Publications by authors named "Giuseppe Gritti"

27 Publications

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Immunotherapy of Acute Lymphoblastic Leukemia and Lymphoma With T Cell-Redirected Bispecific Antibodies.

J Clin Oncol 2021 Feb 12;39(5):444-455. Epub 2021 Jan 12.

Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.

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http://dx.doi.org/10.1200/JCO.20.01564DOI Listing
February 2021

Macrophage expression and prognostic significance of the long pentraxin PTX3 in COVID-19.

Nat Immunol 2021 01 18;22(1):19-24. Epub 2020 Nov 18.

Humanitas Clinical and Research Center-IRCCS, Milan, Italy.

Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19). RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
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http://dx.doi.org/10.1038/s41590-020-00832-xDOI Listing
January 2021

Endothelial injury and thrombotic microangiopathy in COVID-19: Treatment with the lectin-pathway inhibitor narsoplimab.

Immunobiology 2020 11 9;225(6):152001. Epub 2020 Aug 9.

Omeros Corporation, Seattle, WA, USA.

In COVID-19, acute respiratory distress syndrome (ARDS) and thrombotic events are frequent, life-threatening complications. Autopsies commonly show arterial thrombosis and severe endothelial damage. Endothelial damage, which can play an early and central pathogenic role in ARDS and thrombosis, activates the lectin pathway of complement. Mannan-binding lectin-associated serine protease-2 (MASP-2), the lectin pathway's effector enzyme, binds the nucleocapsid protein of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), resulting in complement activation and lung injury. Narsoplimab, a fully human immunoglobulin gamma 4 (IgG4) monoclonal antibody against MASP-2, inhibits lectin pathway activation and has anticoagulant effects. In this study, the first time a lectin-pathway inhibitor was used to treat COVID-19, six COVID-19 patients with ARDS requiring continuous positive airway pressure (CPAP) or intubation received narsoplimab under compassionate use. At baseline and during treatment, circulating endothelial cell (CEC) counts and serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were assessed. Narsoplimab treatment was associated with rapid and sustained reduction of CEC and concurrent reduction of serum IL-6, IL-8, CRP and LDH. Narsoplimab was well tolerated; no adverse drug reactions were reported. Two control groups were used for retrospective comparison, both showing significantly higher mortality than the narsoplimab-treated group. All narsoplimab-treated patients recovered and survived. Narsoplimab may be an effective treatment for COVID-19 by reducing COVID-19-related endothelial cell damage and the resultant inflammation and thrombotic risk.
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http://dx.doi.org/10.1016/j.imbio.2020.152001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415163PMC
November 2020

Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma.

Blood 2021 Feb;137(5):637-645

Mayo Clinic, Rochester, MN.

Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.
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http://dx.doi.org/10.1182/blood.2019004753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869188PMC
February 2021

Venetoclax-rituximab with or without bendamustine vs bendamustine-rituximab in relapsed/refractory follicular lymphoma.

Blood 2020 12;136(23):2628-2637

Department of Medicine III, University of Munich, Munich, Germany.

This open-label phase 2 study (CONTRALTO) assessed the safety and efficacy of BCL-2 inhibitor venetoclax (VEN) plus rituximab (R), and VEN plus bendamustine (B) and R, vs B + R (BR) alone in relapsed/refractory (R/R) follicular lymphoma. Patients in the chemotherapy-free arm (arm A: VEN + R) received VEN 800 mg/d plus R 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, 10, and 12. After a safety run-in with VEN 600 mg, patients in the chemotherapy-containing cohort were randomized to either VEN + BR (arm B; VEN 800 mg/d for 1 year + 6 cycles of BR [B 90 mg/m2 on days 1 and 2 and R 375 mg/m2 on day 1]) or 6 cycles of BR (arm C). Overall, 163 patients were analyzed (9 in the safety run-in and 52, 51, and 51 in arms A, B, and C, respectively). Complete metabolic/complete response rates were 17% (arm A), 75% (arm B), and 69% (arm C). Of patients in arm B, only 61% received ≥90% of the planned B dose vs 96% of patients in arm C. More frequent hematologic toxicity resulted in more reduced dosing/treatment discontinuation in arm B vs arm C. Rates of grade 3/4 adverse events were 51.9%, 93.9%, and 60.0% in arms A, B, and C, respectively. VEN + BR led to increased toxicity and lower dose intensity of BR than in arm C, but efficacy was similar. Optimizing dose and schedule to maintain BR dose intensity may improve efficacy and tolerability of VEN + BR, while VEN + R data warrant further study. This study was registered at www.clinicaltrials.gov as #NCT02187861.
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http://dx.doi.org/10.1182/blood.2020005588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735159PMC
December 2020

Sleeping Beauty-engineered CAR T cells achieve antileukemic activity without severe toxicities.

J Clin Invest 2020 11;130(11):6021-6033

Tettamanti Research Center, Department of Pediatrics, University of Milano-Bicocca/Fondazione MBBM, Monza, Italy.

BACKGROUNDChimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability.METHODSWe report the early results of a phase I/II trial in B cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine-induced killer (CIK) cells.RESULTSThe cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3+ lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were 2 grade I and 1 grade II cytokine-release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GVHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients receiving the highest doses achieved CR and CR with incomplete blood count recovery (CRi) at day 28. Five out of 6 patients in CR were also minimal residual disease negative (MRD-). Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion.CONCLUSIONSB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Antileukemic activity was achieved without severe toxicities.TRIAL REGISTRATIONClinicalTrials.gov NCT03389035.FUNDINGThis study was supported by grants from the Fondazione AIRC per la Ricerca sul Cancro (AIRC); Cancer Research UK (CRUK); the Fundación Científica de la Asociación Española Contra el Cáncer (FC AECC); Ministero Della Salute; Fondazione Regionale per la Ricerca Biomedica (FRRB).
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http://dx.doi.org/10.1172/JCI138473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598053PMC
November 2020

Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma.

Clin Cancer Res 2020 07 23;26(14):3546-3556. Epub 2020 Apr 23.

University Hospital Vall d'Hebron, Barcelona, Spain.

Purpose: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas.

Patients And Methods: Patients received continuous, once-daily oral TAK-659, 60-120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD.

Results: Overall, 105 patients were enrolled [dose escalation, = 36 (solid tumors, = 19; lymphoma, = 17); expansion, = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast ( ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60-120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT).

Conclusions: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3239DOI Listing
July 2020

SAKK38/07 study: integration of baseline metabolic heterogeneity and metabolic tumor volume in DLBCL prognostic model.

Blood Adv 2020 03;4(6):1082-1092

Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, Switzerland.

Several functional parameters from baseline (18)F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography have been proposed as promising biomarkers of treatment efficacy in diffuse large B-cell lymphoma (DLBCL). We tested their ability to predict outcome in 2 cohorts of DLBCL patients receiving conventional immunochemotherapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone [R-CHOP] regimen), either every 14 (R-CHOP14) or 21 days (R-CHOP21). Baseline PET analysis was performed in 141 patients with DLBCL treated with R-CHOP14 in the prospective SAKK38/07 study (NCT00544219) of the Swiss Group for Clinical Cancer Research (testing set). Reproducibility was examined in a validation set of 113 patients treated with R-CHOP21. In the SAKK38/07 cohort, progression-free survival (PFS) at 5 years was 83% for patients with low metabolic tumor volume (MTV) and 59% for those with high MTV (hazard ratio [HR], 3.4; 95% confidence interval [CI], 1.6-7.0; P = .0005), whereas overall survival (OS) was 91% and 64%, respectively (HR, 4.4; 95% CI, 1.9-10; P = .0001). MTV was the most powerful predictor of outcome also in the validation set. Elevated metabolic heterogeneity (MH) significantly predicted poorer outcomes in the subgroups of patients with elevated MTV. A model integrating MTV and MH identified high-risk patients with shorter PFS (testing set: HR, 5.6; 95% CI, 1.8-17; P < .0001; validation set: HR, 5.6; 95% CI, 1.7-18; P = .0002) and shorter OS (testing set: HR, 9.5; 95% CI, 1.7-52; P < .0001; validation set: HR, 7.6; 95% CI, 2.0-28; P = .0003). This finding was confirmed by an unsupervised regression tree analysis indicating that prognostic models based on MTV and MH may allow early identification of refractory patients who might benefit from treatment intensification. This trial was registered at www.clinicaltrials.gov as #NCT00544219.
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http://dx.doi.org/10.1182/bloodadvances.2019001201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094027PMC
March 2020

Copanlisib synergizes with conventional and targeted agents including venetoclax in B- and T-cell lymphoma models.

Blood Adv 2020 03;4(5):819-829

Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Bellinzona, Switzerland.

Copanlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor with preferred activity toward PI3Kα and PI3Kδ. Despite the clear overall clinical benefit, the number of patients achieving complete remissions with the single agent is relatively low, a problem shared by the vast majority of targeted agents. Here, we searched for novel copanlisib-based combinations. Copanlisib was tested as a single agent, in combination with an additional 17 drugs in 26 cell lines derived from mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and T-cell lymphomas. In vivo experiments, transcriptome analyses, and immunoblotting experiments were also performed. Copanlisib as a single agent showed in vitro dose-dependent antitumor activity in the vast majority of the models. Combination screening identified several compounds that synergized with copanlisib. The strongest combination was with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax. The benefit of the combination over single agents was also validated in an MZL xenograft model and in MCL primary cells, and was due to increased induction of apoptosis, an effect likely sustained by the reduction of the antiapoptotic proteins myeloid cell leukemia 1 (MCL1) and BCL-XL, observed in MCL and MZL cell lines, respectively. These data supported the rationale for the design of the Swiss Group for Clinical Cancer Research (SAKK) 66/18 phase 1 study currently exploring the combination of copanlisib and venetoclax in relapsed/refractory lymphomas.
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http://dx.doi.org/10.1182/bloodadvances.2019000844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065481PMC
March 2020

Nivolumab Combined With Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study.

J Clin Oncol 2019 11 9;37(33):3081-3089. Epub 2019 Aug 9.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Primary mediastinal B-cell lymphoma (PMBL) is a rare but aggressive non-Hodgkin lymphoma with poor outcomes in patients with relapsed/refractory (R/R) disease. PMBL is characterized by high expression of programmed death-1 ligand and variable expression of CD30. Nivolumab, an anti-programmed death-1 immune checkpoint inhibitor, and brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, may have synergistic activity in R/R PMBL.

Methods: The expansion cohort of the open-label, phase I/II CheckMate 436 study enrolled patients with confirmed R/R PMBL who were previously treated with either autologous hematopoietic cell transplantation or two or more prior chemotherapy regimens if ineligible for autologous hematopoietic cell transplantation. Patients received nivolumab (240 mg intravenously) and BV (1.8 mg/kg intravenously) every 3 weeks until disease progression or unacceptable toxicity. Primary end points were investigator-assessed objective response rate (ORR) per the Lugano 2014 criteria and safety.

Results: Thirty patients with PMBL were treated and evaluable. At a median follow-up of 11.1 months, ORR (95% CI) was 73% (54% to 88%), with a 37% complete remission rate per investigator, and ORR of 70% (51% to 85%), with a 43% complete metabolic response rate per independent review. Median duration of response, median progression-free survival, and median overall survival have not been reached. Eleven responders had consolidation with autologous (n = 5) or allogeneic (n = 6) transplantation. Treatment-related adverse events were reported in 25 patients (83%). Sixteen patients (53%) had grade 3 to 4 treatment-related adverse events; the most common were neutropenia (n = 9), thrombocytopenia (n = 3), and peripheral neuropathy (n = 3). There were no treatment-related deaths.

Conclusion: In patients with R/R PMBL, the combination of nivolumab plus BV represents a promising option, with high antitumor activity and a manageable safety profile.
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http://dx.doi.org/10.1200/JCO.19.01492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864847PMC
November 2019

Evaluation of tenascin-C by tenatumomab in T-cell non-Hodgkin lymphomas identifies a new target for radioimmunotherapy.

Oncotarget 2018 Feb 3;9(11):9766-9775. Epub 2018 Jan 3.

Hematology Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy.

The clinical outcome of T-cell non-Hodgkin lymphoma (NHL) is poor and innovative treatments are needed. Tenascin-C is a large extracellular glycoprotein not expressed under physiological conditions, but overexpressed in cancer. Aim of the study was to evaluate tenascin-C expression within pathologic tissue of T-cell NHL and determine its clinical significance. We used an immunohistochemistry approach using the anti-tenascin-C monoclonal antibody Tenatumomab in 75 systemic T-cell NHL (including 72 mature and 3 precursor T-cell NHL), and 25 primary cutaneous T-cell NHL. Data were analyzed in terms of staining intensity, proportion of involved areas and histologic pattern, and results were correlated with clinical characteristics and outcome. Ninety-three percent of the cases were tenascin-C positive and 59% of systemic diseases were characterized by a predominant involvement (>50%). Stromal expression was detected in all the cases while vascular and vascular plus cytoplasmic expression was present in 49% and 23%. The constant overexpression of the tenascin-C gene was observed in two independent publicly available T-cell NHL gene expression datasets. In conclusions, tenascin-C represents an attractive target that sets the rationale to investigate the therapeutic activity of radiolabeled Tenatumomab in T-cell NHL.
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http://dx.doi.org/10.18632/oncotarget.23919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839400PMC
February 2018

Italian real life experience with brentuximab vedotin: results of a large observational study on 234 relapsed/refractory Hodgkin's lymphoma.

Oncotarget 2017 Oct 23;8(53):91703-91710. Epub 2017 May 23.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

A large Italian multicenter observational retrospective study was conducted on the use of brentuximab vedotin (BV) for patients with relapsed Hodgkin's lymphoma (HL) to check if clinical trial results are confirmed even in a real life context. 234 CD30+ HL patients were enrolled. Best response was observed after a median of 4 cycles in 140 patients (59.8%): 74 (31.6%) patients obtained a complete response (CR) and 66 (28.2%) achieved a partial response (PR); overall response rate at the end of the treatment was 48.3% (62 CR and 51 PR). The best response rate was higher in the elderly subset: 14 (50%) CR and 5 (17.8%) PR. Disease free survival was 26.3% at 3 years and progression free survival 31.9% at 4.5 years. Duration of response did not differ for who achieved at least PR and then either did or did not undergo consolidative transplant. Overall, the treatment was well tolerated and no death has been linked to BV-induced toxicity. Our report confirms activity in elderly patients, duration of response unrelated to the consolidation with transplant procedure, the relevance of the CR status at first restaging, and the role of BV as a bridge to transplant for chemorefractory patients.
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http://dx.doi.org/10.18632/oncotarget.18114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710959PMC
October 2017

Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies.

Nat Med 2017 Dec 13;23(12):1416-1423. Epub 2017 Nov 13.

Cancer Institute, University College London, London, UK.

Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor β-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1 and TRBC2 compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1, but not TRBC2, T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity.
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http://dx.doi.org/10.1038/nm.4444DOI Listing
December 2017

Italian real-life experience with brentuximab vedotin: results of a large observational study of 40 cases of relapsed/refractory systemic anaplastic large cell lymphoma.

Haematologica 2017 11 3;102(11):1931-1935. Epub 2017 Aug 3.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Italy

Between November 2012 and July 2014, in accordance with national law 648/96, brentuximab vedotin was available in Italy for patients with relapsed systemic anaplastic large cell lymphoma outside a clinical trial context. A large Italian observational retrospective study was conducted on the use of brentuximab vedotin in everyday clinical practice to check whether clinical trial results are confirmed in a real-life context. The primary endpoint of this study was best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and safety profile. A total of 40 heavily pretreated patients were enrolled. Best response was observed after a median of four cycles in 77.5%: globally, 47.5% patients obtained a complete response, 64.2% in the elderly subset. The overall response rate was 62.5%. At the latest follow up, 15/18 patients are still in complete remission (3 with consolidation). The progression-free survival rate at 24 months was 39.1% and the disease-free survival rate at the same time was 54% (median not reached). All the long-term responders were aged <30 years at first infusion. The treatment was well tolerated even in this real-life context and no deaths were linked to drug toxicity. Brentuximab vedotin induces clinical responses quite rapidly, i.e. within the first four cycles of treatment in most responders, thus enabling timely use of transplantation. For patients ineligible for transplant or for those in whom a transplant procedure failed, brentuximab vedotin may represent a feasible effective therapeutic option in everyday clinical practice.
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http://dx.doi.org/10.3324/haematol.2017.171355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664397PMC
November 2017

FarmaREL: An Italian pharmacovigilance project to monitor and evaluate adverse drug reactions in haematologic patients.

Hematol Oncol 2018 Feb 3;36(1):299-306. Epub 2017 Aug 3.

Commissione Qualità e Risk Management REL, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Adverse drug reactions (ADRs) reduce patients' quality of life, increase mortality and morbidity, and have a negative economic impact on healthcare systems. Nevertheless, the importance of ADR reporting is often underestimated. The project "FarmaREL" has been developed to monitor and evaluate ADRs in haematological patients and to increase pharmacovigilance culture among haematology specialists. In 13 haematology units, based in Lombardy, Italy, a dedicated specialist with the task of encouraging ADRs reporting and sensitizing healthcare professionals to pharmacovigilance has been assigned. The ADRs occurring in haematological patients were collected electronically and then analysed with multiple logistic regression. Between January 2009 and December 2011, 887 reports were collected. The number of ADRs was higher in older adults (528; 59%), in male (490; 55%), and in non-Hodgkin lymphoma patients (343; 39%). Most reactions were severe (45% required or prolonged hospitalization), but in most cases, they were fully resolved at the time of reporting. According to Schumock and Thornton criteria, a percentage of ADRs as high as 7% was found to be preventable versus 2% according to reporter opinion. Patients' haematological diagnosis, not age or gender, resulted to be the variable that most influenced ADR, in particular severity and outcome. The employment of personnel specifically dedicated to pharmacovigilance is a successful strategy to improve the number and quality of ADR reports. "FarmaREL", the first programme of active pharmacovigilance in oncohaematologic patients, significantly contributed to reach the WHO "Gold Standard" for pharmacovigilance in Lombardy, Italy.
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http://dx.doi.org/10.1002/hon.2451DOI Listing
February 2018

Randomized Trial Comparing R-CHOP Versus High-Dose Sequential Chemotherapy in High-Risk Patients With Diffuse Large B-Cell Lymphomas.

J Clin Oncol 2016 11 31;34(33):4015-4022. Epub 2016 Oct 31.

Sergio Cortelazzo, Atto Billio, Andrea Piccin, and Giovanni Negri, Ospedale Centrale di Bolzano, Bolzano; Corrado Tarella and Riccardo Bruna, Azienda Ospedaliera Ordine Mauriziano and University of Turin; Marco Ladetto and Manuela Zanni, Azienda Ospedaliera Universitaria (AOU) Città della Salute e della Scienza, Turin; Alessandro Massimo Gianni, Paolo Corradini, and Massimo Di Nicola, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, University of Milano; Andrés J.M. Ferreri, IRCCS San Raffaele Scientific Institute; Valentina Tabanelli and Stefano Pileri, Istituto Europeo di Oncologia; Alessandro Rambaldi, University of Milano, Milan; Anna Maria Barbui, Andrea Rossi, Giuseppe Gritti, Arianna Masciulli, Federica Delaini, Cristina Boschini, and Alessandro Rambaldi, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo; Caterina Patti and Antonino Mulé, Azienda Ospedali Riuniti Villa Sofia-Cervello, Palermo; Valerio Zoli, Ospedale San Camillo Forlanini, Rome; Claudia Castellino, Ospedale S. Croce e Carle, Cuneo; Francesco Di Raimondo, AOU Policlinico Vittorio Emanuele University of Catania, Catania; Fabio Benedetti, University of Verona; Marco Chilosi, Azienda Ospedaliera Universitaria Integrata Verona, Verona; Giorgio La Nasa, Ospedale Binaghi, Cagliari; Guido Gini, Ospedali Riuniti, Ancona; Livio Trentin, Azienda Ospedaliera-Università di Padova, Padua; Maurizio Frezzato, Ospedale San Bortolo, Vicenza; Leonardo Flenghi, Azienda Ospedaliera di Perugia, Perugia; and Simona Falorio, Ospedale Civile Spirito Santo, Pescara, Italy.

Purpose The benefit of high-dose chemotherapy with autologous stem-cell transplantation (ASCT) as first-line treatment in patients with diffuse large B-cell lymphomas is still a matter of debate. To address this point, we designed a randomized phase III trial to compare rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-14 (eight cycles) with rituximab plus high-dose sequential chemotherapy (R-HDS) with ASCT. Patients and Methods From June 2005 to June 2011, 246 high-risk patients with a high-intermediate (56%) or high (44%) International Prognostic Index score were randomly assigned to the R-CHOP or R-HDS arm, and 235 were analyzed by intent to treat. The primary efficacy end point of the study was 3-year event-free survival, and results were analyzed on an intent-to-treat basis. Results Clinical response (complete response, 78% v 76%; partial response, 5% v 9%) and failures (no response, 15% v 11%; and early treatment-related mortality, 2% v 3%) were similar after R-CHOP versus R-HDS, respectively. After a median follow-up of 5 years, the 3-year event-free survival was 62% versus 65% ( P = .83). At 3 years, compared with the R-CHOP arm, the R-HDS arm had better disease-free survival (79% v 91%, respectively; P = .034), but this subsequently vanished because of late-occurring treatment-related deaths. No difference was detected in terms of progression-free survival (65% v 75%, respectively; P = .12), or overall survival (74% v 77%, respectively; P = .64). Significantly higher hematologic toxicity ( P < .001) and more infectious complications ( P < .001) were observed in the R-HDS arm. Conclusion In this study, front-line intensive R-HDS chemotherapy with ASCT did not improve the outcome of high-risk patients with diffuse large B-cell lymphomas.
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http://dx.doi.org/10.1200/JCO.2016.67.2980DOI Listing
November 2016

Is There a Role for Minimal Residual Disease Monitoring in Follicular Lymphoma in the Chemo-Immunotherapy Era?

Mediterr J Hematol Infect Dis 2017 1;9(1):e2017010. Epub 2017 Jan 1.

Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy; Department of Oncology and Oncohematology, Università degli Studi di Milano, Milano, Italy.

After 25 years, evaluation of minimal residual disease (MRD) in follicular lymphoma (FL) has become a standardized technique frequently integrated into clinical trials for its consistent and independent prognostic significance. Achievement of a sustained MRD negativity is a marker of treatment sensibility that has been associated with excellent clinical outcome in terms of clinical response and progression-free survival, independently from the employed therapy. However, no survival advantages has been reported for MRD negative patients and despite the compelling results of clinical trials, MRD evaluation has currently no role in clinical practice. Ongoing clinical trials will help in clarifying the potential setting in which MRD monitoring may have a routine clinical application i.e. allowing de-escalation of standard maintenance therapy in very low risk patients. In this review the clinical implications of MRD monitoring in Rituximab-era are discussed in light of the current treatment paradigms most aimed at reducing toxicities, and the response definition that now routinely integrates PET scan.
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http://dx.doi.org/10.4084/MJHID.2017.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224815PMC
January 2017

Primary treatment response rather than front line stem cell transplantation is crucial for long term outcome of peripheral T-cell lymphomas.

PLoS One 2015 27;10(3):e0121822. Epub 2015 Mar 27.

Hematology and Bone Marrow Transplant Units, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.

Outcome of systemic peripheral T-cell lymphomas (PTCL) is unsatisfactory and no controlled clinical study guides the therapy. Phase II studies suggest to consolidate response achieved after front-line treatment with stem cell transplant (SCT). We retrospectively evaluate the impact of front-line SCT consolidation in a single Center cohort of 209 patients treated during the last two decades. Median age was 49 years (range 15-85) with a prevalence of male sex (61%), advanced stage (68%) while IPI was >2 in 44%. Primary treatment was MACOP-B (39%) CHO(E)P (39%), intensive regimens (18%) or others (4%). Complete response to primary treatment (i.e. before SCT) was 60% (5% partial remission). Forty-four patients further proceeded to SCT while 92 did not receive consolidation. Outcome of primary responders was good, with a 3-year overall survival of 74% (82% in ALCL ALK+ and 69% for the other histologies). By multivariate analysis a better overall survival was significantly associated with IPI<2 (P=0.001), primary response (P=0.000), and ALCL ALK+ (P=0.012). The multivariate analysis performed on responders, showed that only IPI was predictive of a better survival while ALCL ALK+ and undergoing SCT were not. Response to primary treatment rather than post-remission programs is the crucial determinant of PTCL outcome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121822PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376730PMC
March 2016

Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy.

Haematologica 2015 Jan 24;100(1):77-86. Epub 2014 Oct 24.

Center of Cellular Therapy "G. Lanzani", Division of Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy

The novel Bruton tyrosine kinase inhibitor ibrutinib and phosphatidyl-4-5-biphosphate 3-kinase-δ inhibitor idelalisib are promising drugs for the treatment of chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma, either alone or in combination with anti-CD20 antibodies. We investigated the possible positive or negative impact of these drugs on all known mechanisms of action of both type I and type II anti-CD20 antibodies. Pretreatment with ibrutinib for 1 hour did not increase direct cell death of cell lines or chronic lymphocytic leukemia samples mediated by anti-CD20 antibodies. Pre-treatment with ibrutinib did not inhibit complement activation or complement-mediated lysis. In contrast, ibrutinib strongly inhibited all cell-mediated mechanisms induced by anti-CD20 antibodies rituximab, ofatumumab or obinutuzumab, either in purified systems or whole blood assays. Activation of natural killer cells, and antibody-dependent cellular cytotoxicity by these cells, as well as phagocytosis by macrophages or neutrophils were inhibited by ibrutinib with a half maximal effective concentration of 0.3-3 μM. Analysis of anti-CD20 mediated activation of natural killer cells isolated from patients on continued oral ibrutinib treatment suggested that repeated drug dosing inhibits these cells in vivo. Finally we show that the phosphatidyl-4-5-biphosphate 3-kinase-δ inhibitor idelalisib similarly inhibited the immune cell-mediated mechanisms induced by anti-CD20 antibodies, although the effects of this drug at 10 μM were weaker than those observed with ibrutinib at the same concentration. We conclude that the design of combined treatment schedules of anti-CD20 antibodies with these kinase inhibitors should consider the multiple negative interactions between these two classes of drugs.
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http://dx.doi.org/10.3324/haematol.2014.107011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281316PMC
January 2015

Rate of primary refractory disease in B and T-cell non-Hodgkin's lymphoma: correlation with long-term survival.

PLoS One 2014 25;9(9):e106745. Epub 2014 Sep 25.

Division of Hematology I, A. O. Città della Salute, Torino, Italy.

Background: Primary refractory disease is a main challenge in the management of non-Hodgkin's Lymphoma (NHL). This survey was performed to define the rate of refractory disease to first-line therapy in B and T-cell NHL subtypes and the long-term survival of primary refractory compared to primary responsive patients.

Methods: Medical records were reviewed of 3,106 patients who had undergone primary treatment for NHL between 1982 and 2012, at the Hematology Centers of Torino and Bergamo, Italy. Primary treatment included CHOP or CHOP-like regimens (63.2%), intensive therapy with autograft (16.9%), or other therapies (19.9%). Among B-cell NHL, 1,356 (47.8%) received first-line chemotherapy with rituximab. Refractory disease was defined as stable/progressive disease, or transient response with disease progression within six months.

Results: Overall, 690 (22.2%) patients showed primary refractory disease, with a higher incidence amongst T-cell compared to B-cell NHL (41.9% vs. 20.5%, respectively, p<0.001). Several other clinico-pathological factors at presentation were variably associated with refractory disease, including histological aggressive disease, unfavorable clinical presentation, Bone Marrow involvement, low lymphocyte/monocyte ration and male gender. Amongst B-cell NHL, the addition of rituximab was associated with a marked reduction of refractory disease (13.6% vs. 26.7% for non-supplemented chemotherapy, p<0.001). Overall, primary responsive patients had a median survival of 19.8 years, compared to 1.3 yr. for refractory patients. A prolonged survival was consistently observed in all primary responsive patients regardless of the histology. The long life expectancy of primary responsive patients was documented in both series managed before and after 2.000. Response to first line therapy resulted by far the most predictive factor for long-term outcome (HR for primary refractory disease: 16.52, p<0.001).

Conclusion: Chemosensitivity to primary treatment is crucial for the long-term survival in NHL. This supports the necessity of studies aimed to early identify refractory disease and to develop different treatment strategies for responsive and refractory patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106745PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177839PMC
June 2015

The lymphocyte to monocyte ratio improves the IPI-risk definition of diffuse large B-cell lymphoma when rituximab is added to chemotherapy.

Am J Hematol 2013 Dec 30;88(12):1062-7. Epub 2013 Sep 30.

Hematology and Bone Marrow Transplant Units of Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.

The peripheral blood lymphocyte to monocyte ratio (LMR) at diagnosis can be clinically relevant in patients with diffuse large B-cell lymphoma (DLBCL). We reviewed the outcome of 1,057 DLBCL patients followed from 1984 to 2012 at four centers. LMR was analyzed as a clinical biomarker by receiver-operating characteristic (ROC) analysis and Harrell's C-statistics. Patients were characterized by a median age of 61 years, International Prognostic Index (IPI) score of >2 in 39%, and were treated with a rituximab-containing chemotherapy in 66%. LMR proved strongly predictive for survival in patients treated with rituximab-based programs, but not in those receiving chemotherapy alone. Additionally, an LMR value of ≤2.6 (as determined by ROC analysis) was associated with a worst performance status, a higher lactate dehydrogenase (LDH) level, an advanced clinical stage, and a higher IPI score (P = 0.000). In patients treated with rituximab-supplemented chemotherapy programs, an LMR value of <2.6 was found in most of the primary refractory patients (75%) which proved as the best cutoff to predict both response and survival (P = 0.018). Finally, multivariate analysis and Harrell's C-statistics confirmed the IPI-independent role of LMR on survival (P = 0.0000). In conclusion, LMR is a potent predictor of clinical response and survival in DLBCL treated with rituximab-containing chemotherapy.
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http://dx.doi.org/10.1002/ajh.23566DOI Listing
December 2013

Low-dose alemtuzumab-associated immune thrombocytopenia in chronic lymphocytic leukemia.

Am J Hematol 2012 Sep 20;87(9):936-7. Epub 2012 Jun 20.

Hematology and Transplantation Unit, Foundation IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy.

Chronic lymphocytic leukemia (CLL) is frequently complicated during its course by autoimmune disorders (from 2 to 12% of cases), such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). In particular, ITP has been reported in about 2–5% of CLL population. Recently, Cuker et al. reported the occurrence of ITP in 6/216 patients with relapsing-remitting multiple sclerosis in a phase 2 clinical trial of annual alemtuzumab. Alemtuzumab is an anti-CD52 monoclonal antibody used in CLL both as first-line treatment and in relapsed/refractory patients. We evaluated a cohort of 64 consecutive patients affected by relapsed-refractory CLL treated with low-dose alemtuzumab and we observed a incidence of ITP higher than predicted. Our data, associated with the report of Cuker et al., seem to suggest an important role of alemtuzumab in the pathogenesis of ITP which could be related to its induced dysregulation of T-lymphocyte activity.
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http://dx.doi.org/10.1002/ajh.23268DOI Listing
September 2012

Successful management with intravenous immunoglobulins in alemtuzumab-induced acute inflammatory demyelinating neuropathy: clinical report of three patients.

Immunopharmacol Immunotoxicol 2012 Aug 2;34(4):717-20. Epub 2012 Jan 2.

Dipartimento di Medicina Interna, Università degli Studi di Milano and Dipartimento di Medicina, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Several neurological complications have been associated with the use of monoclonal antibodies (mAbs), and demyelinating disorders have been estimated to affect the 0.02-0.20% of treated patients. Alemtuzumab is a humanized chimeric mAbthat targets the CD52 antigen, it is currently approved for relapsed/refractory and high-risk untreated chronic lymphocytic leukemia (CLL). The major complication of alemtuzumab therapy is the increased risk of opportunistic infections secondary to the profound immunosuppression. Autoimmune diseases as Graves disease, immune thrombocytopenic purpura and Good pasture syndrome, have been reported to be associated to the treatment. In the present report, we present three CLL patients developing acute inflammatory demyelinating neuropathy during treatment with alemtuzumab. Despite the severity of the complication, all the patients showed an univocal good clinical response after treatment with intravenous immunoglobulin (IVIG). As alemtuzumab represents, nowadays, a key therapeutic option for CLL, clinicians should be aware of this rare and disabling toxicity.
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http://dx.doi.org/10.3109/08923973.2011.644295DOI Listing
August 2012

An Italian retrospective study on the routine clinical use of low-dose alemtuzumab in relapsed/refractory chronic lymphocytic leukaemia patients.

Br J Haematol 2012 Feb 9;156(4):481-9. Epub 2011 Dec 9.

Haematology-BMT Unit, IRCCS Ca'Granda Ospedale Maggiore Policlinico Foundation, Milan, Italy.

Low-dose alemtuzumab has shown a favourable toxicity profile coupled with good results in terms of efficacy in relapsed/refractory chronic lymphocytic leukaemia (CLL). We conducted a multicentre retrospective study on the routine clinical use of low-dose alemtuzumab in this patient setting. One hundred and eight relapsed/refractory CLL patients from 11 Italian centres were included in the analysis. All patients had an Eastern Cooperative Oncology Group performance status ≤2 and the majority (84%) had adenopathies <5 cm. Low-dose alemtuzumab was defined as a total weekly dose ≤45 mg and a cumulative dose ≤600 mg given for up to 18 weeks. The overall response rate was 56% (22% complete remissions). After a median follow-up of 42.2 months, the median overall survival and progression-free survival were 39.0 and 19.4 months, respectively. In univariate analysis, response was inversely associated with lymph node (P = 0.01) and spleen (P = 0.02) size, fludarabine-refractoriness (P = 0.01) and del(11q) (P = 0.009). Advanced age and del(17p) were not associated with a worse outcome. Cumulative dose of alemtuzumab was not associated to response. Toxicities were usually mild and manageable; severe infections occurred in seven patients (7%) during therapy. This retrospective analysis confirms that low-dose alemtuzumab is a valid and currently used therapeutic option for the treatment of relapsed/refractory CLL.
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http://dx.doi.org/10.1111/j.1365-2141.2011.08965.xDOI Listing
February 2012

Low dose alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia.

Leuk Lymphoma 2012 Mar 5;53(3):424-9. Epub 2012 Jan 5.

Department of Medical Sciences, University of Milan, Milan, Italy.

Alemtuzumab has been shown to be effective in poor-prognosis chronic lymphocytic leukemia (CLL); treatment, however, has been associated with significant toxicity. With the aim of seeking better tolerability, we treated 39 patients with fludarabine-refractory CLL subcutaneous alemtuzumab 10 mg three times a week, for 18 weeks. In 18 randomly selected patients, after obtaining lymphocyte count reduction by 1 Log, the antibody was administered once weekly at the dose of 30 mg. Overall response rate was 44%, including 8% complete remissions. Median overall survival and progression free survival were 29.1 and 10.3 months, respectively. Treatment was well tolerated, severe non-CMV infection occurred in 7% of the patients. CMV reactivation was detected in 27% of the patients, with only one case of CMV disease. No deaths occurred during therapy. In conclusion, low-dose alemtuzumab shows a promising safety profile coupled with satisfactory effectiveness in this category of poor prognosis CLL patients.
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http://dx.doi.org/10.3109/10428194.2011.623258DOI Listing
March 2012

Circulating and progenitor endothelial cells are abnormal in patients with different types of von Willebrand disease and correlate with markers of angiogenesis.

Am J Hematol 2011 Aug 31;86(8):650-6. Epub 2011 May 31.

Department of Hematology-1, Fondazione IRCCS Cà Granda Maggiore Policlinico Hospital and Università degli Studi di Milano, Milan, Italy.

von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by quantitative or qualitative defects of von Willebrand factor (VWF). VWF, synthesized by endothelium and megakaryocytes (MK), circulates in plasma and is present in subendothelium and platelets. Circulating endothelial cells (CEC) and progenitor endothelial cells (EPC) have been recently proposed as markers of peripheral and bone marrow-derived angiogenesis. To evaluate the association of CEC/EPC with known inherited defects of cellular and circulating VWF, we have measured the number of CEC/EPC together with cytokines involved in angiogenesis in different VWD types. A group of 74 patients was composed by the following VWD types: VWD1 (n = 22), VWD2A (n = 9), VWD2B (n = 19), VWD2M (n = 17), and VWD3 (n = 7). Healthy individuals (n = 20) were used as controls. CEC (CD146(+) , CD31(+) , and CD45(-) ) and EPC (CD34(+) , CD133(+) , and CD45(-) ) were evaluated by flow cytometry. Circulating serum levels of VEGF, E-selectin, P-selectin, EPO, and TPO were determined by ELISA. CEC, VEGF, E-selectin, and EPO were higher and EPC lower in VWD patients than in controls (P < 0.01). Among the five groups of VWD patients and controls, a significant difference was found for CEC (one-way ANOVA: P = 0.005), EPC (P = 0.001), E-Selectin (P < 0.0001), EPO (P = 0.021), and TPO (P = 0.004): the latter was high in VWD3 patients. In VWD1, we found an inverse relationship between CEC and VWF:Ag levels (P = 0.048; R(2) = 0.19). Based on these data, CEC are increased in VWD and are associated with the high levels of cytokines involved in angiogenesis (up-regulation). EPC are decreased, suggesting down-regulation of bone marrow-derived angiogenesis in VWD.
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http://dx.doi.org/10.1002/ajh.22070DOI Listing
August 2011