interestingly, this analysis reveals that the proportion of CXCR4+ primitive cells was lower when using G-CSF combined to Plerixafor in respect to Plerixafor alone. These data indicate that the combination of the two mobilizing agents induce a higher amount of circulating CD34+ cells but containing a lower proportion of cells capable of homing to BM in NSG mice. . As a result, at a defined dose of transplanted CD34+ cells, less SRCs are observed when G-CSF is added to Plerixafor. Indeed, it is expected to observe also a rapid rescue of hematopoiesis in myeloablated subjects conferred by high amount of short-term progenitors. Insights into the transcriptional program reveal the molecular machinery underlying stemness features of cells derived from different sources, defining their specific functional properties. Noteworthy, CD34+ cells exposed to Plerixafor but still resident in the BM acquire an intermediate signature between steady-state and circulating cells, suggesting an effect of this agent on HSC function. From preliminary data, genes of Prostaglandin signaling are up-regulated in HSCs mobilized by Plerixafor, suggesting a role of this pathway. These data uncover unique HSCs properties shaped by their origin and illuminate the choice of different transplantation strategies accordingly to the clinical need. Disclosures No relevant conflicts of interest to declare.
- Published
- 2015
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