Publications by authors named "Mario Arpinati"

49 Publications

Clinical Efficacy of Ponatinib in Philadelphia-Positive T-Cell Acute Lymphoblastic Leukemia with Extramedullary Involvement.

Acta Haematol 2021 Jun 15:1-5. Epub 2021 Jun 15.

Istituto di Ematologia "Seràgnoli" IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

T-cell acute lymphoblastic leukemia (T-ALL) is a rare entity in the adult acute leukemia setting. Translocation (9;22)(q34;q11) and BCR-ABL1 rearrangement are occasionally found in T-ALL and have been reported in no more than 100 cases in the literature (most of which are chronic myeloid leukemia blast crisis). Here, we report the remarkable effectiveness of third-generation tyrosine-kinase inhibitor ponatinib in obtaining hematological and metabolic remission, in a patient with Philadelphia chromosome-positive de novo T-ALL and outcomes of a therapeutic strategy containing chemotherapy intensification, nelarabine, and allogeneic hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1159/000516003DOI Listing
June 2021

Incidence, Risk Factors and Complications of Ocular Graft-Versus-Host Disease Following Hematopoietic Stem Cell Transplantation.

Am J Ophthalmol 2021 07 22;227:25-34. Epub 2021 Feb 22.

Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliero Universitaria di Bologna (FB, MA), Bologna, Italy.

Purpose: The purpose of this research was to evaluate the incidence, risk factors, and complications of ocular graft-versus-host disease (GVHD) in a large single-center study.

Design: Retrospective observational case series.

Methods: This study included 283 patients who underwent hematopoietic stem cell transplantation (HSCT) between 2005 and 2020. Ocular GVHD was diagnosed according to International Chronic Ocular GVHD Consensus Group criteria. Potential risk factors for ocular GVHD were evaluated using the Cox proportional hazards model.

Results: The cumulative incidence of ocular GVHD was 19.7% at 1 year, 29.3% at 2 years, 40.7% at 3 years, 47.2% at 4 years, and 49.7% at 5 years. Ocular GVHD was significantly associated with recipient age (hazard ratio [HR]: 1.228; 95% confidence interval [CI]: 1.033-1.459; P = .020); female sex (HR: 1.797; 95% CI: 1.195-2.703; P = .005); peripheral blood stem cell use (PBSC) (HR: 2.079; 95% CI: 1.268-3.411; P = .004); and previous acute GVHD (HR: 1.276; 95% CI: 1.073-1.518; P = .006). Ocular complications after HSCT included cataract, corneal ulcer, corneal perforation, lacrimal obstruction, herpetic keratitis, and cytomegalovirus retinitis.

Conclusions: Half of patients developed ocular GVHD in the 5 years following HSCT. Older age, female sex, use of PBSC, and acute GVHD disease were significant predictors of ocular GVHD. Hematologists and ophthalmologists should be aware of its vision threating complications.
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http://dx.doi.org/10.1016/j.ajo.2021.02.022DOI Listing
July 2021

Longitudinal Corneal Endothelial Cell Changes in Patients Undergoing Hematopoietic Stem Cell Transplantation.

Cornea 2021 Apr;40(4):462-466

*Ophthalmology Unit, DIMES, Alma Mater Studiorum University of Bologna and S.Orsola-Malpighi Teaching Hospital, Bologna, Italy; †Department of Ophthalmology, University Magna Graecia of Catanzaro, Catanzaro, Italy; and ‡Hematology Unit, DIMES, Alma Mater Studiorum University of Bologna and S.Orsola-Malpighi Teaching Hospital, Bologna, Italy.

Purpose: To evaluate longitudinally corneal endothelial cell changes in patients undergoing hematopoietic stem cell transplantation (HSCT) and to further investigate possible correlations with hematological and ocular characteristics.

Methods: Prospective observational study conducted at a single center. All patients underwent a comprehensive ophthalmological examination, before and after HSCT, including slitlamp examination, Schirmer test, tear breakup time, ocular surface staining, specular microscopy of corneal endothelium, and Ocular Surface Disease Index questionnaire.

Results: Twenty-five patients undergoing HSCT and 25 age- and sex-matched controls were included. At baseline, hematological patients showed significantly lower values of endothelial cell density (ECD) compared with those of controls (2514.5 ± 390.2 vs. 2723.7 ± 298.0 cells/mm, P = 0.038). After HSCT, ocular surface disease index score significantly increased (P = 0.020) and tear breakup time significantly decreased (P = 0.036). Conversely, no significant changes were found in Schirmer test and corneal fluorescein staining (always P > 0.05). Eight patients (32%) developed ocular graft-versus-host disease (GVHD). ECD values significantly decreased after HSCT (from 2514.5 ± 390.2 to 2409.5 ± 330.9 cells/mm, P = 0.009). The decrease in ECD values after HSCT was more pronounced in patients with ocular GVHD compared with those without (231.1 ± 188.8 vs. 45.6 ± 156.5, P = 0.016). No significant correlations between the changes in ECD and hematological and ocular characteristics were found (always P > 0.05).

Conclusions: Hematological patients showed a lower endothelial cell count already before HSCT, compared with controls. After HSCT, the endothelial cell count further significantly decreased, particularly in patients who developed ocular GVHD.
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http://dx.doi.org/10.1097/ICO.0000000000002441DOI Listing
April 2021

Diagnosis and Treatment of VOD/SOS After Allogeneic Hematopoietic Stem Cell Transplantation.

Front Immunol 2020 3;11:489. Epub 2020 Apr 3.

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS) is a rare complication characterized by hepatomegaly, right-upper quadrant pain, jaundice, and ascites, occurring after high-dose chemotherapy, hematopoietic stem cell transplantation (HSCT) and, less commonly, other conditions. We review pathogenesis, clinical appearance and diagnostic criteria, risk factors, prophylaxis, and treatment of the VOD occurring post-HSCT. The injury of the sinusoidal endothelial cells with loss of wall integrity and sinusoidal obstruction is the basis of development of postsinusoidal portal hypertension responsible for clinical syndrome. Risk factors associated with the onset of VOD and diagnostic tools have been recently updated both in the pediatric and adult settings and here are reported. Treatment includes supportive care, intensive management, and specific drug therapy with defibrotide. Because of its severity, particularly in VOD with associated multiorgan disease, prophylaxis approaches are under investigation. During the last years, decreased mortality associated to VOD/SOS has been reported being it attributable to a better intensive and multidisciplinary approach.
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http://dx.doi.org/10.3389/fimmu.2020.00489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147118PMC
March 2021

MEC (mitoxantrone, etoposide, and cytarabine) induces complete remission and is an effective bridge to transplant in acute myeloid leukemia.

Eur J Haematol 2020 Jul 7;105(1):47-55. Epub 2020 Apr 7.

Department of Hematology and Oncology, Institute of Hematology L. e A. Seràgnoli, Azienda Ospedaliero-Universitaria S. Orsola Malpighi, Bologna, Italy.

Introduction: Clinical response and chemosensitivity of relapse or refractory AML patients were evaluated after rescue and bridge-to-transplant MEC (mitoxantrone, etoposide, and cytarabine) regimen.

Methods And Patients: Fifty-five consecutive AML patients were treated with MEC from 2009 to 2018. Chemosensitivity was evaluated by WT1 quantification.

Results: 27/55 patients (49.1%) had AML resistant to induction and 28/55 patients (50.9%) had AML relapse. 25/55 patients (45.5%) achieved a CR after one course of MEC, and 12 patients (21.8%) achieved WT1 negativity. In 12 patients, a second MEC was administered. Four out of 12 patients improved significantly their response with the 2nd MEC. MEC was an effective bridge to transplant, 32/55 patients (58.2%) received an allogenic stem cell transplant. Median overall survival (OS) from MEC was 455 days (95% CI 307-602 days.); patient with WT1 negative CR had the best OS (P<.000).

Conclusion: WT1 is a useful marker of chemosensitivity after MEC as rescue and bridge-to-transplant therapy.
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http://dx.doi.org/10.1111/ejh.13406DOI Listing
July 2020

Health technology assessment-based approach to flow cytometric immunophenotyping of acute leukemias: a literature classification.

Tumori 2020 Feb 14:300891620904412. Epub 2020 Feb 14.

Fondazione IRCCS Istituto Nazionale dei Tumori, Direzione Scientifica, Milan, Italy.

Objective: Acute leukemia (AL) is a broad, heterogeneous group of malignant diseases. The diagnostic workup of AL is based on several clinical and laboratory findings, including flow cytometric immunophenotyping. However, the role of this assay in the diagnosis of AL has not been systematically investigated. The aim of this study was to determine the accuracy and utility of flow cytometric immunophenotyping in the identification, characterization, and staging of AL.

Methods: We performed a systematic selection and classification of the literature since 1980, focused on flow cytometric immunophenotyping of AL. We applied a 6-variables model to cover both the technical capabilities and the clinical value of flow cytometric immunophenotyping in the diagnosis of AL.

Results: Using 3 key words (acute leukemia, immunophenotyping, flow cytometry), we screened the literature from January 1985 to April 2015 in PubMed and Embase databases and found 1010 articles. A total of 363 were selected and submitted to the expert panel, which selected a final data set of 248 articles to be analyzed. Of these, 160 were focused on clinical and biological issues, 55 were technical articles, and 31 were reviews. These 248 articles were then analyzed according to the 6-variables model and definitively classified.

Conclusions: We assessed the literature on flow cytometric immunophenotyping of AL over 3 decades as the first step toward an evidence-based analysis of the impact of this technology on the clinical management of patients with AL.
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http://dx.doi.org/10.1177/0300891620904412DOI Listing
February 2020

Longitudinal Analysis of Infrared Meibography in Patients Undergoing Hematopoietic Stem Cell Transplantation.

Cornea 2020 Jul;39(7):812-817

Department of Ophthalmology, University of "Magna Graecia," Catanzaro, Italy.

Purpose: To evaluate meibomian gland (MG) changes in patients undergoing hematopoietic stem cell transplantation (HSCT) by infrared meibography and to further investigate possible correlations with hematological characteristics.

Methods: Thirty-three patients were included: infrared meibography of the lower eyelid, Schirmer test, tear break-up time, ocular surface staining, and Ocular Surface Disease Index questionnaire were conducted before (V0) and 4 months after HSCT (V1). A paired samples t test was used to compare parameters before and after HSCT. A mixed analysis of variance was used to assess the effect of hematological characteristics on changes of MG loss (MGL) after HSCT.

Results: MGL and corneal staining significantly increased after HSCT (respectively, from 24.3% ± 10.1% to 32.2 ± 15.0 and from 1.2 ± 1.5 to 2.0 ± 1.7; always P < 0.011), whereas tear break-up time significantly decreased (from 6.6 ± 4.2 seconds to 3.2 ± 2.2; P < 0.001). At V1, 19 patients (57.6%) belonged to ocular graft-versus-host disease severity grade 0, 8 (24.2%) to grade I, and 6 (18.2%) to grade II. The percentage of MGL at V0 and the increase of MGL from V0 to V1 did not differ between patients who developed ocular graft-versus-host disease and those who did not (always P > 0.05). At V1, MGs' quality reduced in 16 patients (48.5%), remained unchanged in 14 (42.4%), and improved in 3 (9.1%). The increase of MGL after HSCT was higher in patients receiving myeloablative conditioning regimen (P = 0.005).

Conclusions: MG function, loss, and quality significantly worsened after HSCT. Myeloablative conditioning regimen was associated with higher MGL.
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http://dx.doi.org/10.1097/ICO.0000000000002271DOI Listing
July 2020

The timing of plerixafor addition to G-Csf and chemotherapy affects immunological recovery after autologous stem cell transplant in multiple myeloma.

Bone Marrow Transplant 2020 05 25;55(5):946-954. Epub 2019 Nov 25.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.

Plerixafor inhibits CXCR4, thus inducing the mobilization of hematopoietic stem/progenitor cells in lymphoma and multiple myeloma (MM) patients eligible for autologous stem cell transplantation (ASCT). However, the kinetics of plerixafor-induced mobilization of lymphocyte subsets is poorly known. Here, we evaluated the graft content, the engraftment, and the immunological reconstitution of MM patients receiving plerixafor. Thirty-seven patients undergoing one or tandem ASCT were enrolled. After mobilization with cyclophosphamide plus G-CSF, plerixafor was added at hematological recovery regardless of CD34 cell count. We evaluated the number of CD34, CD34/CD38, CD3, CD4, CD8, CD19, CD56/CD3, CD4/CD25/FOXP3, and CD138/CD38 cells on each apheresis. Hematological and immunological recovery were determined at 30 days, 3, 6, 9, and 12 months after ASCT. Overall, 34/37 patients mobilized a median of 10.1 × 10 CD34 cells/Kg (IQ 7.7-13.4). Patients with <20/µL CD34 cells at plerixafor administration (18/33) had a significantly higher CD34 cell fold increase, but not a higher absolute number, than 16/33 patients with ≥20/µL CD34 cells. A similar CD34 and immune graft composition was reported. A higher number of CD3 and CD8 cells/µL was observed at 3 months after first ASCT (p < 0.05) in the group with ≥20 CD34 cells/µL. Thus, in MM patients, the timing of plerixafor administration influences immunological recovery.
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http://dx.doi.org/10.1038/s41409-019-0756-1DOI Listing
May 2020

Regulatory T cells from patients with end-stage organ disease can be isolated, expanded and cryopreserved according good manufacturing practice improving their function.

J Transl Med 2019 08 5;17(1):250. Epub 2019 Aug 5.

Azienda Ospedaliero-Universitaria di Bologna S. Orsola-Malpighi, Bologna, Italy.

Background: Here, we isolated, expanded and functionally characterized regulatory T cells (Tregs) from patients with end stage kidney and liver disease, waiting for kidney/liver transplantation (KT/LT), with the aim to establish a suitable method to obtain large numbers of immunomodulatory cells for adoptive immunotherapy post-transplantation.

Methods: We first established a preclinical protocol for expansion/isolation of Tregs from peripheral blood of LT/KT patients. We then scaled up and optimized such protocol according to good manufacturing practice (GMP) to obtain high numbers of purified Tregs which were phenotypically and functionally characterized in vitro and in vivo in a xenogeneic acute graft-versus-host disease (aGVHD) mouse model. Specifically, immunodepressed mice (NOD-SCID-gamma KO mice) received human effector T cells with or without GMP-produced Tregs to prevent the onset of xenogeneic GVHD.

Results: Our small scale Treg isolation/expansion protocol generated functional Tregs. Interestingly, cryopreservation/thawing did not impair phenotype/function and DNA methylation pattern of FOXP3 gene of the expanded Tregs. Fully functional Tregs were also isolated/expanded from KT and LT patients according to GMP. In the mouse model, GMP Tregs from LT or KT patient proved to be safe and show a trend toward reduced lethality of acute GVHD.

Conclusions: These data demonstrate that expanded/thawed GMP-Tregs from patients with end-stage organ disease are fully functional in vitro. Moreover, their infusion is safe and results in a trend toward reduced lethality of acute GVHD in vivo, further supporting Tregs-based adoptive immunotherapy in solid organ transplantation.
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http://dx.doi.org/10.1186/s12967-019-2004-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683529PMC
August 2019

Clinical utility of measuring Epstein-Barr virus-specific cell-mediated immunity after HSCT in addition to virological monitoring: results from a prospective study.

Med Microbiol Immunol 2019 Dec 9;208(6):825-834. Epub 2019 Jul 9.

Department of Specialized, Experimental, and Diagnostic Medicine, Operative Unit of Clinical Microbiology, St. Orsola-Malpighi Polyclinic, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.

Lack of virus-specific cell-mediated immunity (CMI) is associated with worse viral infection outcome in hematopoietic stem cell transplantation (HSCT). We aimed to evaluate the role of immunological monitoring of Epstein-Barr virus (EBV) infection in addition to virological one in 33 adult and 18 pediatric allogeneic HSCT recipients. Virological monitoring of infection was performed on whole blood samples by a quantitative real-time PCR assay. Immunological monitoring was performed by Enzyme-linked ImmunoSPOT assay, evaluating EBV-specific CMI, at fixed time-points and when EBV DNAemia was ≥ 10,000 copies/mL. Fifty-one percent of patients developed a post-transplant EBV infection and reduced-intensity conditioning regimen was the only factor associated to infection (P = 0.023). Lack of EBV-specific CMI during active EBV infection was associated with a greater severity of infection. Patients without EBV-specific CMI showed higher median peak level of EBV DNAemia than patients with EBV-specific CMI (P = 0.014), and consequently received more frequently, at EBV DNAemia peak, anti-CD20 therapy (0 versus 54.5%, P = 0.002). No patients with EBV-specific CMI versus 27.2% without EBV-specific CMI developed EBV-related complications (P = 0.063), including two lethal EBV-related post-transplant lymphoproliferative disorders. Combined immunological and virological measurements could improve EBV infection management in HSCT, anticipating the beginning of preemptive treatment from the EBV DNAemia peak to the finding of the lack of EBV-specific CMI.
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http://dx.doi.org/10.1007/s00430-019-00629-2DOI Listing
December 2019

Liver Stiffness Measurement Allows Early Diagnosis of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Adult Patients Who Undergo Hematopoietic Stem Cell Transplantation: Results from a Monocentric Prospective Study.

Biol Blood Marrow Transplant 2019 05 18;25(5):995-1003. Epub 2019 Jan 18.

Institute of Hematology L. and A Seràgnoli, Sant'Orsola Malpighi University Hospital, Bologna, Italy.

Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complication affecting patients undergoing hematopoietic stem cell transplantation (HSCT). The survival rate is higher when specific therapy is initiated early; thus, improving early, noninvasive diagnosis of VOD/SOS is an important need. In an adult population undergoing HSCT, we aimed to assess the role of liver stiffness measurement (LSM), evaluated by transient elastography (TE), for diagnosing VOD/SOS. Between April 2016 and March 2018, 78 consecutive adult patients with indications for allogeneic HSCT were prospectively included. LSM was performed before HSCT and at days +9/10, +15/17, and +22/24 post-HSCT. New European Society for Blood and Marrow Transplantation criteria were used to establish VOD/SOS diagnosis. Four patients developed VOD/SOS (5.1%) during the study period, with a median time of +17 days post-HSCT. A sudden increase in LSM compared with previously assessed values and pre-HSCT values, was seen in all patients who developed VOD/SOS. LSM increases occurred from 2 to 12 days before clinical SOS/VOD appearance. The VOD/SOS diagnostic performance of increased LSM over pre-HSCT assessment showed an area under the receiver operating characteristic curve of 0.997 (sensitivity 75%; specificity 98.7%). LSM gradually decreased following successful VOD/SOS-specific treatment. Interestingly, LSM values did not increase significantly in patients experiencing hepatobiliary complications (according to the Common Terminology Criteria) other than VOD/SOS. LSM by TE can be considered a promising method to perform an early, preclinical diagnosis and follow-up of VOD/SOS.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.019DOI Listing
May 2019

Eyelid metrics assessment in patients with chronic ocular graft versus-host disease.

Ocul Surf 2019 01 12;17(1):98-103. Epub 2018 Oct 12.

Ophthalmology Unit, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy.

Purpose: To assess eyelid metrics in the setting of chronic ocular graft versus-host disease (oGVHD), and to further correlate them with hematological and ocular characteristics.

Methods: Prospective case-control study conducted at a single tertiary-referred Center. The following eyelid tests were performed in oGVHD patients and control subjects: vertical lid pull; anterior/lower distraction; lateral/medial distraction; distance between lateral canthal angle and orbital rim; margin reflex distances (MRD) 1 and 2; duration of tarsus exposure; snap back. Correlations of eyelid metrics with hematological and ocular parameters in the oGVHD group were performed.

Results: Twenty-seven patients with oGVHD and 27 healthy matched subjects were finally included. Significantly higher values of vertical lid pull, anterior/lower distraction, lateral/medial distraction, and distance between lateral canthal angle and orbital rim were found in the oGVHD group compared to controls (always p < 0.02). Conversely, MRD1 was lower in oGVHD patients compared to controls (p < 0.001). Duration of tarsus exposure and snap back test were pathological in a higher percentage in oGVHD group compared to controls (respectively 66.7 and 59.3% vs 33.3 and 25.9%; p < 0.005). Vertical lid pull test was significantly higher in oGVHD patients with superior limbic keratoconjunctivitis (13.8 ± 2.4 vs 10.9 ± 2.4, p = 0.010). Ocular GVHD patients with subtarsal fibrosis had a higher percentage of pathological values for duration of tarsus exposure test (77.3 vs 20.0%; p = 0.014).

Conclusions: The present study highlighted for the first time higher eyelid laxity in oGVHD patients. This intriguing association may add a further piece to the puzzle of clinical features occurring in the setting of oGVHD.
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http://dx.doi.org/10.1016/j.jtos.2018.10.005DOI Listing
January 2019

Intrabone transplant provides full stemness of cord blood stem cells with fast hematopoietic recovery and low GVHD rate: results from a prospective study.

Bone Marrow Transplant 2019 05 19;54(5):717-725. Epub 2018 Sep 19.

DIMES, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Umbilical Cord Blood (UCB) represents a valid option for patients with hematopoietic malignancies lacking an HLA matched donor. To overcome the limitation of the low stem cell dose of UCB, the intrabone (IB) route has been proposed. We report the results of a prospective study on a poor-prognosis cohort of 23 patients receiving intrabone single UCB transplant (Clinicaltrials.gov NCT00886522). Cumulative incidence of hematological recovery at day 90 was 82 ± 9% (ANC > 0.5 × 10/L) and 70 ± 10% (platelet > 50 × 10/L) and correlated with CD34 + cells in the graft. NRM was 20 ±  9%. No severe aGVHD and only one extensive cGVHD occurred, with fast immune reconstitution. To test the hypothesis that the direct IB injection could affect the expression of stem cells regulatory pathways, CD34 + cells from BM aspirates at day + 10, + 20, + 30, processed in hypoxic conditions mimicking the BM-microenvironment (7%pO), were studied for the expression of c-Mpl, Notch1 and CXCR4. We found that the expression of c-Mpl in CD34 + cells at day + 10 significantly correlated with hematological recovery. In conclusion, IB-UCB transplant success is associated with low incidence of GVHD and high-speed platelet recovery; intrabone route may preserve full hematopoietic stemness by direct delivery of UCB stem cells into the hypoxic HSC niche.
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http://dx.doi.org/10.1038/s41409-018-0335-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760547PMC
May 2019

Low-Dose Anti-T Lymphoglobulin as Prophylaxis for Graft-versus-Host Disease in Unrelated Donor Transplantations for Acute Leukemias and Myelodysplastic Syndromes.

Biol Blood Marrow Transplant 2018 12 17;24(12):2450-2458. Epub 2018 Jul 17.

Department of Hematology "L. and A. Seràgnoli," University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.

Chronic graft-versus-host disease (cGVHD) is a major complication after stem cell transplantation (HSCT). Several randomized studies already demonstrated that anti-T lymphoglobulin (ATLG) is effective in preventing GVHD after myeloablative unrelated and HLA-identical sibling transplants. However, the issue of doses and the potential increase of relapses still remain unsolved. Here we report data on 190 patients with acute leukemia and myelodysplastic syndrome who underwent an unrelated HSCT with low-dose ATLG (15 to 30 mg/kg) given at an earlier timing (days -6 to -2). HSCT was performed from HLA 10/10 (n = 62, 33%), 9/10 (n = 91, 48%), 8/10 (n = 30, 16%), and <8/10 (n = 7, 4%) identical unrelated donor. Peripheral blood was the stem cell source in 42% (n = 80). Median follow-up was 51 months. Grades II to IV and III to IV acute GVHD were 26% and 9%, respectively, and 2-year overall and moderate to severe cGVHD were 23% and 14%, respectively. The 3-year incidences of relapse and nonrelapse mortality were 26% and 18%, respectively. The rates of 3-year overall survival (OS), disease-free survival (DFS), and GVHD-free and relapse-free survival (GRFS) were 60%, 56% and 44%, respectively. Factors such as younger donor, good performance status, and early disease were associated with better outcome in terms of OS, DFS, and GRFS. Our data indicate that doses of ATLG lower that those used in randomized clinical trials can be used for GVHD prevention, even in the adult setting, without clear increases in relapse and infections; these findings need to be further validated by a prospective randomized study.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.011DOI Listing
December 2018

Meibomian Gland Dropout in Hematological Patients Before Hematopoietic Stem Cell Transplantation.

Cornea 2018 Oct;37(10):1264-1269

Ophthalmology Unit, Alma Mater Studiorum University of Bologna, DIMES, S.Orsola-Malpighi University Hospital, Bologna, Italy.

Purpose: To perform qualitative and quantitative analysis of meibomian gland (MG) dropout in hematological patients before hematopoietic stem cell transplantation (HSCT) and to correlate it with both ocular surface and hematological characteristics.

Methods: This prospective study included 46 consecutive patients undergoing HSCT and 30 age- and sex-matched healthy controls. Noninvasive meibography of the lower eyelid, meiboscore (Pult scale), Schirmer test type I, tear film breakup time, and corneal and conjunctival staining were measured. Subjective symptoms were scored by the Ocular Surface Disease Index. The dry eye diagnosis was ascertained according to TFOS DEWS II Criteria. Hematological data included diagnosis (acute leukemias vs. other malignancies), stage of the disease, time from diagnosis to ophthalmological examination, and previous therapy (chemotherapy, radiotherapy, or autograft).

Results: Hematological patients presented a significantly lower tear film breakup time and a higher meiboscore compared with controls (respectively 4.8 ± 3.0 seconds vs. 11.0 ± 3.0 and 2.0 ± 1.1 vs. 0.9 ± 0.4; P < 0.001). Conversely, other parameters did not differ between both groups. Dry eye was diagnosed in 14 out 46 hematological patients (30.4%). MG loss was significantly higher in hematological patients than in controls (29.8% ± 15.0% vs. 21.2 ± 13.0; P = 0.007) and was higher in the nasal third compared with both central and temporal thirds (respectively, 39.8% ± 21.4% vs. 18.5 ± 15.6 and 25.1 ± 18.3; P < 0.0001). The diagnosis of acute leukemia (β = 0.449; P = 0.003) and the history of previous chemotherapy (β = 0.444; P = 0.003) were associated with lower MG loss.

Conclusions: Hematological patients presented significantly reduced MG areas even before HSCT, particularly those affected by nonacute malignancies. The topographical pattern of MG dropout resembles that of conventional dry eye.
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http://dx.doi.org/10.1097/ICO.0000000000001585DOI Listing
October 2018

T Cell-Mediated Rejection of Human CD34 Cells Is Prevented by Costimulatory Blockade in a Xenograft Model.

Biol Blood Marrow Transplant 2017 Dec 14;23(12):2048-2056. Epub 2017 Aug 14.

Division of Hematology/Oncology, University of Illinois Hospital & Health Sciences System, Chicago, Illinois; University of Illinois Cancer Center, Chicago, Illinois; University of Illinois Center for Global Health, Chicago, Illinois. Electronic address:

A xenograft model of stem cell rejection was developed by co-transplantating human CD34 and allogeneic CD3 T cells into NOD-scid ɣ-chain mice. T cells caused graft failure when transplanted at any CD34/CD3 ratio between 1:50 and 1:.1. Kinetics experiments showed that 2 weeks after transplantation CD34 cells engrafted the marrow and T cells expanded in the spleen. Then, at 4 weeks only memory T cells populated both sites and rejected CD34 cells. Blockade of T cell costimulation was tested by injecting the mice with abatacept (CTLA4-IgG1) from day -1 to +27 (group A), from day -1 to +13 (group B), or from day +14 to +28 (group C). On day +56 groups B and C had rejected the graft, whereas in group A graft failure was completely prevented, although with lower stem cell engraftment than in controls (P = .03). Retransplantation of group A mice with same CD34 cells obtained a complete reconstitution of human myeloid and B cell lineages and excluded latent alloreactivity. In this first xenograft model of stem cell rejection we showed that transplantation of HLA mismatched CD34 cells may be facilitated by treatment with abatacept and late stem cell boost.
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http://dx.doi.org/10.1016/j.bbmt.2017.08.009DOI Listing
December 2017

Dry Eye Disease Is Already Present in Hematological Patients Before Hematopoietic Stem Cell Transplantation.

Cornea 2016 May;35(5):638-43

*Ophthalmology Unit, DIMES Department, Alma Mater Studiorum University of Bologna and S. Orsola-Malpighi Teaching Hospital, Bologna, Italy; and†Haematology Institute "L.A. Seragnoli," DIMES Department, Alma Mater Studiorum University of Bologna and S. Orsola-Malpighi Teaching Hospital, Bologna, Italy.

Purpose: To analyze ocular surface parameters in patients before hematopoietic stem cell transplantation (HSCT) and to correlate them with hematological characteristics.

Methods: This is a retrospective analysis of prospectively collected data from 203 patients undergoing HSCT. Demographic data and hematological parameters (disorder type and stage) were collected from clinical charts. Ocular surface parameters (ocular surface disease index; Schirmer test I; tear film break-up time; corneal esthesiometry; and corneal and conjunctival staining) were analyzed the day before beginning the conditioning treatment for HSCT preparation.

Results: A high prevalence of dry eye (DE) was found: 116 patients (57.2%) were diagnosed as not suffering from DE, whereas 87 patients (42.8%) were diagnosed as having DE. Of these, 26 were classified as dry eye workshot (DEWS) severity score 1, 46 as DEWS score 2, and 15 as DEWS score 3. Tear film break-up time was found to be the only parameter statistically worse in the chronic lymphoproliferative disorder group compared with the stem cell malignancy group. Older age [odds ratio (OR) 1.03], female sex (OR 2.03), advanced stage of hematological disease (OR 1.4), and previous auto- or allo-HSCT (OR 1.9) showed a significant positive association in predicting DE onset before transplantation.

Conclusions: DE was already present in a significant number of patients suffering from hematological disease before HSCT. Some hematological parameters seemed to influence this percentage. These results highlight the role of ocular surface examination by an ophthalmologist in hematological patients before HSCT, with the aim of diagnosing and, if necessary, treating DE patients early.
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http://dx.doi.org/10.1097/ICO.0000000000000747DOI Listing
May 2016

Human hematopoietic CD34+ progenitor cells induce natural killer cell alloresponses via NKG2D activation.

Exp Hematol 2016 Jan 23;44(1):14-23.e1. Epub 2015 Oct 23.

Institute of Hematology and Medical Oncology "L.&A. Seragnoli," University of Bologna, Bologna, Italy. Electronic address:

Human CD34+ cells cross-interact with allogeneic T lymphocytes. In this study we addressed the interaction between CD34+ cells and allogeneic natural killer (NK) cells. Purified NK cells were cultured with allogeneic KIR-permissive CD34+ or CD14+ blood cells, obtained from HLA group C homozygous donors, or with high-dose interleukin-2. A cytotoxicity assay was used to test the ability of NK cells to lyse NK-sensitive K562 or NK-resistant Daudi cells. Cytofluorometric assays were employed to assess cell phenotype and cytokine release. CD34+ cells induced greater lysis of K562 (p = 0.02) and Daudi cells (p = 0.01) than monocytes. CD34 cell stimulation resulted in upregulation of CD69 and CD25 on NK cells and in the production of interferon γ and tumor necrosis factor α. NK activation by CD34+ cells was inhibited by an anti-NKG2D antibody. However, NKG2D ligands such as MIC (MHC class I chain)-A/B and ULBP (UL16 binding protein)-1/3 were not detected on CD34+ cells. Cross-talk between NK and CD34+ cells also induced the upregulation of CD40 and CD86 co-stimulatory molecules on CD34+ cells. Our study indicates a direct NKG2D-dependent stimulatory effect of human CD34+ cells on allogeneic NK cells. These findings may be relevant to the NK-mediated rejection effect in HLA-mismatched hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1016/j.exphem.2015.10.001DOI Listing
January 2016

Managing the challenge of PTLD in liver and bowel transplant recipients.

Br J Haematol 2015 Apr 7;169(2):157-72. Epub 2014 Nov 7.

General Surgery and Transplant Unit, Department of Hematology & Oncological Sciences 'Seragnoli', Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

Post-transplant lymphoproliferative disorder (PTLD) remains a common complication of liver and bowel transplantion. The ubiquity of Epstein-Barr virus (EBV) combined with engraftment of organs rich with lymphatic tissue and the requirement of highly immunosuppressive regimens are factors that account for the high frequency and poor prognosis of PTLD in this population. Early detection of the virus followed by pre-emptive reduction of immunosuppression are essential components in the management of PTLD, but can increase the risk of graft loss. More recently, the anti-CD20 monoclonal antibody (rituximab) has been shown to improve survival in various transplant populations with PTLD, while other therapeutic options, such as chemotherapy, surgery or radiotherapy, have minimal clinical impact. EBV-directed cytotoxic T cells have shown promise in the management of PTLD but clinical use is currently limited by lack of technical facilities worldwide.
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http://dx.doi.org/10.1111/bjh.13213DOI Listing
April 2015

Transfusion-related Listeria monocytogenes infection in a patient with acute myeloid leukaemia.

Blood Transfus 2014 Oct 5;12(4):611-4. Epub 2014 Jun 5.

Department of Immunohaematology and Transfusion Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.2450/2014.0322-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212044PMC
October 2014

Immunotherapy in acute myeloid leukemia.

Immunotherapy 2014 ;6(1):95-106

Department of Hematology & Oncological Sciences 'Seragnoli', University of Bologna, Italy.

Treatment of acute myeloid leukemia (AML) with current chemotherapy regimens is still disappointing, with overall survival rates of ≤ 40% at 5 years. It is now well established that AML cells can evade the immune system through multiple mechanisms, including the expression of the enzyme indoleamine 2,3 dioxygenase. Immunotherapeutic strategies, including both active, such as vaccination with leukemia-associated antigens, and passive, such as adoptive transfer of allogeneic natural killer cells, may overcome leukemia escape and lead to improved cure. Allogeneic hemopoeitic stem cell transplantation, the most effective treatment of AML, is the best known model of immunotherapy. Following transplant, recipient AML cells are eradicated by donor immune cells through the graft-versus-leukemia (GVL) effect. However, GVL is clinically associated with graft-versus-host disease, the major cause of mortality after transplant. GVL is mediated by donor T cells recognizing either leukemia-associated antigens or minor as well as major histocompatibility antigens. Several innovative strategies have been devised to generate leukemia reactive T cells so as to increase GVL responses with no or little graft-versus-host disease.
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http://dx.doi.org/10.2217/imt.13.152DOI Listing
August 2014

Molecular monitoring of BCR-ABL transcripts after allogeneic stem cell transplantation for chronic myeloid leukemia.

Biol Blood Marrow Transplant 2013 May 17;19(5):735-40. Epub 2013 Jan 17.

Department of Hematology and Oncological Sciences Seragnoli, University of Bologna, Italy.

The monitoring of minimal residual disease (MRD) through low sensitivity real-time (RT) polymerase chain reaction (PCR) analysis of BCR-ABL transcripts allows early detection of chronic myeloid leukemia (CML) relapse after allogeneic hematopoietic stem cell transplantation (HSCT). The introduction of more sensitive techniques, such as RT quantitative (Q)-PCR, may lead to an overestimation of the risk of CML relapse. In this study, we reviewed the results of peripheral blood RT Q-PCR in CML patients who underwent allogeneic HSCT from 1983 to 2007. In our laboratory, RT Q-PCR analysis was routinely performed since 2002. Eighty-seven of 189 patients had available RT Q-PCR data; 63 patients had at least 3 RT Q-PCR analyses assessable. Fifty-two of 63 patients (83%) had, at least once, detectable transcript levels, but with an BCR-ABL/ABL ratio <.1% defined as .1% confirmed by the finding of Ph+ cells in bone marrow. No patients with persistent undetectable transcripts relapsed (P = .19). Relapse did not correlate with the number of occurrences of
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http://dx.doi.org/10.1016/j.bbmt.2013.01.007DOI Listing
May 2013

Efficacy of standardized and quality-controlled cord blood serum eye drop therapy in the healing of severe corneal epithelial damage in dry eye.

Cornea 2013 Apr;32(4):412-8

Ophthalmology Unit, University of Bologna and S. Orsola-Malpighi Hospital, Bologna, Italy.

Purpose: We standardized quality-controlled cord blood serum (CBS)-based eye drops and evaluated the efficacy of 1-month CBS treatment in the healing of diseased corneal epithelium in severe dry eye (DE) patients.

Methods: Seventeen graft-versus-host disease (GVHD) and 13 Sjogren syndrome patients with severe persistent corneal defects were enrolled in the framework of a registered clinical trial (ClinicalTrials.gov NCT01234623). Sterile CBS eye drops were prepared to supply 0.15 ng per eye per day epithelial growth factor and administered for 1 month in a 1-day dose dispensing. The extent of epithelial defect was evaluated in square millimeters area, and subjective symptom score (Ocular Surface Disease Index score), Schirmer test I, break-up time, tear osmolarity, corneal esthesiometry (Cochet-Bonnet esthesiometer), conjunctival scraping, and imprint cytology with goblet cell count were performed at baseline (V0) and after 15 (V1) and 30 (V2, endpoint) days of treatment. Satisfaction and tolerability questionnaires were evaluated at V1 and V2.

Results: A significant reduction was shown at the endpoint versus baseline in corneal epithelial damage (mean ± SD, 16.1 ± 13.7 vs. 40.9 ± 30 mm²/area, respectively), discomfort symptoms (Ocular Surface Disease Index score, 22.3 ± 10.3 vs. 39.3 ± 16.9), scraping cytology score (3.8 ± 1.2 vs. 6.6 ± 2.1), and tear osmolarity (312.5 ± 7 vs. 322 ± 9.1 mOsm/L), whereas a significant improvement was shown in corneal esthesiometry (48.2 ± 2.1 vs. 49.7 ± 2.1 nylon/mm/length, P < 0.05). All patients reported a high degree of satisfaction upon drop instillation.

Conclusions: Heterologous CBS-based eye drops represent a promising therapeutic approach in the healing of severely injured corneal epithelium and in subjective symptom relief. These drops can be obtained as readily available and quality-controlled blood derivative from cord blood banks on a routine basis.
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http://dx.doi.org/10.1097/ICO.0b013e3182580762DOI Listing
April 2013

Hairy cell leukemia: allogeneic transplantation could be an optimal option in selected patients.

Clin Lymphoma Myeloma Leuk 2012 Aug 24;12(4):287-9. Epub 2012 May 24.

Institute of Hematology and Medical Oncology L. e A. Seràgnoli, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1016/j.clml.2012.05.001DOI Listing
August 2012

Follicle features in adolescent and young adult women with Hodgkin's disease prior to chemotherapy: a preliminary report.

Reprod Biomed Online 2011 Dec 5;23(6):799-805. Epub 2011 Sep 5.

Human Reproductive Medicine Unit, Obstetrics and Gynaecology, S. Orsola Hospital, University of Bologna, Italy.

Treatment of Hodgkin’s disease (HD) has improved over the last two decades, but infertility is a common side effect of chemotherapy. Men with HD have an increased risk of inadequate semen quality and severe damage of fertility before treatment. The aim of this study was to investigate the possible association between the disease itself and germ-cell damage in female patients before treatment for HD. The ovarian cortex from 13 untreated women with HD was processed by light and transmission electron microscopy and compared with the ovarian cortex from the control group of 13 untreated women without HD. Histological examination of fresh ovarian cortex showed that in HD patients, follicles presented an unusual presence of clear vacuoles when compared with control group (73.7% versus 5.7%). Ultrastructural examination demonstrated that the small vacuoles fused into large autophagic vacuoles. The percentage of vacuolated follicles was higher in patients with advanced stage and bulky disease. In conclusion, this study demonstrates for the first time that significant damage to gametes occurs in women with HD. Further investigations are required to establish whether the present features should be considered a common side effect of HD.
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http://dx.doi.org/10.1016/j.rbmo.2011.07.020DOI Listing
December 2011

Human CD4(+)CD25(+) Cells in Combination with CD34(+) Cells and Thymoglobulin to Prevent Anti-hematopoietic Stem Cell T Cell Alloreactivity.

Biol Blood Marrow Transplant 2011 Jan 12;17(1):61-8. Epub 2010 Aug 12.

Section of Hematology/Oncology, University of Illinois at Chicago, Chicago, Illinois 60612, USA.

Cotransplantation of human CD34(+) hematopoietic stem cells (HSC) and CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) could prevent anti-HSC alloreactivity and reduce the risk of rejection in HLA mismatched transplants. To pursue this hypothesis we cocultured CD34(+) cells and CD4(+)CD25(+) cells immunomagnetically isolated (Milteny) from human peripheral blood (unmanipulated or granulocyte-colony stimulating factor [G-CSF] mobilized) or cord blood. Enriched Tregs obtained from the same source (autologous) of CD34(+) cells showed greater inhibitory effect on T cell alloreactivity than third-party (allogeneic) Tregs. The immunosuppressive activity of Tregs was maintained after stimulation with allogeneic CD34(+) cells and Tregs did not modify the clonogenic activity of CD34(+) cells in vitro. Cotransplantation of Tregs with CD34(+) cells at 1:1 or 2:1 ratios in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice resulted in normal hematopoietic stem cell engraftment. Incubation with physiologic doses of rabbit antithymocyte globulin (rATG, thymoglobulin) did not affect the number of Tregs in 6-day culture. Upon exposure to thymoglobulin Tregs maintained their suppressive activity, increased expression of CCR7, and released multiple cytokines, primarily interleukin (IL)10. Our findings suggest that human autologous or allogeneic Tregs could be cotransplanted with CD34(+) cells after preparative regimens including thymoglobulin.
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http://dx.doi.org/10.1016/j.bbmt.2010.08.004DOI Listing
January 2011
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