44 results on '"Francesca Lorentino"'
Search Results
2. Post-transplant cyclophosphamide and sirolimus based graft-versus-host disease prophylaxis after allogeneic stem cell transplantation for acute myeloid leukemia
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Lorenzo Lazzari, Aitana Balaguer-Roselló, Juan Montoro, Raffaella Greco, Rafael Hernani, Maria Teresa Lupo-Stanghellini, Marta Villalba, Fabio Giglio, Ana Facal, Francesca Lorentino, Manuel Guerreiro, Alessandro Bruno, Ariadna Pérez, Elisabetta Xue, Daniela Clerici, Simona Piemontese, José Luis Piñana, Miguel Ángel Sanz, Carlos Solano, Javier de la Rubia, Fabio Ciceri, Jacopo Peccatori, and Jaime Sanz
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Adult ,Sirolimus ,Transplantation ,BLOOD ,Transplantation Conditioning ,CONDITIONING INTENSITY ,GVHD PROPHYLAXIS ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,1ST COMPLETE REMISSION ,Hematology ,Mycophenolic Acid ,OPEN-LABEL ,DIAGNOSIS ,Patologia ,HEMATOLOGIC MALIGNANCIES ,EUROPEAN-SOCIETY ,Leukemia, Myeloid, Acute ,RISK INDEX ,Humans ,MARROW-TRANSPLANTATION ,Unrelated Donors ,Cyclophosphamide ,Retrospective Studies - Abstract
Post-transplant cyclophosphamide (PTCy) has emerged as a promising graft-versus-host disease (GvHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, no studies have reported the efficacy of a GvHD prophylaxis based on PTCy with sirolimus (Sir-PTCy) in patients with acute myeloid leukemia (AML). In this retrospective study, we analyze the use of sirolimus in combination with PTCy, with or without mycophenolate mofetil (MMF), on 242 consecutive adult patients with AML undergoing a myeloablative first allo-HSCT from different donor types, in three European centers between January 2017 and December 2020. Seventy-seven (32%) patients received allo-HSCT from HLA-matched sibling donor, 101 (42%) from HLA-matched and mismatched unrelated donor, and 64 (26%) from haploidentical donor. Except for neutrophil and platelet engraftment, which was slower in the haploidentical cohort, no significant differences were observed in major transplant outcomes according to donor type in univariate and multivariate analysis. GvHD prophylaxis with Sir-PTCy, with or without MMF, is safe and effective in patients with AML undergoing myeloablative allo-HSCT, resulting in low rates of transplant-related mortality, relapse/progression, and acute and chronic GvHD in all donor settings.
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- 2022
3. Infections after Allogenic Transplant with Post-Transplant Cyclophosphamide: Impact of Donor HLA Matching
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Antonella Castagna, Paolo Scarpellini, Laura Galli, Jacopo Peccatori, Elisabetta Xue, Lina Uhr, Francesca Lorentino, Marco Ripa, Daniela Clerici, Chiara Oltolini, Massimo Bernardi, Maria Teresa Lupo Stanghellini, Raffaella Greco, Consuelo Corti, Fabio Ciceri, Fabio Giglio, Oltolini, C., Greco, R., Galli, L., Clerici, D., Lorentino, F., Xue, E., Lupo Stanghellini, M. T., Giglio, F., Uhr, L., Ripa, M., Scarpellini, P., Bernardi, M., Corti, C., Peccatori, J., Castagna, A., and Ciceri, F.
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medicine.medical_specialty ,Multivariate analysis ,Cyclophosphamide ,Post transplant cyclophosphamide ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Human leukocyte antigen ,Infections ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Cystitis ,medicine ,Humans ,Pre-engraftment bloodstream infections ,Viral infections ,Transplantation ,business.industry ,Incidence (epidemiology) ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Hematology ,030220 oncology & carcinogenesis ,Allogeneic hematopoietic stem cell transplantation ,Unrelated Donors ,Post-transplant cyclophosphamide ,business ,Early phase ,030215 immunology ,medicine.drug - Abstract
Incidence and outcome of infections after allogeneic hematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis are largely unknown. Study aims were to estimate the incidence of pre-engraftment bloodstream infections (PE-BSIs) and viral infections (VIs; cytomegalovirus [CMV], adenovirus [ADV], human herpes virus 6 [HHV6], and BK-polyomavirus hemorrhagic-cystitis [BKPyV-HC]), their predictive factors, and infection-related mortality (IRM) after HSCT with PT-Cy. We analyzed 235 patients: 62%, 21%, and 17% received haploidentical (haplo), matched-unrelated donor (MUD), and matched-related donor, respectively. Overall, 72 patients had 77 PE-BSI episodes at a median time of 13 days after HSCT: cumulative incidence function (CIF) at 28 days was 32%, without differences among donor types (P = .988). By multivariate analysis, CIF of PE-BSI was higher in patients with severe neutropenia before HSCT (adjusted hazard ratio [AHR] = 2.90) and in multidrug-resistant Gram-negative bacteria rectal carriers (AHR = 2.68). IRM at 30 days was 5%, without differences by donor type (P = .106). Overall, 208 patients experienced ≥1 VIs (first occurrence among CMV, HHV6, ADV, BKPyV-HC) at a median time of 20 days after HSCT: CIF at 90 days was 91%, significantly higher in MUD and haplo (P = .0089). By multivariate analysis, also acute GVHD grade ≥2 (AHR = 1.32) and host/donor CMV-serology mismatch (positive/positive versus negative/negative: AHR = 2.95, positive/negative versus negative/negative: AHR = 2.41, negative/positive versus negative/negative: AHR = 2.35) affected VIs occurrence. IRM at 180 days was 8%, without differences among donor types (P = .106). In conclusion, study results did not show a significant impact of donor type on PE-BSI incidence; conversely, MUD and haploidentical transplants retained a higher occurrence of VIs in the early phase after HSCT.
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- 2020
4. Treosulfan-Based Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation: Long-Term Results From a Phase 2 Clinical Trial
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Lorenzo Lazzari, Annalisa Ruggeri, Maria Teresa Lupo Stanghellini, Sara Mastaglio, Carlo Messina, Fabio Giglio, Alessandro Lorusso, Tommaso Perini, Simona Piemontese, Magda Marcatti, Francesca Lorentino, Elisabetta Xue, Daniela Clerici, Consuelo Corti, Massimo Bernardi, Andrea Assanelli, Raffaella Greco, Fabio Ciceri, Jacopo Peccatori, Lazzari, L., Ruggeri, A., Lupo Stanghellini, M. T., Mastaglio, S., Messina, C., Giglio, F., Lorusso, A., Perini, T., Piemontese, S., Marcatti, M., Lorentino, F., Xue, E., Clerici, D., Corti, C., Bernardi, M., Assanelli, A., Greco, R., Ciceri, F., and Peccatori, J.
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Cancer Research ,medicine.medical_specialty ,Treosulfan ,Population ,ATLG ,Phases of clinical research ,Gastroenterology ,conditioning regimen ,Internal medicine ,medicine ,Cumulative incidence ,Adverse effect ,education ,RC254-282 ,Original Research ,reduced toxicity ,education.field_of_study ,business.industry ,Hazard ratio ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,allogeneic transplant ,Fludarabine ,Transplantation ,Oncology ,business ,medicine.drug - Abstract
IntroductionReducing toxicities while preserving efficacy in allogeneic stem cell transplant (allo-HCT) remains a particularly challenging problem. Different strategies to enhance the antitumor activity without increasing early and late adverse toxicities of the conditioning regimens have been investigated.MethodsThe aim of “AlloTreo” prospective phase 2 clinical trial was to evaluate the efficacy and safety of a conditioning regimen based on Treosulfan (42 g/m2) and fludarabine (https://clinicaltrials.gov/ct2/show/NCT00598624). We enrolled 108 patients with hematological diseases who received a first allo-HCT between June 2005 and January 2011, inside the frame of this trial at our center. Median age at allo-HCT was 49 (21–69) years. Disease Risk Index was low in 14 (13%) patients, intermediate in 73 (67.7%), high in 17 (15.7%), and very high in 4 (3.7%). Donors were human leukocyte antigen (HLA)-matched related in 50 cases, 10/10-matched unrelated in 36, and 9/10-mismatched unrelated in 22. Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine-A and methotrexate. Anti-T-lymphocyte globulin (ATLG) was administered in patients receiving unrelated allo-HCT. Stem cell source was mainly peripheral blood stem cells (95%).ResultsConditioning regimen was well tolerated. Full donor chimerism was documented for most patients (88%) at day +30. At 12 years, overall survival (OS) was 41.7% (32.2%–50.9%), progression-free survival (PFS) was 31.7% (23%–40.7%), GvHD-free/relapse-free survival was 20.9% (13.7%–29.1%), cumulative incidence (CI) of relapse was 44.5% (34.9%–53.6%), and transplant-related mortality (TRM) was 22.5% (15.1%–30.9%). CI of acute GvHD grades II–IV was 27.8% (19.7%–36.5%) at 100 days; 12-year CI of chronic GvHD was 40.7% (31.3%–49.9%). Relevant long-term adverse effects were 10 secondary malignancy, 3 fatal cardiovascular events, and 1 late-onset transplant-associated thrombotic microangiopathy. Ten successful pregnancies were reported after allo-HCT. In multivariate analysis, older age (≥60 years) at transplant [hazard ratio (HR), 2.157; p = 0.004] and a high/very high disease risk index (HR, 1.913; p = 0.026) were significantly associated with a lower OS.ConclusionsOverall, our data confirmed the myeloablative potential and safe toxicity profile of full dose Treo (42 g/m2) especially for the younger population.
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- 2021
5. Allogeneic Hematopoietic Stem Cell Transplantation in Patients Older than 65 Years with Acute Myeloid Leukemia and Myelodysplastic Syndrome: A 15-Year Experience
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Magda Marcatti, Maria Teresa Lupo Stanghellini, Raffaella Greco, Chiara Secco, Massimo Bernardi, Bernhard Gentner, Lorenzo Lazzari, Elisabetta Xue, Fabio Ciceri, Luca Vago, Francesca Farina, Consuelo Corti, Matteo Carrabba, Sara Mastaglio, Fabio Giglio, Sarah Marktel, Simona Piemontese, Andrea Assanelli, Daniela Clerici, Francesca Lorentino, Jacopo Peccatori, A. Ruggeri, Piemontese, S., Lazzari, L., Ruggeri, A., Marcatti, M., Lupo Stanghellini, M. T., Giglio, F., Greco, R., Lorentino, F., Clerici, D., Assanelli, A., Farina, F., Mastaglio, S., Xue, E., Marktel, S., Vago, L., Gentner, B., Secco, C., Corti, C., Carrabba, M. G., Bernardi, M., Peccatori, J., and Ciceri, F.
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Oncology ,Transplantation ,medicine.medical_specialty ,Transplantation Conditioning ,business.industry ,medicine.medical_treatment ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,Hematopoietic stem cell transplantation ,Leukemia, Myeloid, Acute ,Myelodysplastic Syndromes ,Internal medicine ,medicine ,Humans ,In patient ,business - Abstract
Background. Median age of occurrence of acute myeloid leukemias (AML) and myelodisplastc syndromes (MDS) is 65 years and older. Nevertheless, the use of allogeneic stem cell transplant (allo-HCT) has been historically limited to younger population, namely due to excess in non-relapse-mortality (NRM) in olders. Methods. In the present study, we analyzed all consecutive patients aged ≥ 65y diagnosed with AML (71, 81%) or MDS (19, 19%) who received transplants from adult donors at our center from January 2005 to December 2019. Results. Median age was 68.29y (65.02-76.54), 26pts (29%) aged ≥ 70y. Thirty-three (37%) pts received a HLA-matched donor. Conditioning regimen was myeloablative in 46pts (51%). The 3-year overall survival (OS) was 53+/-6%, and disease free survival (DFS) 45+/-6% (Figure 1). Day-100 and 3-year NRM was 17+/-2% and 29+/-2%, respectively. The 3-year CI of relapse was 22+/-2%. Day-100 CI of aGvHD was 21+/-2% for grade II-IV, 14+/-1% for grade III-IV. The 3-year CI of cGvHD was 35+/-3%, extensive 20+/-2%. In multivariate analysis, the Karnofsky Performance Status (KPS) < 90% was associated with lower OS (HR: 2.999, CI: 1.477- 6.691; p=0.002), DFS (HR: 3.155, CI: 1.593 - 6.250; p=0.001) and higher NRM (HR: 2.997, CI: 1.344-6.682; p=0.041). HCT-CI ≥ 3 was also associated with higher NRM (HR: 2.949, CI: 1.166-7.462, p=0.022,). Diagnosis of MDS and receiving a matched donor with PTCy were associated with longer OS (HR: 0.3440, CI: 0.1029-0.915; p=0.033; HR: 0.197, CI: 0.042-0.934; p=0.041).Conclusions. Age alone should not limit transplant eligibility for AML and MDS. KPS and HCT-CI proved to be useful for patient selection among the elderly. The use of HLA-matched donors with PTCy improved OS compared to ATG in our consecutive series.
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- 2021
6. Immune Reconstitution-Based Score for Risk Stratification of Chronic Graft-Versus-Host Disease Patients
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Fabio Serpenti, Francesca Lorentino, Sarah Marktel, Raffaella Milani, Carlo Messina, Raffaella Greco, Stefania Girlanda, Daniela Clerici, Fabio Giglio, Carmine Liberatore, Francesca Farina, Sara Mastaglio, Simona Piemontese, Elena Guggiari, Francesca Lunghi, Magda Marcatti, Matteo G. Carrabba, Massimo Bernardi, Chiara Bonini, Andrea Assanelli, Consuelo Corti, Jacopo Peccatori, Fabio Ciceri, Maria Teresa Lupo-Stanghellini, Serpenti, F., Lorentino, F., Marktel, S., Milani, R., Messina, C., Greco, R., Girlanda, S., Clerici, D., Giglio, F., Liberatore, C., Farina, F., Mastaglio, S., Piemontese, S., Guggiari, E., Lunghi, F., Marcatti, M., Carrabba, M. G., Bernardi, M., Bonini, C., Assanelli, A., Corti, C., Peccatori, J., Ciceri, F., and Lupo-Stanghellini, M. T.
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,overall survival ,Context (language use) ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Quality of life ,Internal medicine ,medicine ,chronic GvHD ,RC254-282 ,Original Research ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,immune reconstitution ,medicine.disease ,prognostic score ,Transplantation ,Clinical trial ,030104 developmental biology ,Graft-versus-host disease ,Oncology ,Cohort ,Biomarker (medicine) ,biomarker ,business ,030215 immunology - Abstract
IntroductionAllogeneic stem cell transplantation survivors are at a relevant risk of developing chronic GvHD (cGvHD), which importantly affects quality of life and increases morbidity and mortality. Early identification of patients at risk of cGvHD-related morbidity could represent a relevant tool to tailor preventive strategies. The aim of this study was to evaluate the prognostic power of immune reconstitution (IR) at cGvHD onset through an IR-based score.MethodsWe analyzed data from 411 adult patients consecutively transplanted between January 2011 and December 2016 at our Institution: 151 patients developed cGvHD (median follow-up 4 years). A first set of 111 consecutive patients with cGvHD entered the test cohort while an additional consecutive 40 patients represented the validation cohort. A Cox multivariate model for OS (overall survival) in patients with cGvHD of any severity allowed the identification of six variables independently predicting OS and TRM (transplant-related mortality). A formula for a prognostic risk index using the β coefficients derived from the model was designed. Each patient was assigned a score defining three groups of risk (low, intermediate, and high).ResultsOur multivariate model defined the variables independently predicting OS at cGvHD onset: CD4+ >233 cells/mm3, NK 3, IgA 3/mm3. Low-risk patients were defined as having a score ≤3.09, intermediate-risk patients >3.09 and ≤6.9, and high-risk patients >6.9. By ROC analysis, we identified a cut-off of 6.310 for both TRM and overall mortality.In the training cohort, the 6-year OS and TRM from cGvHD occurrence were 85% (95% CI, 70-92) and 13% (95% CI, 5-25) for low-risk, 64% (95% CI, 44-89) and 30% (95% CI, 15-47) for intermediate-risk, 26% (95% CI, 10-47), and 42% (95% CI, 19-63) for high-risk patients (OS pThe validation cohort confirmed the model with a 6-year OS and TRM of 83% (95% CI, 48-96) and 8% (95% CI, 1-32) for low-risk, 78% (95% CI, 37-94) and 11% (95% CI, 1-41) for intermediate-risk, 37% (95% CI, 17-58), and 63% (95% CI, 36-81) for high-risk patients (OS p = 0.0075; TRM p = 0.0009).ConclusionsIR score at diagnosis of cGvHD predicts GvHD severity and overall survival. IR score may contribute to the risk stratification of patients. If confirmed in a larger and multicenter-based study, IR score could be adopted to identify patients at high risk and modulate cGvHD treatments accordingly in the context of clinical trial.
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- 2021
7. Donor Lymphocyte Infusions After Allogeneic Stem Cell Transplantation in Acute Leukemia: A Survey From the Gruppo Italiano Trapianto Midollo Osseo (GITMO)
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Francesca Patriarca, Alessandra Sperotto, Francesca Lorentino, Elena Oldani, Sonia Mammoliti, Miriam Isola, Alessandra Picardi, William Arcese, Giorgia Saporiti, Roberto Sorasio, Nicola Mordini, Irene Cavattoni, Maurizio Musso, Carlo Borghero, Caterina Micò, Renato Fanin, Benedetto Bruno, Fabio Ciceri, and Francesca Bonifazi
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,acute leukemia ,allogeneic stem cell transplantation ,donor lymphocyte infusions ,pre-emptive treatment ,relapse ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,lcsh:RC254-282 ,Gastroenterology ,Donor lymphocyte infusion ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Adverse effect ,Original Research ,Acute leukemia ,business.industry ,Myeloid leukemia ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Transplantation ,030104 developmental biology ,Graft-versus-host disease ,Oncology ,030220 oncology & carcinogenesis ,Methotrexate ,business ,medicine.drug - Abstract
We conducted a retrospective multicenter study including pediatric and adult patients with acute leukemia (AL) who received donor lymphocyte infusions (DLIs) after allogeneic hematopoietic stem cell transplantation (HCT) between January 1, 2010 and December 31, 2015, in order to determine the efficacy and toxicity of the immune treatment. Two hundred fifty-two patients, median age 45.1 years (1.6–73.4), were enrolled from 34 Italian transplant centers. The underlying disease was acute myeloid leukemia in 180 cases (71%). Donors were HLA identical or 1 locus mismatched sibling (40%), unrelated (40%), or haploidentical (20%). The first DLI was administered at a median time of 258 days (55–3,784) after HCT. The main indication for DLI was leukemia relapse (73%), followed by mixed chimerism (17%), and pre-emptive/prophylactic use (10%). Ninety-six patients (38%) received one single infusion, whereas 65 (26%), 42 (17%), and 49 patients (19%) received 2, 3, or ≥4 infusions, respectively, with a median of 31 days between two subsequent DLIs. Forty percent of evaluable patients received no treatment before the first DLI, whereas radiotherapy, conventional chemotherapy or targeted treatments were administered in 3, 39, and 18%, respectively. In informative patients, a few severe adverse events were reported: grade III–IV graft versus host disease (GVHD) (3%), grade III–IV hematological toxicity (11%), and DLI-related mortality (9%). Forty-six patients (18%) received a second HCT after a median of 232 days (32–1,390) from the first DLI. With a median follow-up of 461 days (2–3,255) after the first DLI, 1-, 3-, and 5- year overall survival (OS) of the whole group from start of DLI treatment was 55, 39, and 33%, respectively. In multivariate analysis, older recipient age, and transplants from haploidentical donors significantly reduced OS, whereas DLI for mixed chimerism or as pre-emptive/prophylactic treatment compared to DLI for AL relapse and a schedule including more than one DLI significantly prolonged OS. This GITMO survey confirms that DLI administration in absence of overt hematological relapse and multiple infusions are associated with a favorable outcome in AL patients. DLI from haploidentical donors had a poor outcome and may represent an area of further investigation.
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- 2020
8. Comparative evaluation of biological human leukocyte antigen DPB1 mismatch models for survival and graft-versus-host disease prediction after unrelated donor hematopoietic cell transplantation
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Anna Maria Gallina, Anna De Grassi, Francesca Lorentino, Valeria Miotti, Pietro Crivello, Katharina Fleischhauer, Alessandra Picardi, Lucia Farina, Elena Oldani, Nicoletta Sacchi, Paolo Bernasconi, Riccardo Saccardi, Fabio Benedetti, Francesca Patriarca, Francesca Bonifazi, Fabio Ciceri, Luca Vago, Michela Cerno, and Benedetto Bruno
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Hematopoietic cell ,business.industry ,medicine.medical_treatment ,Histocompatibility Testing ,Histocompatibility Antigens Class I ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Single-nucleotide polymorphism ,Hematology ,Human leukocyte antigen ,Hematopoietic stem cell transplantation ,medicine.disease ,Comparative evaluation ,Transplantation ,Graft-versus-host disease ,HLA Antigens ,Immunology ,Genotype ,Medicine ,Humans ,business ,Online Only Articles ,Unrelated Donors - Published
- 2020
9. The place of ceftazidime/avibactam and ceftolozane/tazobactam for therapy of haematological patients with febrile neutropenia
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Antonella Castagna, Marco Ripa, Fabio Giglio, Daniela Clerici, Chiara Oltolini, Jacopo Peccatori, Francesca Pavesi, Fabio Ciceri, Francesca Farina, Barbara Castiglion, Raffaella Greco, Consuelo Corti, Carmine Liberatore, Francesca Lorentino, Paolo Scarpellini, Chiara Tassan Din, Sara Mastaglio, Massimo Bernardi, Clerici, D., Oltolini, C., Greco, R., Ripa, M., Giglio, F., Mastaglio, S., Lorentino, F., Pavesi, F., Farina, F., Liberatore, C., Castiglion, B., Tassan Din, C., Bernardi, M., Corti, C., Peccatori, J., Scarpellini, P., Ciceri, F., and Castagna, A.
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0301 basic medicine ,Male ,Ceftazidime ,Bacteremia ,Gastroenterology ,chemistry.chemical_compound ,0302 clinical medicine ,Ceftazidime/avibactam ,Drug Resistance, Multiple, Bacterial ,Pharmacology (medical) ,030212 general & internal medicine ,Autografts ,Multi-drug resistant Gram-negative blood-stream infections ,education.field_of_study ,Haematopoietic stem cell transplantation ,General Medicine ,Middle Aged ,Allografts ,Anti-Bacterial Agents ,Drug Combinations ,Infectious Diseases ,Treatment Outcome ,Ceftolozane ,Female ,medicine.drug ,Microbiology (medical) ,Adult ,medicine.medical_specialty ,Tazobactam ,Avibactam ,030106 microbiology ,Population ,03 medical and health sciences ,Young Adult ,Internal medicine ,Gram-Negative Bacteria ,medicine ,Humans ,education ,Aged ,Febrile Neutropenia ,Retrospective Studies ,business.industry ,bacterial infections and mycoses ,medicine.disease ,Ceftolozane/tazobactam ,Cephalosporins ,Transplantation ,chemistry ,Carbapenems ,Empirical therapy of febrile neutropenia ,business ,Gram-Negative Bacterial Infections ,Azabicyclo Compounds ,Febrile neutropenia - Abstract
Objectives To evaluate ceftazidime/avibactam (C/A) and ceftolozane/tazobactam (C/T) use in haematological patients with febrile neutropenia receiving high-dose chemotherapy and haematopoietic stem cell transplantation (HSCT). Methods A retrospective study was conducted to assess C/A and C/T efficacy through infection-related mortality (IRM) and bacteraemia clearance for carbapenem-resistant Gram-negative bacteria (CR-GNB) pre-engraftment blood-stream infections (PE-BSIs) between January–December 2018. Results Seventy patients underwent allogeneic HSCT: C/A and C/T were dispensed in 13% and 3%, respectively. C/A was administered as definite therapy for carbapenem-resistant Klebsiella pneumoniae (CR-Kp) PE-BSI in four carriers (bacteraemia clearance in 5 days), empirical therapy for a clinically documented infection in two patients (one carrier with pneumonia and one non-carrier with shock) and empirical therapy for fever of unknown origin in three CR-Kp carriers. C/T was administered as definite therapy for carbapenem-resistant Pseudomonas aeruginosa (CR-Pa) intra-abdominal infection in one carrier and empirical therapy for a clinically documented infection (pneumonia) in one non-carrier. Among patients without PE-BSIs and with Gram-positive bacteria PE-BSIs, IRM was 0% at +30 days; conversely, it was 30% in GNB PE-BSIs (two CR-Kp and one CR-Pa C/T-resistant). Thirty-nine patients underwent autologous HSCT: C/A and C/T were administered, respectively, as definite therapy for CR-Kp PE-BSI in one carrier (bacteraemia clearance in 3 days) and for Pa PE-BSI (three strains, one CR-Pa) in one non-carrier (bacteraemia clearance in 2 days). Overall, IRM at +30 days was 0%. Conclusions Monitoring multidrug-resistant GNB colonisation enabled selection of carriers who benefit from prompt administration of new antibiotics, improving HSCT outcomes in a high-risk population. C/A and C/T were effective in bacteraemia clearance; unfortunately, multidrug-resistant GNB PE-BSIs were still a burden to IRM.
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- 2020
10. Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation
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Pier Edoardo Rovatti, Valentina Gambacorta, Francesca Lorentino, Fabio Ciceri, Luca Vago, Rovatti, P. E., Gambacorta, V., Lorentino, F., Ciceri, F., and Vago, L.
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lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,T-Lymphocytes ,Immunology ,Cell- and Tissue-Based Therapy ,Graft vs Host Disease ,Graft vs Leukemia Effect ,Review ,Human leukocyte antigen ,Disease ,Malignancy ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Recurrence ,Internal medicine ,medicine ,Animals ,Humans ,Transplantation, Homologous ,Immunology and Allergy ,Molecular Targeted Therapy ,relapse ,Leukemia ,haploidentical allogeneic hematopoietic stem cell transplantation ,Hematopoietic cell ,business.industry ,immune escape ,Hematopoietic Stem Cell Transplantation ,Histocompatibility Antigens Class II ,medicine.disease ,Evasion (ethics) ,immune check point ,HLA ,Transplantation ,030104 developmental biology ,Haplotypes ,Tumor Escape ,Immunotherapy ,lcsh:RC581-607 ,business ,030215 immunology - Abstract
Over the last decade, the development of multiple strategies to allow the safe transfer from the donor to the patient of high numbers of partially HLA-incompatible T cells has dramatically reduced the toxicities of haploidentical hematopoietic cell transplantation (haplo-HCT), but this was not accompanied by a similar positive impact on the incidence of post-transplantation relapse. In the present review, we will elaborate on how the unique interplay between HLA-mismatched immune system and malignancy that characterizes haplo-HCT may impact relapse biology, shaping the selection of disease variants that are resistant to the “graft-vs.-leukemia” effect. In particular, we will present current knowledge on genomic loss of HLA, a relapse modality first described in haplo-HCT and accounting for a significant proportion of relapses in this setting, and discuss other more recently identified mechanisms of post-transplantation immune evasion and relapse, including the transcriptional downregulation of HLA class II molecules and the enforcement of inhibitory checkpoints between T cells and leukemia. Ultimately, we will review the available treatment options for patients who relapse after haplo-HCT and discuss on how a deeper insight into relapse immunobiology might inform the rational and personalized selection of therapies to improve the largely unsatisfactory clinical outcome of relapsing patients.
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- 2020
11. Adjuvant role of SeptiFast to improve the diagnosis of sepsis in a large cohort of hematological patients
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Consuelo Corti, Fabio Giglio, Chiara Oltolini, Maria Chiara Barbanti, Francesca Lorentino, Matteo Carrabba, Massimo Bernardi, Alessandra Forcina, Lara Crucitti, Carlo Messina, Maria Teresa Lupo Stanghellini, Sarah Marktel, Mara Morelli, Luca Vago, Raffaella Greco, Paolo Scarpellini, Nicasio Mancini, Jacopo Peccatori, Massimo Clementi, Fabio Ciceri, Laura Infurnari, Andrea Assanelli, Daniela Clerici, Raffaella, Greco, Maria Chiara Barbanti, Mancini, Nicasio, Lara, Crucitti, Chiara, Oltolini, Alessandra, Forcina, Francesca, Lorentino, Vago, LUCA ALDO EDOARDO, Carlo, Messina, Daniela, Clerici, Mara, Morelli, Fabio, Giglio, Maria Teresa Lupo Stanghellini, Laura, Infurnari, Carrabba, Matteo G., Sarah, Marktel, Andrea, Assanelli, Paolo, Scarpellini, Massimo, Bernardi, Jacopo, Peccatori, Consuelo, Corti, Clementi, Massimo, and Ciceri, Fabio
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Concordance ,030106 microbiology ,Gram-Positive Bacteria ,Sepsis ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Gram-Negative Bacteria ,medicine ,Humans ,030212 general & internal medicine ,Aged ,Febrile Neutropenia ,Retrospective Studies ,Transplantation ,Blood Specimen Collection ,business.industry ,Fungi ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,Antimicrobial ,Hematologic Diseases ,Absolute neutrophil count ,Female ,Reagent Kits, Diagnostic ,business ,Adjuvant ,Febrile neutropenia ,Cohort study - Abstract
Febrile neutropenia and sepsis are common and life-threatening complications in hematological diseases. This study was performed retrospectively in 514 patients treated for febrile neutropenia at our institute, to investigate the clinical usefulness of a molecular tool, LightCycler® SeptiFast test (SF), to promptly recognize pathogens causing sepsis in hematological patients. We collected 1837 blood samples of 514 consecutive hematological patients. The time of processing is short. Overall, 757 microorganisms in 663 episodes were detected by molecular test and standard blood cultures (BC): 73.6% Gram-positive bacteria, 23.9% Gram-negative bacteria, and 2.5% fungal species. This large analysis demonstrated a significant episode-to episode agreement (71.9%) between the two methods, higher in negative samples (89.14%), and a specificity of 75.89%. Clinical variables that gave a statistically significant contribution to their concordance were absolute neutrophil count, ongoing antimicrobial therapy, timing of test execution, and organ localization of infection. The large analysis highlights the potential of molecular-based assays directly performed on blood samples, especially if implementing the detection of antibiotic resistance genes, which was lacking in the used study.
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- 2018
12. CMV-Specific T Cells Restricted By Shared and Donor, but Not By Host HLA Molecules Reconstitute in the First 180 Days after Allogeneic HSCT and Protect from CMV Reactivation: Results of a Prospective Observational Study
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Fabio Ciceri, Massimo Bernardi, Elena Tassi, Maddalena Noviello, Liselotte Brix, Daniela Clerici, Jacopo Peccatori, Lorenzo Lazzari, Francesca Serio, Chiara Bonini, Fabio Giglio, Consuelo Corti, Roee Dvir, Maria Teresa Lupo Stanghellini, Raffaella Greco, Sara Racca, Pantaleo De Simone, Giacomo Oliveira, and Francesca Lorentino
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education.field_of_study ,biology ,business.industry ,medicine.medical_treatment ,CD3 ,T cell ,Immunology ,Population ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Human leukocyte antigen ,Biochemistry ,Transplantation ,medicine.anatomical_structure ,Cord blood ,biology.protein ,Medicine ,business ,education ,CD8 - Abstract
Introduction: Cytomegalovirus (CMV) reactivation and disease are important risk factors after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and strongly affect morbidity and mortality after transplant. CMV-specific T cell reconstitution controls CMV reactivation and protects against serious adverse events but a protective level of CMV-specific T cell response or standardized method for its monitoring have not been yet determined. Methods: We designed a prospective, single-center observational study to assess if the kinetic and quality of CMV specific T-cell reconstitution impact the incidence and severity of CMV reactivations. We have enrolled 84 consecutive patients affected by hematological malignancies receiving allo-HSCT followed by Cyclophosphamide and Rapamycin between December 2017 and February 2019. Here we report preliminary data on the first 61 patients. Patients received allo-HSCT from family (siblings=10; HLA haploidentical=24), unrelated HLA-matched (n= 24) donors or cord blood (CB, n=3). The CMV serostatus of host (H) and donor (D) pairs was: H+/D+(n=40, 65%), H+/D-(n=20, 33%) and H-/D+ (n=1, 2%); H-/D-(7% of the overall transplanted population at our center) were excluded. CMV DNAemia was assessed weekly in whole blood (WB). Absolute numbers of polyclonal and CMV-specific T cells were quantified by flow cytometry using Troucount™Tubes (BD) and Dextramer®CMV-Kit (Immudex), respectively, in the graft and fresh WB at days -7, +30, +45, +60, +90, +120, +150, +180 and +360. Dextramer CMV kit includes reagents for the identification of CMV-specific lymphocytes restricted for several HLA class I molecules: A*01:01/*02:01/*03:01/*24:02 and B*07:02/*08:01/*35:01. These alleles allowed the longitudinal evaluation of 54 out of 61 (89%) patients. Results: At a median follow-up of 226 days post-HSCT, 31 (57%) patients experienced a CMV-related clinically relevant event (CRE, median +63 days), including 8 patients (15%) with CMV disease (median +59 days). Univariate analyses showed that the incidence of CMV clinically-relevant reactivation (CRE) was influenced by H/D CMV serostatus (0.90 in H+/D- versus 0.44 in H+/D+pairs, p=0.015) and by previous acute Graft-versus-Host Disease (aGvHD) requiring systemic immunosuppression (0.82 in aGvHD grade II-IV versus 0.52 in aGvHD grade 0-I, p=0.051). The disease status at transplant, the donor type (HLA-matched versus HLA-haploidentical/CB donors), donor's or host's age did not significantly affect the probability to develop CRE. For each time-point, we compared the absolute number of CMV-specific lymphocytes in patients experiencing or not a subsequent CRE. Our data demonstrate that higher levels of CMV-specific CD8+T cells in the donor apheresis and at +45 days after allo-HSCT are associated with reduced risk of subsequent CRE (median CMV-specific CD8+cells/kg in the apheresis=5x103in CRE-positive patients (CRE+) and 5x105in CRE-negative patients (CRE-), p=0.012; median CMV-specific CD8+at +45 days=0.14 cells/μL in CRE+and 1.21 cells/μL in CRE-, p=0.034). Furthermore, patients with any Dextramer positivity at +45 days displayed a lower incidence of CRE compared with subjects who were negative (CRE probability: 0.5 vs 1.0, p=0.003). Conversely, the absolute number of neither polyclonal CD3+CD8+T lymphocytes nor total CD3+T cells correlate with subsequent CRE. Taking advantage of the HLA mismatched-HSCT setting, we then dissected CMV-specific T-cell response according to HLA restriction elements (H/D=shared n=45, D-restricted n=14, H-restricted n=11). In H+/D+pairs, we observed a fast and similar kinetic of reconstitution of CMV-specific lymphocytes restricted by H/D and D HLAs. Conversely, in H+/D-pairs, we detected only CMV-specific CD8+lymphocytes restricted for H/D haplotypes. Host-restricted cells remained undetectable for the first 180 days after HSCT. Conclusion: Early after allo-HSCT and in the donor apheresis, the level of CMV-specific CD8+T cells measured by Dextramer staining differs in patients experiencing or not subsequent CRE. Furthermore, our findings indicate that CMV reactivations can prime H/D-restricted T cells presumably educated in the donor thymus; conversely, D- and H-restricted donor-derived lymphocytes have not yet undergone neither cross-priming nor thymic education respectively. Disclosures Brix: Immudex: Employment. Bonini:Kite/Gilead: Consultancy; Intellia Therapeutics: Consultancy; Intellia Therapeutics: Research Funding; Novartis: Consultancy; GSK: Consultancy; Allogene: Consultancy; Molmed: Consultancy; TxCell: Consultancy; -: Patents & Royalties: Adoptive T cell therapy field.
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- 2019
13. Killer cell immunoglobulin-like receptor ligand mismatching and outcome after haploidentical transplantation with post-transplant cyclophosphamide
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Avichai Shimoni, Johanna Tischer, Boris V. Afanasyev, Maria Teresa Van Lint, Yener Koc, Francesca Lorentino, Mohamad Mohty, Arnon Nagler, Didier Blaise, Pietro Pioltelli, Benedetto Bruno, Myriam Labopin, Zafer Gulbas, Fabio Ciceri, Shimoni, Avichai, Labopin, Myriam, Lorentino, Francesca, van Lint, Maria Teresa, Koc, Yener, Gülbas, Zafer, Tischer, Johanna, Bruno, Benedetto, Blaise, Didier, Pioltelli, Pietro, Afanasyev, Bori, Ciceri, Fabio, Mohty, Mohamad, and Nagler, Arnon
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0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Transplantation Conditioning ,Cyclophosphamide ,KIR Ligand ,Graft vs Host Disease ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Receptors, KIR ,Internal medicine ,medicine ,Humans ,Survival rate ,Aged ,Retrospective Studies ,Acute leukemia ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Prognosis ,Histocompatibility ,Transplantation ,Killer Cells, Natural ,Survival Rate ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,030220 oncology & carcinogenesis ,Transplantation, Haploidentical ,Female ,business ,Immunosuppressive Agents ,medicine.drug ,Follow-Up Studies - Abstract
Haploidentical stem cell transplantation with T cell-replete grafts and post-transplant cyclophosphamide (PTCy) is increasingly used with encouraging outcome. Natural killer (NK) cell alloreactivity, predicted by missing killer cell immunoglobulin-like receptor (KIR) ligands in the recipient that are present in their donor improves outcome of T cell-depleted haploidentical transplants. We explored the role of KIR ligand mismatching in 444 acute leukemia patients after T cell-replete transplants with PTCy. Thirty-seven percent of all patients had KIR ligand mismatching. Patients were in first remission (CR1) (39%), second remission (CR2) (26%), or active disease (35%). Stem cell source was peripheral blood (PBSC, 46%) or bone marrow (54%). The 2-year relapse, non-relapse mortality (NRM), and survival rates were 36.0% (95% confidence interval (CI), 31.4–40.7), 23.9% (20.0–28.0), and 45.9% (40.8–51.0), respectively. Multivariate analysis identified acute myeloid leukemia compared with acute lymphoblastic leukemia (hazard ratio (HR) 0.55, P = 0.002), female gender (HR 0.72, P = 0.04), and good performance status (HR 0.71, P = 0.04) as factors associated with better survival, while advanced age (HR 1.13, P = 0.04), active disease (HR 3.38, P < 0.0001), and KIR ligand mismatching (HR 1.41, P = 0.03) as associated with worse survival. KIR ligand mismatching was associated with a trend for higher relapse but not with graft-versus-host disease or NRM. The KIR ligand-mismatching effect was more prominent in patients given PBSC. In conclusion, there is no evidence that KIR ligand mismatching results in better outcome in the PTCy setting.
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- 2018
14. Clinical Impact of Pretransplant Multidrug-Resistant Gram-Negative Colonization in Autologous and Allogeneic Hematopoietic Stem Cell Transplantation
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Francesca Lorentino, Fabio Ciceri, Chiara Oltolini, Alessandra Forcina, Matteo Carrabba, Raffaella Greco, Massimo Bernardi, Jacopo Peccatori, Maria Teresa Lupo-Stanghellini, Magda Marcatti, Consuelo Corti, Vincenzo Marasco, Forcina, Alessandra, Lorentino, Francesca, Marasco, Vincenzo, Oltolini, Chiara, Marcatti, Magda, Greco, Raffaella, Lupo-Stanghellini, Maria Teresa, Carrabba, Matteo, Bernardi, Massimo, Peccatori, Jacopo, Corti, Consuelo, and Ciceri, Fabio
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Adult ,Male ,medicine.medical_specialty ,Multivariate analysis ,Transplantation Conditioning ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Bacteremia ,Disease ,Hematopoietic stem cell transplantation ,Gastroenterology ,Transplantation, Autologous ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Drug Resistance, Multiple, Bacterial ,Overall survival ,Medicine ,Humans ,Transplantation, Homologous ,Colonization ,Gram ,Aged ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Independent factor ,Multiple drug resistance ,surgical procedures, operative ,Multidrug-resistant Gram-negative bacteria ,030220 oncology & carcinogenesis ,HSCT ,Female ,business ,Pretransplant colonization ,030215 immunology - Abstract
Multidrug-resistant Gram-negative bacteria (MDR-GNB) are an emerging cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Three-hundred forty-eight consecutive patients transplanted at our hospital from July 2012 to January 2016 were screened for a pretransplant MDR-GNB colonization and evaluated for clinical outcomes. A pretransplant MDR-GNB colonization was found in 16.9% of allo-HSCT and in 9.6% of auto-HSCT recipients. Both in auto- and in allo-HSCT, carriers of a MDR-GNB showed no significant differences in overall survival (OS), transplant-related mortality (TRM), or infection-related mortality (IRM) compared with noncarriers. OS at 2 years for carriers compared with noncarriers was 85% versus 81% (P =.262) in auto-HSCT and 50% versus 43% (P =.091) in allo-HSCT. TRM at 2 years was 14% versus 5% (P =.405) in auto-HSCT and 31% versus 25% (P =.301) in allo-HSCT. IRM at 2 years was 14% versus 2% (P =.142) in auto-HSCT and 23% versus 14% (P =.304) in allo-HSCT. In multivariate analysis, only grade III to IV acute graft-versus-host disease was an independent factor for reduced OS (P
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- 2018
15. Permissive HLA-DPB1 mismatch and survival after unrelated donor allogeneic stem cell transplantation for hematological malignancies: a comparative analysis of different immunogenetic models on 422 patients from GITMO and IBMDR
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Katharina Fleischhauer, Alessandra Picardi, Nicoletta Sacchi, Paolo Bernasconi, Anna Maria Gallina, Fabio Ciceri, Francesca Lorentino, Benedetto Bruno, Elena Oldani, Francesca Bonifazi, Alessandro Rambaldi, Francesca Patriarca, Michela Cerno, Valeria Miotti, Fabio Benedetti, Riccardo Saccardi, Luca Vago, and Lucia Farina
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Oncology ,Acute leukemia ,medicine.medical_specialty ,HLA-DPB1 ,business.industry ,medicine.medical_treatment ,Immunology ,Medizin ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Human leukocyte antigen ,medicine.disease ,Settore MED/15 ,Biochemistry ,Transplantation ,Graft-versus-host disease ,Internal medicine ,Genotype ,medicine ,business ,Multiple myeloma - Abstract
Introduction: Hematopoietic Stem Cell Transplantation (HSCT) from unrelated donors (UD) is a curative therapy for many hematologic malignancies. HLA matching plays a major role in determining HSCT outcome but the relative role of incompatibilities at the different HLA loci is still debated. In particular, over 80% of UD-HSCT are performed across HLA-DPB1 mismatches (mm): a number of previous studies have devised immunogenetic models to elucidate the impact of HLA-DPB1 mm on HSCT outcome, but a comparative analysis of these models in a recent and well-characterized cohort is lacking. Methods: We selected 422 adult patients (pts) who received an 8/8 (HLA-A, B, -C and -DRB1) allele level-matched UD-HSCT from 2012 to 2015: of them, 382 (90%) had a mm at one or both HLA-DPB1 alleles. We classified functional HLA-DPB1 matching by four models, on the basis of: I) differential immunogenicity of alleles belonging to 3 groups of T-cell epitopes (TCE), as defined by functional studies (Zino, Blood, 2004) and refined by in silico prediction (Crivello, BBMT 2015); II) a similar model subdividing allelles in 4 TCE groups (TCE4, Crocchiolo, Blood 2009); III) differences in "delta functional distance" scores between the alleles of donor and pt, based on 12 polymorphic AA in HLA-DPB1 exon 2 (Crivello, Blood 2016); IV) mismatches in the rs9277534 single-nucleotide polymorphism in the HLA-DPB1 3′ UTR region, predicted on the basis of the DPB1 genotype (Schöne, Hum Immunol 2018), and previously shown to be associated to the expression levels of HLA-DPB1 molecules (HLAexp, Petersdorf, NEJM 2015). Indication for HSCT was acute leukemia (55%), lymphoma and multiple myeloma (29%), myelodysplastic and myeloproliferative syndromes (16%). According to EBMT score definition, 45% of pts were in early, 26% in intermediate, and 29% in advanced disease status. Conditioning regimens were myeloablative (64%) or reduced intensity (36%). Peripheral blood was the preferred stem cell source (81%). Graft-versus-host disease (GvHD) prophylaxis was based on anti-thymocyte globulin (ATG) in 91% of pts, mostly associated with cyclosporine and methotrexate (81%). Median follow-up was 3.2 y. Results: Among the four models adopted to classify functional HLA-DPB1 matching, the TCE4 provided the best results in predicting mm that were permissive (P) or non permissive (NP) for HSCT outcomes. By this model, P mismatched pairs (N=135) had a significantly superior 3-y overall survival (OS) and Graft-versus host disease and Relapse-Free Survival (GRFS) compared to NP pairs (N=247) (60±8% vs 49±7%, p .05; and 36±8% vs 29±5%, p .04). This was associated with a higher transplant-related mortality (TRM), 30±6% in NP mm and 21±6% in P mm, p .09 and a higher 3-y CI of extensive cGvHD in NP mm (12±4%) compared to P (4±2%), p .01 (Figure 1). No effect was found for relapse incidence. Cox multivariate analysis (adjusted for pt age, donor/host gender and CMV, disease status, Sorror score, conditioning intensity, stem cell source, ATG use, HLA matching on 5 loci, center effect), showed that a NP mm compared to P mm was associated with higher hazards for OS (HR 1.6, p .01), GRFS (HR 1.4, p .02), TRM (HR 1.9, p .01), cGvHD (HR 1.6, p .03) and extensive cGvHD (HR 3.6, p Of the 382 transplants with HLA-DPB1 mismatches, 229 had unidirectional mismatches in GvH direction and thus could be classified by the HLAexp model. The predicted expression level of the mismatched allele in the patient was associated with 100-d CI of grade≥2 aGvHD: 32±10% in high expression (N=76) versus 16±6% in low expression (N=153) mismatched alleles, p No significant associations with clinical outcomes were found for the "delta functional distance" or the TCE3 model, respectively. Conclusions: Our study provides further proof that functional HLA-DPB1 matching is crucially associated to UD-HSCT outcome also in recent transplants, and suggest that, at least in the cohort under analysis, mainly composed of Italian pts transplanted using an ATG-based prophylaxis, the TCE4 model appears superior to other models in stratifying risk groups and predicting survival. Figure. Figure. Disclosures Patriarca: Medac: Other: Travel, accommodations, expenses; Jazz: Other: Travel, accommodations, expenses; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Janssen: Other: Advisory role; MSD Italy: Other: Advisory Role. Rambaldi:Italfarmaco: Consultancy; Roche: Consultancy; Omeros: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Amgen Inc.: Consultancy. Fleischhauer:GENDX: Research Funding. Vago:GENDX: Research Funding; Moderna TX: Research Funding.
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- 2018
16. NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: Dynamics and clinical implications
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Maria Teresa Lupo Stanghellini, Raffaella Greco, Sofia Berglund, Leo Luznik, Francesca Lorentino, Giacomo Oliveira, Fabio Giglio, Andrea Assanelli, Mara Morelli, Valentina Gambacorta, Simona Piemontese, Jacopo Peccatori, Antonio Russo, Luca Vago, Nicoletta Cieri, Fabio Ciceri, Chiara Bonini, Cristina Toffalori, Laura Zito, Russo, Antonio, Oliveira, Giacomo, Berglund, Sofia, Greco, Raffaella, Gambacorta, Valentina, Cieri, Nicoletta, Toffalori, Cristina, Zito, Laura, Lorentino, Francesca, Piemontese, Simona, Morelli, Mara, Giglio, Fabio, Assanelli, Andrea, Stanghellini, Maria Teresa Lupo, Bonini, Chiara, Peccatori, Jacopo, Ciceri, Fabio, Luznik, Leo, Vago, Luca, Russo, A, Oliveira, G, Berglund, S, Greco, R, Gambacorta, V, Cieri, N, Toffalori, C, Zito, L, Lorentino, F, Piemontese, S, Morelli, M, Giglio, F, Assanelli, A, Stanghellini, M, Bonini, C, Peccatori, J, Ciceri, F, Luznik, L, and Vago, L
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medicine.medical_specialty ,Cyclophosphamide ,medicine.medical_treatment ,Cell ,Immunology ,Hematopoietic stem cell transplantation ,Biology ,Biochemistry ,03 medical and health sciences ,Interleukin 21 ,0302 clinical medicine ,Internal medicine ,medicine ,Transplantation ,Hematology ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Killer Cells, Natural ,Haematopoiesis ,surgical procedures, operative ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Stem cell ,030215 immunology ,medicine.drug - Abstract
The use of posttransplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis has revolutionized haploidentical hematopoietic stem cell transplantation (HSCT), allowing safe infusion of unmanipulated T cell-replete grafts. PT-Cy selectively eliminates proliferating alloreactive T cells, but whether and how it affects natural killer (NK) cells and their alloreactivity is largely unknown. Here we characterized NK cell dynamics in 17 patients who received unmanipulated haploidentical grafts, containing high numbers of mature NK cells, according to PT-Cy-based protocols in 2 independent centers. In both series, we documented robust proliferation of donor-derived NK cells immediately after HSCT. After infusion of Cy, a marked reduction of proliferating NK cells was evident, suggesting selective purging of dividing cells. Supporting this hypothesis, proliferating NK cells did not express aldehyde dehydrogenase and were killed by Cy in vitro. After ablation of mature NK cells, starting from day 15 after HSCT and favored by the high levels of interleukin-15 present in patients' sera, immature NK cells (CD62L+NKG2A+KIR-) became highly prevalent, possibly directly stemming from infused hematopoietic stem cells. Importantly, also putatively alloreactive single KIR+ NK cells were eliminated by PT-Cy and were thus decreased in numbers and antileukemic potential at day 30 after HSCT. As a consequence, in an extended series of 99 haplo-HSCT with PT-Cy, we found no significant difference in progression-free survival between patients with or without predicted NK alloreactivity (42% vs 52% at 1 year, P = NS). Our data suggest that the majority of mature NK cells infused with unmanipulated grafts are lost upon PT-Cy administration, blunting NK cell alloreactivity in this transplantation setting.
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- 2018
17. Comparable outcomes of haploidentical, 10/10 and 9/10 unrelated donor transplantation in adverse karyotype AML in first complete remission
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Didier Blaise, Gérard Socié, Tobias Gedde-Dahl, Arnon Nagler, Annalisa Ruggeri, Francesca Lorentino, Nathalie Fegueux, Jan J. Cornelissen, Fabio Ciceri, Jacob Passweg, Liisa Volin, Ibrahim Yacoub-Agha, Marrow Transplantation, Monica Poiani, Mohamad Mohty, Massimo Bernardi, Jordi Esteve, Myriam Labopin, Charles Craddock, Hematology, Lorentino, Francesca, Labopin, Myriam, Bernardi, Massimo, Ciceri, Fabio, Socié, Gerard, Cornelissen, Jan J., Esteve, Jordi, Ruggeri, Annalisa, Volin, Liisa, Yacoub-Agha, Ibrahim, Craddock, Charle, Passweg, Jacob, Blaise, Didier, Gedde-Dahl, Tobia, Poiani, Monica, Fegueux, Nathalie, Mohty, Mohamad, Nagler, Arnon, Service d’Hématologie [Institut Paoli Calmettes, Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)
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Male ,Oncology ,Myeloid ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Abnormal Karyotype ,Graft vs Host Disease ,Kaplan-Meier Estimate ,Hematopoietic stem cell transplantation ,0302 clinical medicine ,HLA Antigens ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Registries ,education.field_of_study ,Incidence (epidemiology) ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Allografts ,Combined Modality Therapy ,3. Good health ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,surgical procedures, operative ,medicine.anatomical_structure ,Histocompatibility ,030220 oncology & carcinogenesis ,Female ,Unrelated Donors ,Adult ,medicine.medical_specialty ,Adolescent ,Population ,Disease-Free Survival ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,education ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Proportional hazards model ,business.industry ,medicine.disease ,Transplantation ,business ,030215 immunology - Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is the most powerful therapy preventing relapse in patients with adverse cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1). In the absence of a matched related donor, potential alternatives include 10/10, 9/10 HLA-matched unrelated (UD) or haploidentical (Haplo) donors. We analyzed clinical outcomes of patients undergoing T-cell repleted Haplo (n = 74), 10/10 UD (n = 433) and 9/10 UD HSCT (n = 123) from 2007 to 2015, reported to the EBMT Registry. Adverse risk AML was defined according to the 2017 ELN cytogenetic risk classification. The 2-year nonrelapse mortality was 19% for Haplo, 18% for 10/10 UD and 18% for 9/10 UD (P = .9). The relapse incidence was not significantly affected by donor source, with a 2-year incidence of 27% for Haplo HSCT, 39% for 10/10 UD and 37% for 9/10 UD SCT (P = .3). We show comparable probabilities of leukemia-free survival (LFS) and overall survival (OS) at 2 years among Haplo HSCT, 10/10 UD SCT and 9/10 UD SCT (53% and 59%, 43% and 50%, 44% and 50%, respectively, P = .5 for both parameters). The type of donor was not significantly associated with either acute or chronic graft-vs.-host disease incidence. Using multivariable Cox model, Haplo HSCT recipients experienced comparable OS and LFS to 10/10 and 9/10 UD. In the present series of adverse cytogenetics AML patients in CR1, Haplo HSCT recipients had comparable outcomes to those of 10/10 and 9/10 UDs, suggesting that all these types of HSCT may be considered a valid option in this high risk population.
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- 2018
18. The impact of HLA matching on outcomes of unmanipulated haploidentical HSCT is modulated by GVHD prophylaxis
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Avichai Shimoni, Giuseppe Messina, Carlheinz Mueller, Johanna Tischer, Zafer Gulbas, Andrea Bacigalupo, William Arcese, Fabio Ciceri, Myriam Labopin, Arnon Nagler, Martin Bornhäuser, Francesca Lorentino, Yener Koc, Dietrich W. Beelen, Mohamad Mohty, Benedetto Bruno, Katharina Fleischhauer, A. Ruggeri, Didier Blaise, Lorentino, Francesca, Labopin, Myriam, Fleischhauer, Katharina, Ciceri, Fabio, Mueller, Carlheinz R, Ruggeri, Annalisa, Shimoni, Avichai, Bornhäuser, Martin, Bacigalupo, Andrea, Gülbas, Zafer, Koc, Yener, Arcese, William, Bruno, Benedetto, Tischer, Johanna, Blaise, Didier, Messina, Giuseppe, Beelen, Dietrich W, Nagler, Arnon, and Mohty, Mohamad
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endocrine system ,Transplantation ,Acute leukemia ,Cyclophosphamide ,medicine.medical_treatment ,Hazard ratio ,Medizin ,chemical and pharmacologic phenomena ,Hematology ,Human leukocyte antigen ,Hematopoietic stem cell transplantation ,Biology ,Confidence interval ,03 medical and health sciences ,Regimen ,surgical procedures, operative ,0302 clinical medicine ,immune system diseases ,030220 oncology & carcinogenesis ,Immunology ,medicine ,Settore MED/15 - Malattie del Sangue ,030215 immunology ,medicine.drug - Abstract
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with unmanipulated grafts is increasingly adopted for high-risk acute leukemia, with acute graft-versus-host disease (aGVHD) prophylaxis based on antithymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCy) as main platforms. No consensus exists on selection criteria over several haploidentical donors. We evaluated the impact of donor-recipient antigenic and allelic HLA-A, -B, -C, and -DRB1 mismatches on mismatched haplotype on outcomes of 509 unmanipulated haplo-HSCTs performed for acute leukemia under a PTCy (N = 313) or ATG (N = 196) regimen. An antigenic but not allelic mismatch at the HLA-DRB1 locus was an independent risk factor for grade ≥2 aGVHD in PTCy (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.2-4.0; P = .02) but not in ATG regimens (HR, 1.3; 95% CI, 0.4-3.4; P = .6). Moreover, the hazards of aGVHD were significantly associated with other factors influencing alloreactivity, including peripheral blood as stem cell source (HR, 2.2; 95% CI, 1.4-3; P < .01), reduced-intensity conditioning (HR, 0.6; 95% CI, 0.4-0.9; P = .04), and female donors (HR, 1.8; 95% CI, 1-3.2; P = .05), in PTCy but not ATG regimens. No significant associations were found between cumulative number of HLA mismatches and GVHD, or between HLA-matching status and other study end points including transplant-related mortality, disease-free survival, and relapse. Based on these data, the role of HLA mismatching on unshared haplotype appears not to be sufficiently prominent to justify its consideration in haploidentical donor selection. However, the role of HLA matching in haploidentical HSCT might be modulated by GVHD prophylaxis, calling for further investigations in this increasingly relevant field.
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- 2017
19. High Resolution Donor/Recipient HLA Matching Level in Unrelated Hematopoietic Stem Cell Transplantation and Impact on the Transplant Outcome: The Italian Experience on Behalf of GITMO, IBMDR and Aibt
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Giorgina Specchia, Anna Paola Iori, Anna Maria Gallina, Francesca Patriarca, P Chiusolo, Attilio Olivieri, Giorgia Saporiti, Domenico Russo, Francesca Bonifazi, Alessandro Rambaldi, G. Papalinetti, Luca Vago, Alessandra Picardi, William Arcese, Mariarosaria Sessa, Paolo Bernasconi, Carlo Borghero, Benedetto Bruno, Lucia Farina, Pietro Pioltelli, Nicoletta Sacchi, Fabio Ciceri, Angelo Michele Carella, Michela Cerno, Teresa Lamparelli, Valeria Miotti, Franco Narni, Francesca Lorentino, Giuseppe Milone, Stefano Guidi, Marco Andreani, Elena Oldani, Franca Fagioli, Francesco Zallio, Fabio Benedetti, and Sonia Mammoliti
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Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Human leukocyte antigen ,Hematopoietic stem cell transplantation ,Transplant-Related Mortality ,Total body irradiation ,Settore MED/15 ,medicine.disease ,Biochemistry ,Transplantation ,medicine.anatomical_structure ,Graft-versus-host disease ,Internal medicine ,Medicine ,Bone marrow ,Progression-free survival ,business - Abstract
Introduction: HLA molecules play an important role for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). To elucidate the effect and the potential identification of "permissive" and "non permissive" I and II class HLA mismatching (mm) loci on the early and long term transplant outcome, we conducted a retrospective/prospective observational analysis on 1789 patients transplanted with unmanipulated haematopoietic stem cells from a volunteer unrelated donor (URD). Methods Between January 2012 to December 2015, 1789 adult patients with a median age of 49 years (18-70) affected by haematological malignant diseases, performed an unrelated HSCT, coordinated by the Italian Bone Marrow Donor Registry (IBMDR). All patients have been typed by high resolution (HR) HLA typing for HLA-A/B/C/DRB1/DQB1 loci, at the start of the donor's search process. Patient and donor characteristics are shown in Table 1. As conditioning regimen and GVHD prophylaxis, 71% of patients received a myeloablative conditioning and 76% a combination of anti-Thymoglobuline, Cyclosporine and Metotrexate short course. Total Body Irradiation was part of conditioning regimen in 14% of cases and PBSC was used as stem cell source in 80% of transplants. Median follow for survivors was 38 months (1-76). Regarding to the allelic compatibility, 890 (50%) of donor/recipient (D/R) pairs were 10/10 HLA matched, 677 (38%) showed 1 mm for A, B, C, DRB1 or DQB1 in 249, 141, 173, 2 and 112 cases, respectively and 222 (12%) received HSCT from a 8/10 or less HLA matched donor. Results: Overall 90% and 79% of patients achieved PMN and PLTS engraftment within 30 and 90 days, respectively. Probabilities of 3-y Overall Survival (3-yr OS), Progression Free Survival (3-yr PFS), and Graft Relapse Free Survival (3-yr GRFS) were 52%, 42%, and 30%, respectively. The 3-y CI of Transplant Related Mortality (TRM) was 26%, with a 100-days CI of acute GVHD ≥2 of 26%, whereas the 3-yr CI of chronic GVHD was 30%, of which 10% extensive. Cox multivariate analysis showed that, compared to 10/10 HLA-matched HSCT, 9/10 and ≤8/10 HLA-matched HSCT were associated with worse outcomes in terms of OS (HR 1.16, p=0.04 and HR 1.3, p=0.007, respectively), GRFS (HR 1.2, p=0.005 and HR 1.2, p=0.07, respectively), TRM (HR 1.3, p=0.007 and HR 1.6, p 5%: the presence of A02:01 in the patient's HLA, after adjustment for HLA matching at the other loci and other clinical variables known to affect HSCT outcome, was associated with significant higher risk of TRM (HR 1.9, p= 0.03) and worst OS (HR 1.7, p=0.04). Patient's age > 49 years (p10 HSCT/year) is associated with reduced TRM (HR 0.8, p=0.0001), HSCT from female donor to male recipient was associated with higher risk of extensive cGvHD (HR 1.4, p=0.03), and CMV negative/negative status versus other combinations had protective effect on development of grade 3-4 aGVHD (HR 0.56, p=0.04). Conclusions: Our large cohort data of homogeneously treated 1789 URD transplants, show that 10/10 HLA matching remains a significantly favorable prognostic factor for OS, TRM, GRFS and acute/chronic GVHD, whereas there are no significant differences between 8/10 and 9/10 matching transplants. Moreover, the HLA A02:01 as single mm seems to play a "non permissive" role. Finally the Italian origin of recipient and donor is related to a reduced development of GVHD probably due to the matching of the extended MHC haplotypes in individuals of the same geographic origin. Disclosures Rambaldi: Amgen Inc.: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Omeros: Consultancy; Roche: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy. Vago:Moderna TX: Research Funding; GENDX: Research Funding. Patriarca:Janssen: Other: Advisory role; Jazz: Other: Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; Celgene: Other: Advisory Role; Travel, accommodations, expenses; MSD Italy: Other: Advisory Role.
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- 2018
20. 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
21. Endocrinopathies Following Allogeneic Stem Cell Transplantation: 10 Years Follow-up in 402 Patients
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Maria Teresa Lupo Stanghellini, Gabriele Casirati, Elisabetta Xue, Fabio Serpenti, Chiara Bonini, Raffaella Greco, Sara Mastaglio, Consuelo Corti, Andrea Assanelli, Daniela Clerici, Francesca Lorentino, Fabio Giglio, Francesca Pavesi, Fabio Ciceri, Giovanni Vita, Emanuele Bosi, Carmine Liberatore, Massimo Bernardi, Francesca Farina, Simona Piemontese, Magda Marcatti, Jacopo Peccatori, and Lorenzo Lazzari
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medicine.medical_specialty ,Univariate analysis ,Diet therapy ,business.industry ,medicine.medical_treatment ,Immunology ,Levothyroxine ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Transplantation ,Osteopenia ,Graft-versus-host disease ,Internal medicine ,medicine ,business ,Dyslipidemia ,medicine.drug - Abstract
Introduction Allogeneic stem cell transplantation (allo-HCT) survivors are at a defined relevant risk of developing long-term complications: the prevalence of chronic health conditions approaches 75% among HCT survivors. The endocrine system is one of the most frequent targets of complications, providing justification for a long-term and continuous follow-up (LTFU) to assure a timely and appropriate treatment. The aim of our study is to evaluate the incidence of endocrinopathies in survivors in respect of sex, age, donor type, conditioning regimen and GvHD occurrence. Methods A standardized LTFU is applied at our center. We here analyze data consecutively collected in an Institutional database, starting from 2006, including 402 adult patients (pts) who underwent an allo-HCT between 1992 and 2016 at our Institution. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. We considered for the analysis pts with an overall survival >/=1y. We reviewed pts chapters with a focus on occurrence, management and treatment of diabetes, thyroid disfunctions, dyslipidemia and osteopenia / osteoporosis: diagnosis and follow-up were performed according to guidelines for long-term HCT survivors. Results With a median follow-up of 7y (r 2-25y) 328 pts were evaluable; donor was a match unrelated donor in 107 cases, HLA identical sibling in 88, haploidentical relative in 129 and cord blood in 4. The 5y-incidence of diabetes type 2 was 3%, with a median time after allo-HCT of 1138 days (r 5-4181 days); 13/22 developed diabetes after diagnosis of GvHD (median time 884 days, r 30-3753 days). All pts received indication for diet modification, 11 pts were treated with insulin and 8 pts with metformin. Thyroid disfunction was documented in 38 pts (5y-incidence 8,5%): 2 pts were diagnosed with hyperthyroidism and treated with methimazole or radioiodine treatment. Hypothyroidism was documented in 36 pts (median time after allo-HSCT 799 days, r 65-5021 days). Thirteen pts developed hypothyroidism following the diagnosis of GvHD (median time 1236 days, r 166-3540 days). Only 2 pts did not receive a specific treatment, while all the others received substitutive therapy with levothyroxine. Furthermore 1 pt was diagnosed with a papillary thyroid cancer. The 5y-incidende of dyslipidemia was 30% with a median time after allo-HSCT of 1433 days (r 366-7629), 47 pts developed dyslipidemia after the diagnosis of GVHD (median time 1425 days, r 134-7403 days). Diet-therapy was recommended to all the pts, 29 pts received a statin-based pharmacological treatment, 20 pts a polyenoic-fatty-acids based treatment, while a nutraceutical compound was given in 13 pts. Osteopenia was documented in 120 pts (median time after allo-HSCT 994 days, range 31-6605 days) with a 5y-incidence of 36%. Seventy-nine pts presented osteopenia after diagnosis of GvHD (median time after GvHD diagnosis 707 days, r 13-6379 days). Eight pts did not receive a specific treatment. Two pts received treatment with biphosphonates plus oral vitamin D and calcium supplementation, the 110 remaining pts received oral vitamin D +/- calcium supplementation only. Sixty-four pts developed osteoporosis (median time after allo-HSCT 1000 days, r 60-8836 days), the 5y-incidence was 26%. Forty-four pts developed osteoporosis following the diagnosis of GvHD (median time 724 days, r 28-8280 days). Only 4 pts did not receive any specific therapy; 31 pts received therapy with bisphosphonates, 2 pts denosumab and 27 pts oral vitamin D and calcium supplementation. In univariate analysis no relationship between host sex, age at transplant, TBI exposure, donor or history of GvHD and development of diabetes, thyroid disfunction and dyslipidemia was outlined. Otherwise, osteopenia development was strongly associated with GvHD occurrence and osteoporosis was strongly associated with age, sex and GvHD occurrence (table 1). Conclusions Allo-HCT survivors are at relevant risk of endocrinopathies after transplantation, providing justification for specific monitoring to individualize treatment and follow-up. Of note, classical transplant-related variables are not enough to justify the occurrence of endocrinological disfunction: a further deeper evaluation of a misdiagnosed donor-mediated autoimmune predisposition will be essential. Disclosures Bonini: Intellia Therapeutics: Research Funding.
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- 2018
22. Post-Transplant Cyclophosphamide and Sirolimus in Matched Related and Unrelated Allogeneic Transplant with a Treosulfan-Based Conditioning
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Andrea Assanelli, Daniela Clerici, Magda Marcatti, Massimo Bernardi, Lorenzo Lazzari, Serena Albanese, Maria Teresa Lupo Stanghellini, Sara Mastaglio, Luca Vago, Raffaella Greco, Simona Piemontese, Consuelo Corti, Francesca Lorentino, Jacopo Peccatori, Fabio Giglio, and Fabio Ciceri
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Treosulfan ,medicine.disease ,Biochemistry ,Gastroenterology ,Fludarabine ,Transplantation ,surgical procedures, operative ,Graft-versus-host disease ,Median follow-up ,Internal medicine ,medicine ,Cumulative incidence ,Progression-free survival ,business ,medicine.drug - Abstract
Introduction: Post transplant cyclophosphamide (PT-Cy) has recently emerged as a very promising pharmacological strategy to overcome human leukocyte antigen (HLA) barriers in the setting of haploidentical hematopoietic cell transplant (HCT). We recently reported a promising preliminary experience on the use of PT-Cy and sirolimus as graft-versus-host disease (GVHD) prophylaxis in matched allo-HSCT (Greco R et al, Blood 2016). Herein we describe long-term outcomes of matched allogeneic HSCT, using treosulfan-based conditioning, and GVHD prophylaxis with PT-Cy and sirolimus. Methods: In our center, we collected 104 adult patients (pts) receiving matched HSCT for high-risk hematological malignancies, mainly acute myeloid leukemia (n=43). Donor was matched related (MRD) for 45 pts, 10/10 matched unrelated (MUD) for 39 pts and 9/10 MUD for 20 pts. Median age was 48 years (range 19-78). At HSCT, 51% of patients were not in complete remission (CR), 39% were in CR1 and 11% in subsequent CR. Graft source was mainly PBSCs (95%). All pts received a conditioning regimen based on treosulfan and fludarabine; 89% received an intensified conditioning with the addition of melphalan. All pts received PT-Cy (50 mg/kg/day) on days 3 and 4. Sirolimus was given from day 5, and withdrawn 3 months after HSCT. Mycophenolate mofetil (MMF) was added from day 5 to day 30, only in MUD. All patients were treated according to current institutional programs upon written informed consent for transplant procedures. Results: Median follow up was over 16 months (range 3-51). Median CD34+ and CD3+ cell doses were 5.6x10^6/Kg (range, 1.5-10.9) and 2.0x10^8/Kg (range, 0.2-8.0), respectively. All the recipients of allo-HSCT experienced a sustained donor cell engraftment. The cumulative incidence of grades II-IV and III-IV acute GVHD at 100 days was 21% and 9%, respectively. The cumulative incidence of chronic GVHD was 25% at 2 years; we observed severe chronic GVHD only in 4% of pts. The cumulative incidences of relapse and non-relapse mortality (NRM) were 33% and 8% at 2 years, respectively. Two-year overall survival (OS) was 67% and progression free survival (PFS) 59%. The composite end point of GVHD-free/relapse-free survival (GRFS) was 52% at 2 years, in which events include grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death. There was a longer OS, 2-year OS was 77% (p = 0.05), and a trend towards higher PFS and GRFS, 63% (p=0.07) and 58% (p=0.06) respectively, for pts with CR status at HSCT. We did not found a significant effect of HLA-matching (9/10 versus 10/10) or donor type (related versus unrelated) on major transplant outcomes (NRM, PFS, GRFS, relapse, acute and chronic GvHD). Conclusion: These outcomes confirmed that matched allogeneic HSCT using treosulfan-based chemotherapy, PT-Cy and sirolimus, is associated with low NRM and acceptable severe GVHD, providing relevant long-term survival in high-risk diseases. A randomized trial comparing this strategy with other kind of in-vivo T-cell depletion (i.e. ATG) is warranted. Disclosures Vago: Moderna TX: Research Funding; GENDX: Research Funding.
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- 2018
23. 1559. Hematopoietic Cell Transplantation with Post-transplant Cyclophosphamide: Impact of Donor Type on Pre-engraftment Blood-Stream Infections
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Daniela Clerici, Maria Teresa Lupo Stanghellini, Raffaella Greco, Elisabetta Xue, Massimo Bernardi, Chiara Oltolini, Francesca Lorentino, Fabio Ciceri, Jacopo Peccatori, Paolo Scarpellini, Laura Galli, Antonella Castagna, Consuelo Corti, and Fabio Giglio
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0301 basic medicine ,Hematopoietic cell ,Cyclophosphamide ,business.industry ,Post transplant cyclophosphamide ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Neutropenia ,medicine.disease ,Transplantation ,03 medical and health sciences ,Abstracts ,030104 developmental biology ,Infectious Diseases ,Oncology ,B. Poster Abstracts ,Immunology ,medicine ,business ,Blood stream ,Disease transmission ,medicine.drug - Abstract
Background The aim of the study was to estimate the cumulative incidence of pre-engraftment blood stream infections (PE-BSI), its predictive factors and the infection-related mortality (IRM) after hematopoietic cell transplantation (HCT) from any donor type, with post-transplant cyclophosphamide (PT-Cy). Methods Retrospective cohort study on 235 adults who underwent peripheral blood HCT from every donor type with PT-Cy platform, from 2013 to 2017 at San Raffaele Scientific Institute. The Poisson regression was used to estimate the crude incidence rate (IR) of PE-BSI. The Fine-Gray competing risk model was applied to estimate the cumulative incidence function (CIF) of the first PE-BSI and its predictive factors and of IRM. Results Patients’ characteristics are reported in Table 1. During 5,316 person-days of follow-up (PDFU), 77 PE-BSI episodes occurred in 72 patients: IR = 1.45 per 100-PDFU [95% confidence interval (95% CI) 1.13–1.77]. The median time to PE-BSI was 13 days (IQR: 7–17) and the estimated CIF at 28 days was 32% (95% CI: 26–39%); no differences in CIF according to donor type [30% vs. 34% vs. 32% in match-related, match-unrelated and haploidentical donor, respectively; Gray’s test: P = 0.968]. Among the 87 isolated pathogens, 60% were Gram-positive bacteria (GPB), 39% Gram-negative bacteria (GNB) and 1% nontuberculous mycobacteria. CIFs of GNB and GPB PE-BSI by type of donor are shown in Figure 1. By multivariate analysis (Table 2), after adjustment for age, sex, year of HCT, donor type and disease phase at HCT, the CIF of any PE-BSI was higher in subjects with absolute neutrophils count ≤500 for ≥7 days before HCT [adjusted hazard ratio (AHR) = 2.90] and in multi-drug resistant (MDR) GNB rectal carriers before HCT [AHR = 2.68]. These covariates were confirmed as independent factors also for GNB PE-BSI. Overall, IRM at 30 days was 5% (95% CI: 2–8%) with no differences by donor type (Gray’s test: P = 0.106). Conclusion HCT with PT-Cy platform showed a 32% of cumulative incidence of PE-BSI at 28 days and donor type did not affect its occurrence, which was conversely increased by prolonged and severe neutropenia and MDR GNB rectal carriage before HCT. Haploidentical setting did not retain a higher IRM at 30 days than match-related and match-unrelated donors. Disclosures All authors: No reported disclosures.
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- 2018
24. Human Herpesvirus 6 Infection Following Haploidentical Transplantation: Immune Recovery and Outcome
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Alessandra Forcina, Fabio Ciceri, Sara Marktel, Chiara Oltolini, Matteo Carrabba, Maria Teresa Lupo Stanghellini, Maria Chiara Barbanti, Veronica Valtolina, Paolo Scarpellini, Raffaella Greco, Fabio Giglio, Francesca Lorentino, Chiara Bonini, Massimo Clementi, Andrea Assanelli, Serena Rolla, Daniele Mannina, Jacopo Peccatori, Massimo Bernardi, Maddalena Noviello, Mara Morelli, Consuelo Corti, Roee Dvir, Luca Vago, Sara Racca, Lara Crucitti, Greco, Raffaella, Crucitti, Lara, Noviello, Maddalena, Racca, Sara, Mannina, Daniele, Forcina, Alessandra, Lorentino, Francesca, Valtolina, Veronica, Rolla, Serena, Dvir, Roee, Morelli, Mara, Giglio, Fabio, Barbanti, Maria Chiara, Lupo Stanghellini, Maria Teresa, Oltolini, Chiara, Vago, Luca, Scarpellini, Paolo, Assanelli, Andrea, Carrabba, Matteo G, Marktel, Sarah, Bernardi, Massimo, Corti, Consuelo, Clementi, Massimo, Peccatori, Jacopo, Bonini, Chiara, and Ciceri, Fabio
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Male ,Human herpesvirus 6 ,medicine.medical_treatment ,Herpesvirus 6, Human ,Cytomegalovirus ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,0302 clinical medicine ,Exanthema Subitum ,education.field_of_study ,biology ,medicine.diagnostic_test ,Graft Survival ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Rash ,medicine.anatomical_structure ,Treatment Outcome ,Virus Diseases ,030220 oncology & carcinogenesis ,Allogeneic hematopoietic stem cell transplantation ,Female ,Steroids ,medicine.symptom ,Adult ,Population ,Roseolovirus Infections ,T cell immune reconstitution ,Antiviral Agents ,03 medical and health sciences ,Young Adult ,Immune system ,medicine ,Humans ,Lymphocyte Count ,education ,Aged ,Retrospective Studies ,Hepatitis ,Transplantation ,business.industry ,biology.organism_classification ,medicine.disease ,Survival Analysis ,Bronchoalveolar lavage ,Immunology ,Transplantation, Haploidentical ,Virus Activation ,Bone marrow ,business ,030215 immunology - Abstract
Human herpesvirus 6 (HHV-6) is increasingly recognized as a potentially life-threatening pathogen in allogeneic hematopoietic stem cell transplantation (alloSCT). We retrospectively evaluated 54 adult patients who developed positivity to HHV-6 after alloSCT. The median time from alloSCT to HHV-6 reactivation was 34 days. HHV-6 was present in plasma samples from 31 patients, in bone marrow (BM) of 9 patients, in bronchoalveolar lavage fluid and liver or gut biopsy specimens from 33 patients, and in cerebrospinal fluid of 7 patients. Twenty-nine patients developed acute graft-versus-host disease (GVHD), mainly grade III-IV, and 15 had concomitant cytomegalovirus reactivation. The median absolute CD3+ lymphocyte count was 207 cells/µL. We reported the following clinical manifestations: fever in 43 patients, skin rash in 22, hepatitis in 19, diarrhea in 24, encephalitis in 10, BM suppression in 18, and delayed engraftment in 11. Antiviral pharmacologic treatment was administered to 37 patients; nonetheless, the mortality rate was relatively high in this population (overall survival [OS] at 1 year, 38% ± 7%). A better OS was significantly associated with a CD3+ cell count ≥200/µL at the time of HHV-6 reactivation (P = .0002). OS was also positively affected by the absence of acute GVHD grade III-IV (P = .03) and by complete disease remission (P = .03), but was not significantly influenced by steroid administration, time after alloSCT, type of antiviral prophylaxis, plasma viral load, or organ involvement. Although HHV-6 detection typically occurred early after alloSCT, better T cell immune reconstitution seems to have the potential to improve clinical outcomes. Our findings provide new insight into the interplay between HHV-6 and the transplanted immune system.
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- 2016
25. Post-transplant cyclophosphamide versus antithymocyte-globulin as graft versus host disease prophylaxis in haploidentical transplant
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Florent Malard, Giuseppe Messina, Yuqian Sun, Didier Blaise, Annalisa Ruggeri, José Luis Díez-Martín, Francesca Lorentino, Yener Koc, Fabio Ciceri, Arnon Nagler, Ardeshi Ghavamzadeh, Stella Santarone, Mohamad Mohty, Benedetto Bruno, Myriam Labopin, Zafer Gulbas, Andrea Bacigalupo, William Arcese, Ruggeri, Annalisa, Sun, Yuqian, Labopin, Myriam, Bacigalupo, Andrea, Lorentino, Francesca, Arcese, William, Santarone, Stella, Gã¼lbas, Zafer, Blaise, Didier, Messina, Giuseppe, Ghavamzadeh, Ardeshi, Malard, Florent, Bruno, Benedetto, Diez martin, Jose Lui, Koc, Yener, Ciceri, Fabio, Mohty, Mohamad, and Nagler, Arnon
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Male ,Transplantation Conditioning ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Kaplan-Meier Estimate ,Gastroenterology ,Immunosuppressive Agent ,0302 clinical medicine ,antithymocyte globulin ,HLA Antigens ,Recurrence ,Haplotype ,HLA Antigen ,Transplantation, Homologou ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Hematology ,Articles ,Middle Aged ,Graft-versus-Host-Disease ,Stem Cell Transplantation ,haploidentical transplantation ,post-transplantation cyclophosphamide ,Tissue Donors ,medicine.anatomical_structure ,surgical procedures, operative ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Immunosuppressive Agents ,medicine.drug ,Human ,Adult ,medicine.medical_specialty ,Cyclophosphamide ,Adolescent ,Tissue Donor ,Chemoprevention ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Aged ,Antilymphocyte Serum ,Postoperative Care ,business.industry ,medicine.disease ,Anti-thymocyte globulin ,Surgery ,Transplantation ,Regimen ,Settore MED/15 - MALATTIE DEL SANGUE ,Graft-versus-host disease ,Haplotypes ,Bone marrow ,business ,030215 immunology - Abstract
Severe graft-versus-host disease is a major barrier for non-T-cell-depleted haploidentical stem cell transplantation. There is no consensus on the optimal graft-versus-host disease prophylaxis. This study compared the two most commonly used graft-versus-host disease prophylaxis regimens (post-transplant cyclophosphamide-based vs. the anti-thymocyte globulin-based) in adults with acute myeloid leukemia reported to the European Society for Blood and Bone Marrow Transplantation. A total of 308 patients were analyzed; 193 received post-transplant cyclophosphamide-based regimen and 115 anti-thymocyte globulin-based regimen as anti-graft-versus-host disease prophylaxis. The post-transplant cyclophosphamide-based regimen was more likely to be associated to bone marrow as graft source (60% vs. 40%; P=0.01). Patients in the post-transplant cyclophosphamide-based regimen group had significantly less grade 3-4 acute graft-versus-host disease than those in the anti-thymocyte globulin-based group (5% vs. 12%, respectively; P=0.01), comparable to chronic graft-versus-host disease. Multivariate analysis showed that non-relapse mortality was lower in the post-transplant cyclophosphamide-based regimen group [22% vs. 30%, Hazard ratio (HR) 1.77(95%CI: 1.09-2.86); P=0.02] with no difference in relapse incidence. Patients receiving post-transplant cyclophosphamide-based regimen had better graft-versus-host disease-free, relapse-free survival [HR 1.45 (95%CI: 1.04-2.02); P=0.03] and leukemia-free survival [HR 1.48 (95%CI: 1.03-2.12); P=0.03] than those in the anti-thymocyte globulin-based group. In the multivariate analysis, there was also a trend for a higher overall survival [HR 1.43 (95%CI: 0.98-2.09); P=0.06] for post-transplant cyclophosphamide-based regimen versus the anti-thymocyte globulin-based group. Notably, center experience was also associated with non-relapse mortality and graft-versus-host disease-free, relapse-free survival. Haplo-SCT using a post-transplant cyclophosphamide-based regimen can achieve better leukemia-free survival and graft-versus-host disease-free, relapse-free survival, lower incidence of graft-versus-host disease and non-relapse mortality as compared to anti-thymocyte globulin-based graft-versus-host disease prophylaxis in patients with acute myeloid leukemia.
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- 2016
26. Total marrow irradiation (TMI) combined with treosulfan and fludarabine conditioning regimen for chemosensitive advanced multiple myeloma (MM) patients undergoing matched allogeneic stem-cell transplantation: First results of a phase I/II prospective monocentric study (TrRaMM TMI)
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Maria Teresa Lupo Stanghellini, Fabio Giglio, Raffaella Greco, Jacopo Peccatori, Andrea Assanelli, Daniela Clerici, Francesca Lorentino, M. Cattaneo, Magda Marcatti, Nadia Di Muzio, Andrés J.M. Ferreri, Anna Chiara, Fabio Ciceri, and Sara Broggi
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Oncology ,Cancer Research ,medicine.medical_specialty ,integumentary system ,business.industry ,medicine.medical_treatment ,Total Marrow Irradiation ,Treosulfan ,medicine.disease ,Tomotherapy ,Fludarabine ,Transplantation ,medicine.anatomical_structure ,Internal medicine ,medicine ,Bone marrow ,Stem cell ,business ,Multiple myeloma ,medicine.drug - Abstract
e19019Background: Recent data support the use of Helical Tomotherapy to deliver radiation to target tissues, such as bone marrow, sparing vital organs in an effort to reduce toxicities. We report t...
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- 2018
27. 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.
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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.
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- 2015
28. HLA Disparities Impact on Outcomes after Unmanipulated Haploidentical Hematopoietic Stem Cells Transplantation (HaploSCT) in Acute Leukemia : A Study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)
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Katharina Fleischhauer, Myriam Labopin, Yener Koc, Benedetto Bruno, Annalisa Ruggeri, Francesca Lorentino, Mohamad Mohty, Martin Bornhäuser, Dietrich W. Beelen, Fabio Ciceri, Andrea Bacigalupo, William Arcese, Arnon Nagler, Zafer Gulbas, Didier Blaise, Johanna Tischer, and Giuseppe Messina
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Oncology ,medicine.medical_specialty ,Acute leukemia ,Cyclophosphamide ,business.industry ,Immunology ,Medizin ,Cell Biology ,Hematology ,medicine.disease ,Lower risk ,Biochemistry ,Transplantation ,Leukemia ,High Risk Acute Leukemia ,Internal medicine ,medicine ,Alemtuzumab ,business ,HLA-DRB1 ,medicine.drug - Abstract
Background: HaploSCT from unmanipulated graft is a practiced option for high risk acute leukemia (AL) patients (pts) who lack a matched related or unrelated donor (Piemontese, Leukemia 2015). Since several haploidentical donors are available for most pts, selection based on optimal HLA mismatching could be relevant, but evidence on this issue is scarce. We aimed to evaluate the impact of donor-recipient HLA mismatches (HLAmm) on unshared haplotype on HaploSCT outcomes, hypothesizing that the number of HLAmm and the different HLA loci involved could be associated with specific transplant-related risks. Methods: We retrospectively analyzed 490 pts with de novo acute myeloid leukemia (AML, n=346, 71%) and acute lymphoblastic leukemia (ALL, n=144, 29%) reported to EBMT, receiving a first unmanipulated peripheral blood (PB) or bone marrow (BM) HaploSCT between 2007 and 2014. Donor-recipient pairs were typed at a molecular low (n=323, 66%) or high (n=163, 34%) resolution level at HLA-A, -B, -C and -DRB1 loci. HLAmm were defined at antigen level. Results: Median follow-up was 17 (1.3-84) months; median age at transplant was 44 (18-78) years (y). Three hundred-ten pts (63%) were in complete remission (34% CR1, 29% CR2), 180 pts in advanced phase (CR3 and above, relapse or primary induction failure). Conditioning regimen was reduced intensity (RIC) in 48% of pts and myeloablative in 52%. Source of stem cells was PB for 61% of them, BM for 39%. In vivo T cell depletion (ATG or Campath) was used in 33% of pts and 56% of pts received high-dose post-transplant Cyclophosphamide (PTCy) for GVHD prophylaxis. Median donors' age was 38 (12-71) y. CMV donor/host status was neg/neg for 11% of pts, pos/neg for 6%, neg/pos for 19%, pos/pos for 62%. Of the 490 donor-recipient pairs, 55% had 4 HLAmm on unshared haplotype, 30% had 3 HLAmm, 12% had 2 HLAmm, 3% had 1 HLAmm. Among pairs with less than 4 HLAmm, 17% were matched at locus A, 12% at locus B, 19% at locus C, 16% at locus DRB1. Overall, 92% of pts achieved neutrophil engraftment at a median of 18 (12-63) days (d). At 100 d, cumulative incidence (CI) of grade ≥2 acute GvHD (aGvHD) was 33±4%. The 2-y CI of chronic GvHD (cGvHD), relapse (RI) and non-relapse mortality (NRM) were 30±4%, 37±5% and 29±4%, respectively. The probabilities of leukemia-free survival (LFS) and overall survival (OS) at 2 y were 34±5% and 39±5% respectively. In multivariate analysis, increasing number of HLAmm on unshared haplotype was not an independent prognostic factor for aGvHD (HR 0.8, p 0.2), cGvHD (HR 1.3, p 0.3), NRM (HR 1.3, p 0.3), RI (HR 1.1, p 0.6), LFS (HR 1.2, p 0.3) and OS (HR 1.3, p 0.2). Focusing on single HLA loci, match at HLA B locus on unshared haplotype was associated with lower 2y NRM in univariate analysis (17±8% in matched pairs, 31±11% in mismatched pairs, p 0.02), and this was confirmed in multivariate analysis (HR 0.5, p 0.04) accounting for all known risk factors (AL type, disease status, conditioning regimen intensity, host/donor age and sex, GvHD prevention, CMV status, number of HaploSCT performed in each center). Moreover, donor-recipient pairs matched at HLA DRB1 locus on unshared haplotype had lower rates of 100d CI of grade ≥2 aGvHD (20±8% in matched pairs, 34±4% in mismatched pairs, p 0.01), and this proved to be an independent factor in multivariate analysis (HR 0.5, p 0.02). Among other relevant factors, diagnosis of AML was associated with higher probabilities of LFS and OS (HR=0.6, p Conclusions: In our series of 490 AL pts, number of HLAmm on unshared haplotype did not influence outcomes of unmanipulated HaploSCT. However, a match at HLA-B and HLA-DRB1 loci on unshared haplotype was associated with lower NRM and lower risk of grade 2-4 aGvHD, respectively. If further validated, our data could drive a more accurate selection of haploidentical donors in non T-cell depleted HaploSCT, accounting for potential biological implications of HLA locus-specific differences. Disclosures Tischer: Sanofi-Aventis: Other: advisory board. Nagler:Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Mohty:Janssen: Honoraria; Celgene: Honoraria.
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- 2015
29. 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
30. Pentraxin 3 As a Novel Diagnostic and Prognostic Biomarker for Acute GvHD and Fungal Infections in Adult Allogeneic HSCT Recipients
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Consuelo Corti, Giorgia Levati, Alberto Mantovani, Maria Teresa Lupo Stanghellini, Elisa Sala, Michela Tassara, Fabio Giglio, Francesca Lorentino, Jacopo Peccatori, Roberto Leone, Mara Morelli, Matteo Carrabba, Fabio Ciceri, Raffaella Greco, Barbara Bottazzi, Cecilia Garlanda, Andrea Assanelli, Lara Crucitti, Massimo Bernardi, and Luca Vago
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0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,030105 genetics & heredity ,Treosulfan ,Biochemistry ,Gastroenterology ,03 medical and health sciences ,Internal medicine ,White blood cell ,medicine ,First episode ,Acute leukemia ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Transplantation ,Leukemia ,medicine.anatomical_structure ,business ,Busulfan ,medicine.drug - Abstract
BACKGROUND: Pentraxin 3 (PTX3) is an essential component of the humoral arm of innate immunity, involved in controlling infections and modulating inflammation, and acting as a new prognostic and diagnostic biomarker in these conditions. PTX3 has been recently recognized as an extrinsic oncosuppressor in cancer; its role in hematological malignancies and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is under investigation in both pediatric and adult settings. METHODS: From September 2012 we have conducted a prospective observational study to address the role of PTX3 in 35 adult patients affected by newly diagnosed AML (n=27) or ALL (8), and 73 adult pts who received allo-HSCT for acute leukemia. Stem cell donors were haploidentical (n=45), sibling (n=14), unrelated (n=14). Serial peripheral blood (PB) and bone marrow (BM) samples were collected from all patients. Time-points of sampling for leukemia patients included: diagnosis, relapse, any cycle of chemotherapy (CT; before starting and first day after the end), evaluation of treatment response (including BM), fever (first episode, or clinical suspicion of fungal infection). Samples from allo-HSCT patients were collected as following: before HSCT; at HSCT (day 0); day +7, day +14, 1 month (including BM), 2 months (including BM), 3 months (including BM) and 6 months (including BM) after HSCT; fever (first episode, or clinical suspicion of fungal infection); acute GvHD requiring systemic therapy (at onset or before starting a second line treatment, day+7 of treatment, then weekly during immunosuppressive therapy for 6 weeks). PTX3 level detection was performed with sandwich ELISA (detection limit 0.1 ng/ml). RESULTS: Firstly we analyzed the group of leukemia patients. Although PTX3 levels on PB at leukemia diagnosis were not influenced by patients (age, sex) or disease characteristics (type of leukemia, BM and PB blasts), they correlated with white blood cell counts (p=0,03). No statistical difference was found matching PTX3 levels at diagnosis with disease relapse or overall survival (OS). We did not observe any correlation between PTX3 levels before starting CT and response to treatment. When we moved to examine allo-HSCT patients, we observed an important difference in PTX3 levels on PB at day 0 among patients treated with treosulfan or busulfan-based conditioning (p=0,027). We found a trend towards an increase of PTX3 levels for patients who developed a subsequent GvHD at day +7, and for patients who received ATG instead of PT-Cy at day +14 (p =0,06 for both of them). Moreover, we evaluated 38 events of acute GvHD. Interestingly, PTX3 levels on PB at GvHD onset predict a subsequent evolution to chronic GvHD (p=0,02), also confirmed by ROC analysis (AUC 0.786) which allowed us to identify a threshold of 58 ng/ml (sens 75%, spec 85%). At day +7 from the start of therapy, PTX3 levels were correlated directly with steroid-refractory GvHD (p=0,004) and reflare (p=0,024), and inversely with GvHD resolution (p=0,003). Concomitantly, the ROC analysis identified a threshold of 18 ng/ml as predictor for steroid-resistance (AUC 0,91; sens 75%, spec 85%) and GvHD resolution (AUC 0,848; sens 70%, spec 85%). Finally, we reported 142 infectious events. No difference in PTX3 levels was reported for first and subsequent episodes, or with bloodstream infections. Importantly, in presence of invasive fungal infection (IFI), the levels of PTX3 were significantly increased (p=0,016). CONCLUSIONS: PTX3 is an early biomarker for major transplant-related complications, as IFI and acute GvHD. This study suggests that PTX3 is able to predict GvHD resolution and the risk of subsequent chronic GVHD development; moreover PTX3 predicts steroid-refractory GvHD, offering a new tool in pindividualized clinical management. Disclosures Ciceri: MolMed SpA: Consultancy.
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- 2016
31. 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.
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- 2016
32. Escalated Dose-Rates of Total Marrow Irradiation (TMI) Combined with Treosulfan and Fludarabine-Based Conditioning Chemotherapy Regimen for Chemosensitive Advanced Multiple Myeloma (MM) Patients Undergoing a Matched Allogeneic Stem-Cell Transplantation: First Results of a Phase I/II Prospective Monocentric Study (TrRaMM TMI)
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Tommaso Perini, Francesca Lorentino, Fabio Giglio, Chiara Bonini, Andrea Assanelli, Anna Chiara, Jacopo Peccatori, M. Cattaneo, Sara Broggi, Fabio Ciceri, Nadia Di Muzio, Magda Marcatti, Maria Teresa Lupo Stanghellini, Raffaella Greco, and Mara Morelli
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medicine.medical_specialty ,business.industry ,Immunology ,Urology ,Cell Biology ,Hematology ,Treosulfan ,Total body irradiation ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,030218 nuclear medicine & medical imaging ,Surgery ,Fludarabine ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,medicine ,Cumulative incidence ,business ,Progressive disease ,medicine.drug - Abstract
Background In an effort to reduce transplantation-related morbidity and mortality in patients (pts) undergoing total body irradiation as part of myeloablative conditioning regimen for hematological malignancies candidated to allogeneic transplant, data have been emerging in support of Helical Tomotherapy to deliver radiation doses to target organs, as bone marrow and lymph nodes, sparing normal organs. We report the first results of feasibility and efficacy of myeloablative Treosulfan-based conditioning chemotherapy combined with dose-escalating (8-10-12 Gy) TMI in pts affected by chemosensitive advanced MM (TrRaMM-TMI: Eudract N° 2013-002479-16). Patients and methods Ten pts (7 females and 3 males with a median age of 60 years), affected by chemosensitive advanced MM have been treated from December 2012 to December 2015. Most of them have received previous therapies with Bortezomib (90%) and IMIDs (80%) and all pts experienced relapse after autologous transplant; active disease was present in the 30% of the pts at the time of the transplant. The pts' median score of HCT-comorbidity index was 2. All pts received a myeloablative Treosulfan-based chemotherapy (Treosulfan 14g/mq/day on days -6 to -4; Fludarabine 30mg/mq/day on days -6 to-2), combined with TMI delivery on day -2 and -1 if 8Gy and on day -3, -2 and -1 if 10 Gy or 12 Gy, using Helical Tomotherapy. Each pt had a personalized immobilization device and before any fraction the correct set-up was controlled by a mega-voltage CT scan. Three pts have been submitted as pilot cases to TMI 8 Gy, and four and three pts respectively in the two protocol cohorts of TMI 10 Gy and 12 Gy. Peripheral-blood has been the stem cell source for all the pts: three from a matched sibling donor and seven from a matched unrelated donor (10/10 HLA match in six cases and one 9/10 HLA match). A median of 5x10e6 Cd34+/kg and of 319x10e6 Cd3+/Kg have been infused and graft versus host disease (GVHD) prophylaxis with sirolimus and mycophenolate mofetil has been administered; antithymocyte globulin on days -4 to -2 and rituximab on day -1 were added in the unrelated transplant setting. Results All pts received the planned TMI dose in each cohort; engraftment occurred in all pts and no secondary graft failure was observed. No grade 3 and 4 extra-hematological toxicities were observed, and lower grade toxicities, especially gastrointestinal, were completely reversible. No more than 10% of viral reactivations have been demonstrated and one case only of severe sepsis occurred, promptly resolved. No invasive fungal infections occured. No transplant related mortality (TRM) was registered and the two deaths were due to progressive disease. Immune reconstitution after transplant described a T-cell CD8+ and CD4+ repertoire recovery with a median number of 350/microL and of 100/microL on day +90 respectively; NK cells recovery was rapid with a median of 140/microL on day +90, while B cells were still missing on day +90. With a median follow-up time of 22 months on surviving pts, a 2-year PFS of 64% and a 2-year OS of 77% have been described. The day +100 cumulative incidence of grade II-IV acute GVHD was 40%; if grade >III 10%; chronic GVHD 1-year cumulative incidence was 42%; if moderate and severe 31%. 2-year relapse incidence was 36%. Conclusions The first data coming out from the present experience show that TMI addition to Treosulfan-based chemotherapy has not demonstrated an addition of at least short-term toxicities, confirming the combination feasibility, so that TMI 14 Gy delivery is in the plan for the third cohort of the study. Moreover the efficacy outcomes in terms of survival and acceptable TRM, suggest that myeloablative conditioning is feasible in the context of MM and especially promising even in pts with advanced and heavily pretreated disease. 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
33. 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
34. 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
35. 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
36. 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
37. 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
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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
38. Human Herpes Virus 6 Infection in 54 Patients after Allogeneic Hematopoietic Stem Cell Transplantation: Clinical Manifestations and Outcome
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Maria Teresa Lupo Stanghellini, Raffaella Greco, Consuelo Corti, Roee Dvir, Andrea Assanelli, Maddalena Noviello, Sarah Marktel, Jacopo Peccatori, Matteo Carrabba, Fabio Giglio, Sara Racca, Alessandra Forcina, Veronica Valtolina, Lara Crucitti, Francesca Lorentino, Massimo Clementi, Mara Morelli, Massimo Bernardi, Luca Vago, Serena Rolla, Fabio Ciceri, Chiara Bonini, Giorgia Levati, Greco, R, Crucitti, L, Racca, S, Dvir, R, Lorentino, F, Vago, L, Forcina, A, Rolla, S, Valtolina, V, Noviello, M, Stanghellini, Mtl, Giglio, F, Morelli, M, Levati, G, Assanelli, A, Carrabba, Mg, Marktel, S, Bernardi, M, Corti, C, Peccatori, J, Bonini, C, Clementi, M, and Ciceri, F
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medicine.medical_specialty ,education.field_of_study ,business.industry ,medicine.medical_treatment ,Immunology ,Population ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Rash ,Gastroenterology ,Transplantation ,Graft-versus-host disease ,medicine.anatomical_structure ,Bone marrow suppression ,Internal medicine ,Medicine ,Bone marrow ,medicine.symptom ,business ,education ,Viral load - Abstract
BACKGROUND: Human herpesvirus type 6 (HHV-6) is increasingly recognized as an opportunistic and potentially life-threatening pathogen in recipients of allogeneic hematopoietic stem cell transplantation (AlloSCT). HHV-6 is a member of the beta herpesvirus subfamily (genus Roseolovirus). HHV-6 infection is recognized as the cause of a febrile disease and exanthem subitum in early childhood. Approximately 60% of solid organ transplant and 40% of patients after alloSCT experienced HHV-6 reactivation. Reported clinical manifestations of HHV-6 infection in transplanted patients are skin rash, interstitial pneumonia, bone marrow suppression and encephalitis. Moreover, some clinical reports suggest that HHV-6 can facilitate the occurrence of severe clinical complications of alloSCT, increasing transplant-related mortality. METHODS: From January 2009 to February 2013, we retrospectively evaluated 54 consecutive adult patients (median age 50 years) who developed positivity to HHV-6 after alloSCT for high-risk hematological malignancies. Stem cell donors were family haploidentical (37), HLA identical sibling (8), unrelated volunteer (6), cord blood (3). The viral load was determined by quantitative PCR (Nanogen Advanced Diagnostic S.r.L) in cell-free body fluids such as plasma, bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), bone marrow (BM) aspirates or in gastrointestinal biopsies. RESULTS: Median time from alloSCT to HHV-6 reactivation was 34 days (range: 0-705). Thirty-one patients presented HHV-6 positive in plasma, 9/54 in BM, 33/54 in gut biopsies or BAL, 7/54 in CSF. At the time of viral positivity all pts were receiving acyclovir as viral prophylaxis except five. Twenty-nine patients had acute graft versus host disease (GvHD). Twenty-two out of these twenty-nine patients experienced a grade III-IV acute GvHD, requiring high dose steroids in twenty-six cases. A concomitant CMV positivity was detected in 15/54 patients. The median absolute count of CD3+ lymphocytes was 207 cells/mcl. In 52/54 cases we reported HHV-6 clinical manifestations: fever (43), skin rash (22), hepatitis (19), diarrhoea (24), encephalitis (10), BM suppression (18), delayed engraftment (11). HHV-6 positivity led to antiviral pharmacological treatment in 37/54 cases, using as first choice therapy foscarnet. Amongst the total fifty-four patients with documented HHV-6 positivity thirty-one solved the clinical event. However the mortality rate was relatively high in this population (overall survival (OS) ±SE at 1 year after HHV-6 reactivation was 38% ± 7%), mainly related to severe infections or GvHD. A better OS is significantly associated with CD3+ cells ≥200/mcl at the time of HHV-6 reactivation (fig 1) (OS at 1 year 63% compared to 11% for patients with CD3 CONCLUSIONS: This retrospective study confirms a correlation of HHV-6 with high morbidity and mortality rates after alloSCT, thus suggesting a regular HHV-6 monitoring in alloSCT recipients. The regular monitoring of HHV-6 DNA, using a real-time PCR assay, may be useful for identifying active HHV-6 infection and for the introduction of a pre-emptive treatment, possibly reducing the incidence of the most severe clinical complications. Despite HHV-6 detection typically occurred early after alloSCT, a better immune reconstitution has the potential to improve clinical outcome. Figure 1: Overall survival after alloSCT in HHV-6 positive patients: green line showed patients with more than 200/mcl CD3+ cells, blue line the ones with less than 200/mcl CD3+ cells at HHV-6 reactivation. P value is provided by Log Rank test. Figure 1:. Overall survival after alloSCT in HHV-6 positive patients: green line showed patients with more than 200/mcl CD3+ cells, blue line the ones with less than 200/mcl CD3+ cells at HHV-6 reactivation. P value is provided by Log Rank test. Disclosures Bonini: MolMed S.p.A.: Consultancy.
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- 2014
39. Sirolimus and Post Transplant Cyclophosphamide (PT-Cy) Allow the Use of Haploidentical PBSC Grafts Inducing a Favorable Immune Reconstitution with Low Rates of GvHD: Results in 39 Patients
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Tiago De Freitas, Mara Morelli, Giorgia Levati, Maria Teresa Lupo Stanghellini, Raffaella Greco, Lara Crucitti, Nicoletta Cieri, Chiara Bonini, Consuelo Corti, Francesca Lorentino, Massimo Bernardi, Fabio Ciceri, Andrea Assanelli, Luca Vago, Jacopo Peccatori, Sarah Marktel, and Fabio Giglio
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Melphalan ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Treosulfan ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Fludarabine ,Transplantation ,Regimen ,Graft-versus-host disease ,Internal medicine ,medicine ,Cumulative incidence ,business ,medicine.drug - Abstract
Introduction:Haploidentical hematopoietic stem cell transplantation (HSCT) performed using T–replete BM grafts and post-transplantation cyclophosphamide (PT-Cy) has gained much interest in the transplantation community for the excellent toxicity profile, achieving outcomes equivalent to those of HSCT performed using matched related or unrelated donors (Bashey, JCO 2013). Nonetheless, relapse remains a major challenge with the use of this non-myeloablative regimen (Luznik, BBMT 2008). Thus, we investigated whether the use of PBSC graft, an intensified myeloablative conditioning and sirolimus instead of tacrolimus might help increasing the therapeutic index of this procedure. Patients and Methods:Here we report the results on 39 patients treated between Nov 2012 and June 2014. The median age was 56 years (range, 21–78). Diagnoses included AML (21), ALL (5), CML-BC (1), MDS (1), NHL (5), and HD (6). The majority (62%) of patients were not in disease remission at time of HSCT. Eight patients (20%) received a prior allo-HSCT. For the remaining patients who underwent haplo-PTCy as a first allogeneic transplant, 19 patients (61%) scored high/very high according to the CIBMTR disease score, 12 (39%) scored intermediate, while no patient had a low disease score. The median Sorror Comorbidity Index was 3 (range: 0-9). 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 PBSC. Postgrafting immunosuppression consisted of PT-Cy (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days, and sirolimus for at least 3 months. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Cumulative incidence (CI) of non-relapse mortality (NRM) was calculated using relapse as a competing risk, for GvHD the competing risk was death. Results:PBSC grafts contained an infused median CD34/kg of 6.03 e6 (4.15–8.02 e7), CD3/kg 21.12 e7 (10.5–48.26 e7). All patients but 1 engrafted (97.5%), with a median time to neutrophil and platelet recovery of 18 days (range 13–45) and 19 days (9–65), respectively. Notably, the only patient with primary graft failure had a HLA-DP mismatch in HvG direction. Post-HSCT recovery of lymphocyte subsets was broad and fast: median time to CD3>100/ml was 28 days (range: 8-97), to CD4>200/ml 35 days (21-137) and to CD19>0/ml 34 days (24-137). Circulating T cells comprised naïve and memory subsets, with a recovery of CD31+ recent thymic emigrants (RTEs) starting from day 30. All patients had a significantly higher proportion of circulating RTEs at day 30, 90 and 180 compared to their pre-HSCT levels, suggesting an improvement in their thymic function after HSCT. We observed a significant early increase in circulating Tregs at day 15 post HSCT. With a median follow-up for living patients of 327 days, the 1-year cumulative CI of NRM and relapse were 15% and 32%, respectively. Two of the 9 relapses were HLA-loss variants (Vago, NEJM 2009) occurring at a median time of 277 days post-HSCT. Classical relapses had instead an earlier occurrence (median time to relapse: 92 days, range 37-134). CI of acute GvHD grade II-IV and III-IV at 6 months were 18% and 8%, while CI of chronic GvHD at 12 months was 19%. Estimated 1-year probability of OS and DFS were 58% and 51%. Outcomes were particularly favorable in patients transplanted in CR (1-year OS 93%, DFS 95%) as compared to those of patients transplanted with active disease (1-year OS 37%, DFS 29%; p=0.005 and p=0.001, respectively). Importantly, stratification according to CIBMTR score held similar results: in patients with intermediate score, 1-year OS was 91% vs. 33% in patients with high/very high score (p=0.015); similarly, 1-year DFS was 92% vs. 34% (p=0.009). Conclusions: PT-Cy coupled to sirolimus allow the use of haploidentical PBSC grafts with low rates of GvHD, and intensified myeloablative regimen is a valid option for patients with aggressive/advanced hematologic malignancies. The acceptable rates of GvHD and NRM as well as the favorable immune reconstitution profile open the way for combining it with novel immunomodulatory or cellular therapies to improve DFS in patients at high risk for relapse who would benefit from further treatment intensification early after transplant. Disclosures Bonini: MolMed S.p.A.: Consultancy.
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- 2014
40. Intensification Of Treosulfan and Fludarabine-Based Conditioning With 4 Gy TBI For Allogeneic Stem Cell Transplantation In Patients With Hematological Malignancies
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Fabio Ciceri, Sarah Marktel, Simona Piemontese, Fabio Giglio, Consuelo Corti, Chiara Bonini, Andrea Assanelli, Lara Crucitti, Corrado Zuanelli Brambilla, Jacopo Peccatori, Carlo Messina, Mara Morelli, Massimo Bernardi, Luca Vago, Giorgia Levati, Maria Teresa Lupo Stanghellini, Raffaella Greco, Magda Marcatti, Francesca Lorentino, and Alessandra Forcina
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medicine.medical_specialty ,education.field_of_study ,business.industry ,medicine.medical_treatment ,Immunology ,Population ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Treosulfan ,Interim analysis ,Biochemistry ,Gastroenterology ,Fludarabine ,Transplantation ,Internal medicine ,medicine ,Cumulative incidence ,Rituximab ,business ,education ,medicine.drug - Abstract
Background Hematopoietic stem cell transplantation (HSCT) is so far the only potentially curative option for patients with aggressive hematological malignancies. Since many patients cannot find a suitable HLA-identical (related or unrelated) donor, it is essential to analyze the safety of alternative graft sources, such as haploidentical donors. The use of reduced-intensity conditioning regimens in patients with an advanced disease did not improve the outcome because of a higher incidence of relapse. Here we present an interim analysis of this phase II prospective clinical trial that investigates a new conditioning regimen for allogeneic HSCT based on a well established one (Fludarabine and Treosulfan) intensified adding 4 Gy TBI with the aim of maintaining an acceptable toxicity profile while reducing the incidence of relapse in high-risk patients (TrRaMM4Gy study, Eudract 2011-001534-42). Patients and Methods Ninety-six patients underwent allogeneic HSCT for AML (n=46), ALL (n=13), acute biphenotypic leukaemia (n=2), HD (n=8), NHL (n=7), MDS (n=6), Myelofibrosis (n=5), MM (n=4), CML (n=2), CMML (n=2) or CLL (n=1). The median age was 45 years (range 17-67). At the time of the transplantation most patients (n=76) were in advanced disease phase, while the remaining 20 patients were in early phase. Twenty-eight patients were enrolled for relapse after a previous allogeneic HSCT. Median time from diagnosis to transplantation was 443 days (range 56-5249). Median comorbodity index score (according to Sorror criteria) was 2 (range: 0-8). Sixty-two patients received the graft from haploidentical donors, 17 from MUD, 14 from HLA-identical sibling and 3 patients from a single cord blood unit. Median number of CD34+ and CD3+ cells/kg were 6.46 millions and 241 millions respectively. The conditioning regimen included Treosulfan (14 g/m2 for 3 days), Fludarabine (30 mg/m2 for 5 days) and 4 Gy TBI split in 2 fractions. Patients receiving HSCT from haploidentical donor (arm A) were also treated with ATG-Fresenius (10 mg/kg for 3 days) and Rituximab (200 mg/m2 in single dose), patients receiving HSCT from HLA-identical sibling, MUD or single cord blood unit and in early disease status (arm B) were also treated with ATG-Fresenius (5 mg/kg for 3 days) and Rituximab (200 mg/m2 in single dose), while patients receiving HSCT from HLA-identical sibling, MUD or single cord blood unit and in advanced disease status (arm C) did not receive any ATG or Rituximab. GvHD prophylaxis consisted of Sirolimus (target concentration 8-15 ng/ml, till day +60) and Mycophenolate Mofetil (10 mg/kg tid till day +30). Results Neutrophils engraftment was reported at a median time of 17 days (range: 9-46) in all 91 evaluable patients; five patients died of transplant-related causes (n=4) or disease progression (n=1) before day +15. Platelets engraftment occurred after a median time of 17 days (range: 4-153) in 75 patients (82%). At the first marrow evaluation on day +30 all the evaluable patients showed full donor chimerism, 77 patients (90%) were in complete remission and 9 were in stable disease or progression. After a median follow-up of 425 days, cumulative incidence of grade 2-4 and 3-4 aGvHD were 40% and 26% respectively. Cumulative incidence of moderate or severe cGvHD (according to NIH criteria) was 57%. Cumulative incidence of NRM at day +100 and +365 were 23% and 36% respectively; cumulative incidence of relapse at day +365 was 33%. Overall survival and progression-free survival 1 year after HSCT were 51% and 43% respectively. EBV reactivation occurred in 7 patients, but no PTLD was observed. Conclusions The new conditioning regimen we investigated proved to be feasible in this high-risk population. We did not observe any major difference in terms of NRM and aGvHD compared to the data from our previous trial (TrRaMM, Eudract 2007-5477-54) with similar inclusion criteria and patient characteristics, but a reduced-intensity conditioning regimen based on Treosulfan and Fludarabine. Interestingly, we observed a trend of lower relapse incidence, resulting in a better OS and PFS. The low toxicity profile of Treosulfan and Fludarabine should be considered as a myeloablative platform for further intensification; more studies are warranted in order to find the association for a conditioning regimen endowed with a low toxicity profile but still a strong anti-tumor activity. Disclosures: Bonini: MolMed SpA: Consultancy.
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- 2013
41. Human Herpes Virus 6 Reactivation and Disease After Allogeneic Hematopoietic Stem Cell Transplantation
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Fabio Ciceri, Francesca Lorentino, Fabio Giglio, Alessandra Forcina, Veronica Valtolina, Maria Rosaria Carbone, Jacopo Peccatori, Andrea Assanelli, Consuelo Corti, Maddalena Noviello, Sarah Marktel, Massimo Bernardi, Luca Vago, Lara Crucitti, Mara Morelli, Chiara Bonini, Maria Teresa Lupo Stanghellini, Raffaella Greco, and Magda Marcatti
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education.field_of_study ,business.industry ,medicine.medical_treatment ,Immunology ,Population ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Rash ,Transplantation ,medicine.anatomical_structure ,Graft-versus-host disease ,Bone marrow suppression ,medicine ,Bone marrow ,medicine.symptom ,education ,business ,Viral load - Abstract
Background Human herpesvirus type 6 (HHV-6) is a member of the beta herpesvirus subfamily (genus Roseolovirus) and two distinct variants have been described: types A and B. HHV-6 infection is recognized as the cause of a febrile disease and exanthem subitum in early childhood. The infection rarely causes serious events in healthy individuals, but viral reactivation in immunocompromised patients is frequently associated with severe clinical manifestations. Above all HHV-6 is increasingly recognized as an opportunistic and potentially life-threatening pathogen in recipients of allogeneic hematopoietic stem cell transplantation (AlloSCT). Approximately 60% of solid organ transplant and 40% of patients undergoing alloSCT experience HHV-6 reactivation, mainly of variant B. Reported clinical manifestations of HHV-6 infection in transplanted patients are skin rash, interstitial pneumonia, bone marrow suppression and encephalitis. Moreover, some clinical reports suggest that HHV-6 can facilitate the occurrence of severe clinical complications of alloSCT, increasing transplant-related mortality. Methods From January 2009 to February 2013, we retrospectively evaluated 54 consecutive adult patients (median age 50 years) who developed positivity to HHV-6 after alloSCT for high-risk hematological malignancies. Stem cell donors were family haploidentical (37), HLA identical sibling (8), unrelated volunteer (6), cord blood (3). The viral load was determined by quantitative PCR (Nanogen Advanced Diagnostic S.r.L) in cell-free body fluids such as plasma, bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), bone marrow (BM) aspirates or in gastrointestinal biopsies. Results Median time from alloSCT to HHV-6 reactivation was 34 days (range: 0-705). Thirty-one patients presented HHV-6 positive in plasma, 9/54 in BM, 33/54 in gut biopsies or BAL, 7/54 in CSF. At the time of viral positivity all pts were receiving acyclovir as viral prophylaxis except five. Twenty-nine patients had acute graft versus host disease (GvHD). Twenty-two out of these twenty-nine patients experienced a grade III-IV acute GvHD, requiring high dose steroids in twenty-six cases. A concomitant CMV positivity was detected in 15/54 patients. The median absolute count of CD3+ lymphocytes was 262 cells/mcl. In 52/54 cases we reported HHV-6 clinical manifestations: fever (43), skin rash (22), hepatitis (19), diarrhoea (24), encephalitis (10), BM suppression (18), delayed engraftment (11). HHV-6 positivity led to antiviral pharmacological treatment in 37/54 cases, using as first choice therapy foscarnet. Amongst the total fifty-four patients with documented HHV-6 positivity thirty-one solved the clinical event. However the mortality rate was relatively high in this population (only 30% of patients were alive), mainly related to severe infections or GvHD. A better overall survival is significantly associated with CD3+ cells higher than 200/mcl (p-value 0.011) and time after alloSCT more than 2 months (p-value 0.035). In this analysis the overall survival was not significantly influenced by steroids administration, presence of acute GvHD, plasma viral load and organ involvement. Conclusions This retrospective study further demonstrates the correlation between HHV-6 reactivation and high morbidity and mortality rates in patients after alloSCT. Despite HHV-6 detection typically occurred in the first month after AlloSCT, a better immune reconstitution has the potential to improve the outcome. The regular monitoring of HHV-6 DNA, using a real-time PCR assay, may be useful for identifying active HHV-6 infection and for the introduction of a pre-emptive treatment, possibly reducing the incidence of the most severe clinical complications. Disclosures: Bonini: MolMed SpA: Consultancy.
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- 2013
42. Cidofovir Treatmenf For Hemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplantation For High Risk Hematological Malignancies
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Lara Crucitti, Matteo Carrabba, Sarah Marktel, Andrea Assanelli, Andrea Salonia, Raffaella Greco, Luca Vago, Francesca Lorentino, Maria Teresa Lupo Stanghellini, Massimo Bernardi, Consuelo Corti, Jacopo Peccatori, and Fabio Ciceri
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Total body irradiation ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Gastroenterology ,BK virus ,Transplantation ,chemistry.chemical_compound ,chemistry ,Concomitant ,Internal medicine ,medicine ,business ,Viral load ,Hemorrhagic cystitis ,Cidofovir - Abstract
Background Hemorrhagic cystitis (HC) is a common cause of morbidity after allogeneic stem cell transplantation (allo-SCT), and symptoms vary from asymptomatic microscopic to frank hematuria with clot formation and urinary tract obstruction. Multiple factors including toxicity of chemo-radiotherapy, BK virus reactivation seems to be involved a in post-transplant HC, nevertheless effective risk factors and treatments of this complication are currently unknown and unresolved. Cidofovir (CDV) is an acyclic nucleoside analogue with a broad range of antiviral activity, including BK virus and thus it has been proposed as treatment for HC after allo-SCT. Methods In this study we retrospectively evaluated 59 consecutive adult patients (median age 45 years) who received CDV for HC after allo-SCT from January 2008 to December 2012 at San Raffaele Hospital. All patients were affected by high risk hematologic malignancies and 39 had active disease at time of transplant. Donors were HLA identical sibling (n=8), family mismatched (n=39), unrelated volunteer (n=11), cord blood (n=1). All patients received a fully myeloablative conditioning regimen, infusion of donor T cells, 25 patients (43%) received also Total Body Irradiation (4 Gray) and in 51 cases (86%) was administered anti-thymocyte globulin as part of the conditioning regimen. BK viral load was determined on urine by TaqMan PCR. CDV was administered at the dose of 5mg/kg/week intravenously (i.v.) in 41 patients and intravescically in 21 patients (4 double treatments). The median dose number of CDV doses was 2 (range 1 to 8). The intravescically route was adopted in case of pending renal insufficiency or impossibility to interrupt intravenous antiviral for concomitant viral reactivations. Results HC occurred in median 14 days after allo-SCT (range -4 to 330). Median duration of symptoms was 34 days (range 6 to 166). At treatment onset 13 patients had grade 0-I HC, 13 grade II, 24 grade III and 9 grade IV. In 55 cases (93%) high BK viral load was detected in urine (BK virus median load 10^7 cp/ml) before treatment. After treatment the reduction of BK viruria was documented in 29 out of 33 evaluable cases (87%), with a 1-log reduction of BK viruria median load (p=0.004). Improvement of HC grade was observed in 41 patients (70%) and a complete clinical response within 7 days from last CDV dose was observed in 30 cases (51%). Worsening of HC leading to urological intervention occurred in 5 treated patients. Four patients died with an ongoing uncontrolled HC: 2 of acute Graft-versus Host Disease, 1 of pneumonia and 1 of relapse. During i.v. CDV treatment 22 out of 41 patients (54%) had a viral reactivation (Cytomegalovirus n=14, Epstein-Barr Virus n=8, Herpes Simplex-1 n=3, Herpes Simplex-6 n=4) and 2 patients developed acute renal failure requiring drug discontinuation. Conclusions CDV treatment after allo-SCT is associated with a reduction of BK viruria load and HC clinical responses in more than half of cases. This is in agreement with data reported in other retrospective trials. Viral reactivations under CDV treatment should be better investigated in the allo-setting, since the long-half life of the drug and its potential nephrotoxicity limits the possibility of concomitant antiviral therapy with other agents. Our data warrant prospective trials to investigate the role of CDV in allo-SCT. Disclosures: Off Label Use: Cidofovir is an acyclic nucleoside analogue with a broad range of antiviral activity, including BK virus and thus it has been proposed as treatment for hemorrhagic cystitis after Allogeneic Stem Cell Transplantation.
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- 2013
43. Human Herpes Virus-6 and Clinical Manifestations After Allogeneic Hematopoietic Stem Cell Transplantation
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Fabio Ciceri, Massimo Bernardi, Simona Malato, Matteo Carrabba, Luca Vago, Magda Marcatti, Maria Teresa Lupo Stanghellini, Raffaella Greco, Andrea Assanelli, Daniela Clerici, Francesca Lorentino, Alessandra Forcina, Consuelo Corti, Claudio Bordignon, and Francesca Matteazzi
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medicine.medical_specialty ,Cytopenia ,Neutrophil Engraftment ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Neutropenia ,medicine.disease ,Biochemistry ,Gastroenterology ,Transplantation ,Bone marrow suppression ,Internal medicine ,medicine ,business ,Viral load ,Encephalitis - Abstract
Abstract 1960 BACKGROUND: Human herpesvirus 6 (HHV-6) is increasingly recognized as an opportunistic and potentially life-threatening pathogen in recipients of allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Reported clinical manifestations of HHV-6 infection in transplanted patients are skin rash, interstitial pneumonia, bone marrow suppression and encephalitis. Moreover, an increasing number of clinical reports suggest that HHV-6 can facilitate the occurrence of other severe clinical complications of allogeneic HSCT, including Graft-versus-Host Disease (GvHD), ultimately increasining transplant-related mortality. Still, the actual incidence of HHV-6 infection in recipients of HSCT and the causative link between infection and clinical complications remain elusive, mostly due to the small and heterogeneous patient cohorts analyzed to date. METHODS: From January 2009 to July 2011, we retrospectively evaluated 43 consecutive adult patients (median age 51 years) who developed positivity to HHV-6 after allogeneic HSCT for high-risk hematological malignancies. Stem cell donor was for 30 patients family haploidentical, for 5 an HLA identical sibling, and for 8 an unrelated volunteer (1 of which cord blood). The viral load was determined by quantitative PCR in cell-free body fluids such as plasma, bronchoalveolar lavage, cerebrospinal fluid, bone marrow aspirates or in gastrointestinal biopsies. At the time of positivity all patients were receiving acyclovir as viral prophylaxis except 5. Sixteen patients had clinical acute GvHD at time of HHV-6 positivity (grade III-IV in 14), and 33 were profoundly immunosuppressed with variable association of 2–4 immunosuppressive drugs (steroids included). Moreover concomitant CMV positivity was detected in 11 patients, while a severe neutropenia in 12. RESULTS: Median time from allogeneic HSCT to HHV-6 reactivation was 36 days (range: 7–625). In 19 patients HHV-6 was detected in plasma, with a median viral load of 19,454 cp/mL (34-4,524,600); 15 had concomitant fever, 5 skin rash of new onset, 4 impaired liver function, and 5 developed cytopenia subsequently to the infection. In 7 patients HHV-6 was detected in the bone marrow: the median viral load was 163'800 cp/mL (568-1'552'982). In 8 patients, all febrile, HHV-6 was observed in bronchoalveolar lavage samples with a median of 4'149 cp/mL (85–39250). In 16 patients, 10 with documented gut aGvHD, 11 with diarrhoea, HHV-6 was detected in gastrointestinal biopsies with a median of 7'510 cp/mL (120-4'524'600). HHV-6 was found in cerebrospinal fluid in 4 cases (all within 30 days after HSCT); the median viral load was 29'352 cp/mL (4'508-1'552'982); all these patients experienced encephalitis with confusion and anxiety, 2 suffered seizures and 3 showed abnormal findings on brain MRI. Amongst patients with organ localizations of HHV-6 only 28% had concomitant plasma positivity. HHV-6 positivity led to antiviral pharmacological treatment only when associated with clinical manifestations (n=21), using as first choice therapy foscarnet. Amongst the total 43 patients with documented HHV-6 positivity 11 completely solved the clinical event, whereas 19 (44%) died. CONCLUSIONS: HHV-6 infection/reactivation is associated with high morbidity and mortality in patients who undergo allogeneic HSCT. HHV-6 infection typically occurred close to the time of neutrophil engraftment. HSCT from an HLA-mismatched donor and steroid administration were associated with increased risk of active HHV-6 infection. Development of encephalitis was associated with high HHV-6 viral load. The regular monitoring of HHV-6 DNA in allogeneic HSCT recipients, using a real-time PCR assay, may be useful for identifying active HHV-6 infection and for the introduction of a pre-emptive treatment, possibly reducing the incidence of the most severe clinical complications. Disclosures: No relevant conflicts of interest to declare.
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- 2011
44. Haploidentical T-Repleted Stem Cell Transplantation (SCT) Has Comparable Survival to 10/10 and 9/10 Unrelated SCT in Poor-Cytogenetics Risk Acute Myeloid Leukemia in First Complete Remission: A Study on Behalf of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)
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Liisa Volin, Didier Blaise, Arnon Nagler, Charles Craddock, Nathalie Fegueux, Ibrahim Yakoub-Agha, Myriam Labopin, Mohamad Mohty, Fabio Ciceri, Gérard Socié, Massimo Bernardi, Jordi Esteve, Jan J. Cornelissen, Jakob Passweg, Francesca Lorentino, and Tobias Gedde-Dahl
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Oncology ,medicine.medical_specialty ,education.field_of_study ,Acute leukemia ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Hazard ratio ,Population ,Context (language use) ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,Transplantation ,Internal medicine ,medicine ,Cumulative incidence ,business ,education ,medicine.drug - Abstract
Background: Allogeneic stem cell transplantation (SCT) is the most powerful therapy to prevent relapse in poor-cytogenetics risk acute myeloid leukemia (poorAML) patients (pts) in first complete remission (CR1). For pts who lack a matched related donor (MRD), SCT from an unrelated (UD) or alternative donor is indicated. Pts with poorAML and thus at high risk of relapse can theoretically benefit the most from SCT from haploidentical donors (HaploSCT), which is an attractive option as the time required to find a well-matched UD could be inacceptable. Several recent reports show comparable outcomes between HaploSCT and transplants from UD (Piemontese S, JHO 2017; Versluis J, Blood Advances 2017). Comparative studies able to include sufficient numbers of pts with poorAML in CR1 are limited; this prompted us to compare the outcomes of HaploSCT to those of 10/10 and 9/10 HLA-matched UD in this disease category. Methods: We retrospectively selected denovo poorAML pts in CR1 receiving T-repleted haplo (n=74), 10/10 UD (n=433) and 9/10 UD SCT (n=123) from 2007 to 2015 who were reported to the ALWP of EBMT Registry. PoorAML was defined as the presence of: complex karyotype (at least 3 structural abnormalities per clone); monosomal karyotype (1 autosomal monosomy plus 1 monosomy or structural abnormality); inv(3)/t(3;3); -5 or del(5q); -7 or abn(7q); t(v;11)(v;q23); abn(17p); t(6;9); t(9;22). Primary endpoints were leukemia-free survival (LFS) and overall survival (OS). Secondary endpoints were acute and chronic GVHD (aGVHD and cGVHD), relapse and nonrelapse mortality (NRM). Results: Main population characteristics are depicted in Table 1. Recipients of haplo-, 10/10 UD- and 9/10 UD-SCT were comparable concerning time from diagnosis to SCT and time from CR1 to SCT. HaploSCT more likely received bone marrow as stem cell source. In-vivo T cell depletion (TCD) with ATG was most likely adopted in UD-SCT, with a conversely increased use of high-dose post-transplant Cyclophosphamide as GvHD prophylaxis backbone in HaploSCT (65% Vs 3% for 10/10 UD and 2% for 9/10 UD, p LFS and OS at 2 years were not significantly different between haploSCT, 10/10 UD SCT and 9/10 UD SCT (53±12% and 59±12%, 43±5% and 50±6%, 44±9% and 50±9%, respectively, p=0.5 and p=0.5, respectively). In Haplo-SCT, the 100-day cumulative incidence (CI) of grade≥2 aGvHD was in line with the one reported for 10/10 and 9/10 UD (33±11% for haplo, 30±4% for 10/10 UD and 34±9% for 9/10 UD, p=0.6). Likewise, the 2-y CI of cGvHD (35±12%) of HaploSCT was similar to those of 10/10 UD (36±4%) and 9/10 UD (36±9%), p=0.8. The 2-y CI of NRM was 19±8% after haploSCT, 18±4% after 10/10 UD SCT and 18±6% after 9/10 UD SCT (p=0.9). Relapse incidence was not significantly affected by donor source, with a 2-y CI of 27±9% for haploSCT, 39±5% for 10/10 UD SCT and 37±9% for 9/10 UD SCT (p=0.3). After adjustment for centre effect, pts age, time from diagnosis to SCT, conditioning intensity, in-vivo TCD, donor/pts gender and CMV serostatus, the multivariable model showed that haploSCT recipients didn't experience worse outcomes compared to 10/10 and 9/10 UD. Indeed, compared to haploSCT (reference) the hazard ratio (HR) for LFS was 1.2 for 10/10 UD (p=0.3) and 1.2 for 9/10 UD (p=0.4). The hazards for OS in 10/10 and 9/10 UD did not differ from haplo-SCT (1.3, p 0.3 and 1.2, p 0.4, respectively). Moreover, compared to haplo, SCT from 10/10 and 9/10 UD was not associated with lower hazards for relapse (HR: 1.4, p=0.2 and 1.4, p=0.3, respectively), NRM (HR: 1, p=0.9 and 1, p=0.9, respectively), grade≥2 aGvHD (HR: 1.2, p=0.6 and 1.4, p=0.3, respectively) and cGvHD (HR: 1.2, p=0.5 and 1.3, p=0.4, respectively). The only factor associated with worse LFS and OS was pts age (for each 10-year interval: HR 1.1, p=0.02 and 1.2, p=0.001, respectively). Conclusions: In the present series of poorAML pts transplanted in CR1, haploSCT recipients experienced comparable outcomes with respect to 10/10 and 9/10 HLA-matched UDs. This suggests that the immunotherapeutic effect of allogeneic SCT is exerted similarly across these different donor sources in this peculiar population. Therefore, in the absence of a MRD, pts with poor risk cytogenetics who have a very high risk of relapse could be allocated to haploSCT in their first remission, especially in the context of the recent improvements, which fostered an abatement of GvHD and NRM rates, historically the main detrimental factors for Haploidentical transplants. Disclosures 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. Mohty: Sanofi: Honoraria, Speakers Bureau.
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