Publications by authors named "Franco Narni"

48 Publications

Cytomegalovirus reactivation after hematopoietic stem cell transplant with CMV-IG prophylaxis: A monocentric retrospective analysis.

J Med Virol 2021 Feb 12. Epub 2021 Feb 12.

Section of Hematology, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy.

Human cytomegalovirus (CMV) represents the most common viral infection after hematopoietic stem cell transplant (HSCT), mainly occurring as reactivation from latency in seropositive patients, with a different prevalence based on the extent and timing of seroconversion in a specific population. Here, we retrospectively analyzed a cohort of patients who underwent HSCT at our Institution between 2013 and 2018, all of whom were prophylactically treated with CMV-IG (Megalotect Biotest®), to define the incidence and clinical outcomes of CMV reactivation and clinically significant infection. CMV infection occurred in 69% of our patient series, mainly resulting from reactivation, and CMV clinically significant infection (CS-CMVi) occurred in 48% of prophylactically treated patients. CMV infection and CS-CMVi impacted neither on relapse incidence nor on overall survival nor on relapse-free survival. Moreover, a very low incidence of CMV end-organ disease was documented. CMV-IG used alone as prophylactic therapy after HSCT does not effectively prevent CMV reactivation.
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http://dx.doi.org/10.1002/jmv.26861DOI Listing
February 2021

Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial.

Lancet Haematol 2021 Jan 22;8(1):e34-e44. Epub 2020 Dec 22.

Department of Translational and Precision Medicine, Sapienza University of Rome, Roma, Italy.

Background: Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population.

Methods: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m on day 1; intravenous doxorubicin 50 mg/m, vincristine 1·4 mg/m, and cyclophosphamide 750 mg/m on day 2; oral prednisone 100 mg/m on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m on day 1, intravenous rituximab 375 mg/m on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m every 12 h on days 1-3, intravenous rituximab 375 mg/m on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 10 cells per L or 10 mg per day for platelets 60-100 × 10 cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313).

Findings: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events.

Interpretation: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma.

Funding: Fondazione Italiana Linfomi and Celgene.
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http://dx.doi.org/10.1016/S2352-3026(20)30358-6DOI Listing
January 2021

Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study.

Lancet Haematol 2020 Dec;7(12):e861-e873

Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy. Electronic address:

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study.

Methods: In this randomised, open-label, phase 3 study, patients aged 18-65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1-2, 4-5, 8-9, and 11-12 in the VTD regimen, and 40 mg on days 1-4 and 9-12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484.

Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2-131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28-41) compared with 17% (13-23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50-0·77]; p<0·0001). 60% (95% CI 54-67) of patients in the VTD group were alive at 10 years versus 46% (40-54) of patients in the TD group (HR 0·68 [95% CI 0·51-0·90]; p=0·0068). VTD was an independent predictor of improved progression-free survival (HR 0·60 [95% CI 0·48-0·76]; p<0·0001) and overall survival (HR 0·68 [0·50-0·91]; p=0·010). The incidence of second primary malignancies per 100 person-years was 0·87 (95% CI 0·49-1·44) in the VTD group compared with 1·41 (0·88-2·13) in the TD group.

Interpretation: Incorporation of VTD into double autologous HSCT resulted in clinically meaningful improvements in long-term progression-free survival and overall survival, confirming that a regimen including bortezomib and an immunomodulatory drug is the gold standard treatment for patients with newly diagnosed myeloma who are fit for high-dose chemotherapy.

Funding: Seràgnoli Institute of Haematology, University of Bologna, and BolognAIL.
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http://dx.doi.org/10.1016/S2352-3026(20)30323-9DOI Listing
December 2020

Cancer treatment during the coronavirus disease 2019 pandemic: Do not postpone, do it!

Eur J Cancer 2020 07 12;133:29-32. Epub 2020 May 12.

Department of Medical and Surgical Sciences for Children and Adults, Division of Oncology, University Hospital of Modena, Italy.

At the end of January 2020, a novel betacoronavirus, known as severe acute respiratory syndrome coronavirus 2, progressively spread in Italy. Patients with cancer are considered more prone to infections because of the immunosuppressive status due to both malignancy and anticancer treatments. From the first Italian government restrictions (23rd February), Modena Cancer Center adopted practical health vigilance recommendations to minimise the risk of exposure to the virus without overlooking cancer management. From 23rd February to 31st March 2020, 1257 patients on active anticancer treatment for oncological or haematological malignancies attended our institution. All the staff activities were rescheduled following our practical coronavirus disease 2019 (COVID-19) guideline. During this period, we have tallied 9 cases of COVID-19 infection (0.71%) in patients with cancer and 3 cases (1.66%) in health workers. The mortality rate of our patients with cancer was 22%, consistent with the data reported in the literature. In conclusion, following our practical health vigilance recommendations, physicians should be confident in maintaining life-saving anticancer treatment without exceedingly increasing the risk of nosocomial COVID-19 infection. The high rate of mortality suggested that all patients on active anticancer treatment with flu-like symptoms have to be carefully screened for COVID-19 infection.
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http://dx.doi.org/10.1016/j.ejca.2020.04.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214318PMC
July 2020

Acute Myeloid Leukemia in Patients Living with HIV Infection: Several Questions, Fewer Answers.

Int J Mol Sci 2020 Feb 6;21(3). Epub 2020 Feb 6.

Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Policlinico, 41124 Modena, Italy.

Both human immunodeficiency virus (HIV) infection and acute myeloid leukemia (AML) may be considered relatively uncommon disorders in the general population, but the precise incidence of AML in people living with HIV infection (PLWH) is uncertain. However, life expectancy of newly infected HIV-positive patients receiving anti-retroviral therapy (ART) is gradually increasing, rivaling that of age-matched HIV-negative individuals, so that the occurrence of AML is also expected to progressively increase. Even if HIV is not reported to be directly mutagenic, several indirect leukemogenic mechanisms, mainly based on bone marrow microenvironment disruption, have been proposed. Despite a well-controlled HIV infection under ART should no longer be considered per se a contraindication to intensive chemotherapeutic approaches, including allogeneic hematopoietic stem cell transplantation, in selected fit patients with AML, survival outcomes are still generally unsatisfactory. We discussed several controversial issues about pathogenesis and clinical management of AML in PLWH, but few evidence-based answers may currently be provided, due to the limited number of cases reported in the literature, mainly as case reports or small retrospective case series. Prospective multicenter clinical trials are warranted to more precisely investigate epidemiology and cytogenetic/molecular features of AML in PLWH, but also to standardize and further improve its therapeutic management.
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http://dx.doi.org/10.3390/ijms21031081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036847PMC
February 2020

Prolonged survival in the absence of disease-recurrence in advanced-stage follicular lymphoma following chemo-immunotherapy: 13-year update of the prospective, multicenter randomized GITMO-IIL trial.

Haematologica 2019 11 11;104(11):2241-2248. Epub 2019 Apr 11.

Onco-Hematology Division, IEO, European Institute of Oncology IRCCS, Milano

A prospective trial conducted in the period 2000-2005 showed no survival advantage for high-dose chemotherapy with rituximab and autograft (R-HDS) conventional chemotherapy with rituximab (CHOP-R) as first-line therapy in 134 high-risk follicular lymphoma patients aged <60 years. The study has been updated at the 13-year median follow up. As of February 2017, 88 (66%) patients were alive, with overall survival of 66.4% at 13 years, without a significant difference between R-HDS (64.5%) and CHOP-R (68.5%). To date, 46 patients have died, mainly because of disease progression (47.8% of all deaths), secondary malignancies (3 solid tumor, 9 myelodysplasia/acute leukemia; 26.1% of all deaths), and other toxicities (21.7% of all deaths). Complete remission was documented in 98 (73.1%) patients and associated with overall survival, with 13-year estimates of 77.0% and 36.8% for complete remission no-complete remission, respectively. Molecular remission was documented in 39 (65%) out of 60 evaluable patients and associated with improved survival. In multivariate analysis, complete remission achievement had the strongest effect on survival (<0.001), along with younger age (=0.002) and female sex (=0.013). Overall, 50 patients (37.3%) survived with no disease recurrence (18 CHOP-R, 32 R-HDS). This follow up is the longest reported on follicular lymphoma treated upfront with rituximab-chemotherapy and demonstrates an unprecedented improvement in survival compared to the pre-rituximab era, regardless of the use of intensified or conventional treatment. Complete remission was the most important factor for prolonged survival and a high proportion of patients had prolonged survival in their first remission, raising the issue of curability in follicular lymphoma. (Registered at clinicaltrials.gov identifier: 00435955).
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http://dx.doi.org/10.3324/haematol.2018.209932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821615PMC
November 2019

Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia.

Oncotarget 2019 Jan 25;10(8):869-882. Epub 2019 Jan 25.

Pediatric Hematology/Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy.

Nucleophosmin(NPM1)-mutated protein, a leukemia-specific antigen, represents an ideal target for AML immunotherapy. We investigated the dynamics of NPM1-mutated-specific T cells on PB and BM samples, collected from 31 adult -mutated AML patients throughout the disease course, and stimulated with mixtures of 18 short and long peptides (9-18mers), deriving from the complete C-terminal of the NPM1-mutated protein. Two 9-mer peptides, namely LAVEEVSLR and AVEEVSLRK (13.9-14.9), were identified as the most immunogenic epitopes. IFNγ-producing NPM1-mutated-specific T cells were observed by ELISPOT assay after stimulation with peptides 13.9-14.9 in 43/85 (50.6%) PB and 34/80 (42.5%) BM samples. An inverse correlation between MRD kinetics and anti-leukemic specific T cells was observed. Cytokine Secretion Assays allowed to predominantly and respectively identify Effector Memory and Central Memory T cells among IFNγ-producing and IL2-producing T cells. Moreover, NPM1-mutated-specific CTLs against primary leukemic blasts or PHA-blasts pulsed with different peptide pools could be expanded from -mutated AML patients or primed in healthy donors. We describe the spontaneous appearance and persistence of -mutated-specific T cells, which may contribute to the maintenance of long-lasting remissions. Future studies are warranted to investigate the potential role of both autologous and allogeneic adoptive immunotherapy in -mutated AML patients.
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http://dx.doi.org/10.18632/oncotarget.26617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368236PMC
January 2019

Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study.

Lancet Haematol 2019 Feb;6(2):e89-e99

University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension.

Methods: In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (1:1) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mg/kg with either total body irradiation (12 Gy) or busulfan (12·8 mg/kg intravenously or 16 mg/kg orally), with or without etoposide (30-60 mg/kg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. The original trial (number, NCT00678275) and follow-up extension (number, NCT03042676) are registered at ClinicalTrials.gov.

Findings: In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n=83) or to the non-ATLG group (n=72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p=0·02; treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate -14·8 [95% CI -26·4 to -3·1]; p=0·014) and social function (-19·1 [-38·0 to -0·2]; p=0·047), gastrointestinal side-effects (8·8 [2·5-15·1]; p=0·008) and effect on family (13·5 [1·2-25·8]; p=0·032). Extended follow-up (median 5·9 years [IQR 1·7-7·9]) confirmed a lower 5-year cGVHD incidence (30·0% [95% CI 21·4-41·9] vs 69·1% [59·1-80·1]; analysis for entire follow-up, p<0·001), no increase in relapses (35·4% [26·4-47·5] vs 22·5% [14·6-34·7]; p=0·09), improved cGRFS (34·3% [24·2-44·5] vs 13·9% [7·1-22·9]; p=0·005), and fewer patients still in immunosuppression (9·6% vs 28·3%; p=0·017) in the ATLG group compared with the non-ATLG group. 5-year overall survival, relapse-free survival, and non-relapse mortality did not differ significantly between groups.

Interpretation: The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone.

Funding: Neovii Biotech.
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http://dx.doi.org/10.1016/S2352-3026(18)30214-XDOI Listing
February 2019

Busulfan- or Thiotepa-Based Conditioning in Myelofibrosis: A Phase II Multicenter Randomized Study from the GITMO Group.

Biol Blood Marrow Transplant 2019 05 20;25(5):932-940. Epub 2018 Dec 20.

"Papa Giovanni XXIII" Hospital, Bergamo, Italy; Department of Hematology-Oncology, University of Milano, Milan, Italy.

We report a randomized study comparing fludarabine in combination with busulfan (FB) or thiotepa (FT), as conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis. The primary study endpoint was progression-free survival (PFS). Sixty patients were enrolled with a median age of 56 years and an intermediate-2 or high-risk score in 65%, according to the Dynamic International Prognostic Staging System (DIPSS). Donors were HLA-identical sibling (n = 25), matched unrelated (n = 25) or single allele mismatched unrelated (n = 10). With a median follow-up of 22 months (range, 1 to 68 months), outcomes at 2 years after HSCT in the FB arm versus the FT arm were as follows: PFS, 43% versus 55% (P = .28); overall survival (OS), 54% versus 70% (P = .17); relapse/progression, 36% versus 24% (P = .24); nonrelapse mortality (NRM), 21% in both arms (P = .99); and graft failure, 14% versus 10% (P = .96). A better PFS was observed in patients with intermediate-1 DIPSS score (P = .03). Both neutrophil engraftment and platelet engraftment were significantly influenced by previous splenectomy (hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.16 to 4.51; P = .02) and splenomegaly at transplantation (HR, 0.51; 95% CI, 0.27 to 0.94; P = .03). In conclusion, the clinical outcome after HSCT was comparable when using either a busulfan or thiotepa based conditioning regimen.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.064DOI Listing
May 2019

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen.

Biol Blood Marrow Transplant 2017 Jul 5;23(7):1102-1109. Epub 2017 Apr 5.

Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; Dept of Oncology, University of Milan, Milan, Italy.

The treatment of patients with refractory/relapsed B cell non-Hodgkin lymphoma (NHL) is evolving because of the availability of novel drugs. Allogeneic stem cell transplantation (alloSCT) can be curative, but its morbidity and mortality remain a matter of concern. We conducted a multicenter prospective phase II trial to evaluate the benefit of including only 1 dose of rituximab in the conditioning regimen before alloSCT. The primary endpoint was progression-free survival. The study enrolled 121 patients with relapsed/refractory B cell lymphomas. The conditioning regimen consisted of thiotepa, cyclophosphamide, fludarabine, and rituximab (500 mg/m). Rabbit antithymocyte globulin was administered only in case of unrelated donors. Sixty-seven (55%) and 54 (45%) patients received grafts from related and unrelated donors, respectively. The crude cumulative incidence (CCI) of nonrelapse mortality (NRM) was 21% at 3 years. The CCIs of chronic graft-verus-host disease (GVHD) at 3 years were 54% and 31% in recipients of matched sibling and unrelated grafts, respectively. At a median follow-up of 41 months, the estimated 3-year progression-free and overall survival were 50% and 61%, respectively. Long-term outcome was also evaluated with the composite endpoint of GVHD-free and relapse-free survival (GRFS). This is the first work evaluating the GRFS in a prospective trial of lymphoma patients: the 1-year and 3-year GRFS were 40% and 34%, respectively. AlloSCT can cure a fraction of patients with rather low NRM and an encouraging PFS and GRFS.
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http://dx.doi.org/10.1016/j.bbmt.2017.03.031DOI Listing
July 2017

Detection of Fusarium-specific T cells in hematologic patients with invasive fusariosis.

J Infect 2017 03 23;74(3):314-318. Epub 2016 Dec 23.

Section of Hematology, Department of Surgical and Medical Sciences, University of Modena and Reggio Emilia, Azienda Ospedaliero - Universitaria Policlinico, 41124 Modena, Italy.

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http://dx.doi.org/10.1016/j.jinf.2016.12.008DOI Listing
March 2017

All-trans retinoic acid (ATRA) in non-promyelocytic acute myeloid leukemia (AML): results of combination of ATRA with low-dose Ara-C in three elderly patients with -mutated AML unfit for intensive chemotherapy and review of the literature.

Clin Case Rep 2016 Dec 24;4(12):1138-1146. Epub 2016 Oct 24.

Department Medical and Surgical Sciences Section of Hematology Azienda Ospedaliero-Universitaria Policlinico University of Modena and Reggio Emilia Modena Italy.

Based upon the clinical behavior of three patients, we suggest that the combination of low-dose Ara-C and all-trans retinoic acid may potentially be effective in some elderly patients, unfit for intensive chemotherapy, affected with -mutated acute myeloid leukemia without mutations, warranting perspective clinical studies in these selected patients.
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http://dx.doi.org/10.1002/ccr3.723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134148PMC
December 2016

BCR-ABL-specific T-cell therapy in Ph+ ALL patients on tyrosine-kinase inhibitors.

Blood 2017 02 7;129(5):582-586. Epub 2016 Dec 7.

Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Azienda Ospedaliera Universitaria (AOU) Policlinico, Modena, Italy.

Although the emergence of bone marrow (BM)-resident BCR-ABL-specific T lymphocytes has been correlated with hematologic and cytogenetic remissions in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) undergoing maintenance tyrosine-kinase inhibitor treatment, little is known about the possibility of culturing these cells ex vivo and using them in T-cell therapy strategies. We investigated the feasibility of expanding/priming BCR-ABL-specific T cells in vitro by stimulation with dendritic cells pulsed with BCR-ABL peptides derived from the BCR-ABL junctional region and alternative splicing, and of adoptively administering them to patients with relapsed disease. We report on the feasibility of producing clinical-grade BCR-ABL-specific cytotoxic T lymphocytes (CTLs), endowed with antileukemia activity, from Ph ALL patients and healthy donors. We treated 3 patients with Ph ALL with autologous or allogeneic BCR-ABL-specific CTLs. No postinfusion toxicity was observed, except for a grade II skin graft-versus-host disease in the patient treated for hematologic relapse. All patients achieved a molecular or hematologic complete remission (CR) after T-cell therapy, upon emergence of BCR-ABL-specific T cells in the BM. Our results show that BCR-ABL-specific CTLs are capable of controlling treatment-refractory Ph ALL in vivo, and support the development of adoptive immunotherapeutic approaches with BCR-ABL CTLs in Ph ALL.
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http://dx.doi.org/10.1182/blood-2016-07-731091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290986PMC
February 2017

Mucorales-Specific T Cells in Patients with Hematologic Malignancies.

PLoS One 2016 12;11(2):e0149108. Epub 2016 Feb 12.

Section of Hematology, Department of Surgical and Medical Sciences, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria Policlinico, Modena, Italy.

Background: Invasive mucormycosis (IM) is an emerging life-threatening fungal infection. It is difficult to obtain a definite diagnosis and to initiate timely intervention. Mucorales-specific T cells occur during the course of IM and are involved in the clearance of the infection. We have evaluated the feasibility of detecting Mucorales-specific T cells in hematological patients at risk for IM, and have correlated the detection of such cells with the clinical conditions of the patients.

Methods And Findings: By using an enzyme linked immunospot assay, the presence of Mucorales-specific T cells in peripheral blood (PB) samples has been investigated at three time points during high-dose chemotherapy for hematologic malignancies. Mucorales-specific T cells producing interferon-γ, interleukin-10 and interleukin-4 were analysed in order to detect a correlation between the immune response and the clinical picture. Twenty-one (10.3%) of 204 patients, accounting for 32 (5.3%) of 598 PB samples, tested positive for Mucorales-specific T cells. Two groups could be identified. Group 1, including 15 patients without signs or symptoms of invasive fungal diseases (IFD), showed a predominance of Mucorales-specific T cells producing interferon-gamma. Group 2 included 6 patients with a clinical picture consistent with invasive fungal disease (IFD): 2 cases of proven IM and 4 cases of possible IFD. The proven patients had significantly higher number of Mucorales-specific T cells producing interleukin-10 and interleukin-4 and higher rates of positive samples by using derived diagnostic cut-offs when compared with the 15 patients without IFD.

Conclusions: Mucorales-specific T cells can be detected and monitored in patients with hematologic malignancies at risk for IM. Mucorales-specific T cells polarized to the production of T helper type 2 cytokines are associated with proven IM and may be evaluated as a surrogate diagnostic marker for IM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149108PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752352PMC
July 2016

Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease.

N Engl J Med 2016 Jan;374(1):43-53

From the University Medical Center Hamburg-Eppendorf, Hamburg (N.K., C.W., M.H., F.A.), University Hospital Freiburg, Freiburg (J.F.), University Hospital Tübingen, Tübingen (W.B.), and Psy Consult, Frankfurt (A.V.) - all in Germany; Hospital Clinico Universitario, Valencia (C. Solano), Hospital Ramon y Cajal (J.P.O.) and Hospital Universitario Puerta de Hierro Majadahonda (R.D.), Madrid, Servicio de Hematología, Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, Badalona, (C.F.), Hospital de la Santa Creu i Sant Pau, Barcelona (J.S.), and Hospital Virgen de las Nieves, Granada (M.J.) - all in Spain; S. Orsola-Malpighi University Hospital, University of Bologna, Bologna (G.B., F. Bonifazi), Hematology, DISM, University Udine, Udine (F.P.), Azienda Ospedaliera SS Antonio e Biagio e C. Arrigo, Alessandria (M. Pini), Università Federico II di Napoli, Naples (C. Selleri, A.R.), A.O. Bianchi-Melacrino-Morelli, Reggio Calabria (G. Messina), Ospedale Casa Sollievo della Sofferenza IRCCCS, San Giovanni Rotondo (A.M.C.), Azienda Ospedaliera San Carlo, Potenza (M.C.), Azienda Ospedaliera Careggi, Florence (S.G.), Ospedale Santa Croce, e Carle, Cuneo (N.M.), University of Brescia, Department of Clinical and Experimental Sciences, Brescia (D.R.), University of Pisa, Department of Clinical and Experimental Medicine, Pisa (M. Petrini), Programma di Trapianto Emopoietico Metropolitano, Azienda Policlinico-Vittorio Emanuele, Catania (G. Milone), Policlinico G.B. Rossi, Verona (F. Benedetti), Azienda Ospedaliera, Universitaria Ospedale, Bari (D.P.), Ospedale San Gerardo, Monza (E.T.), Policlinico Modena, Modena (F.N.), and Università di Salerno, Salerno (C. Selleri) - all in Italy; Chaim Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel (A.N.); and Helsinki University Hospital, Helsinki (T.R.).

Background: Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling.

Methods: We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease.

Results: After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005).

Conclusions: The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.).
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http://dx.doi.org/10.1056/NEJMoa1506002DOI Listing
January 2016

The bone marrow represents an enrichment site of specific T lymphocytes against filamentous fungi.

Med Mycol 2016 Mar 24;54(3):327-32. Epub 2015 Dec 24.

Section of Hematology, Department of Surgical and Medical Sciences, University of Modena and Reggio Emilia, Azienda Ospedaliero - Universitaria Policlinico, 41124 Modena, Italy.

Bone marrow has already been described as an enrichment site for several antigen-specific T lymphocytes, but the presence of mould-specific T cells has never been investigated in the bone marrow. We have previously demonstrated that mould-specific T cells emerge in the peripheral blood of patients with invasive fungal infections (IFI) but tend to become undetectable after disease resolution. In seven patients with a history of IFI, we investigated the presence of mould-specific T cells secreting different cytokines in bone marrow and peripheral blood paired samples. The results showed that the frequencies of mould-specific T cells secreting the protective cytokine IFNγ are significantly higher in bone marrow (BM) and are mainly represented by CD8+ T lymphocytes with effector phenotype. A putative disappearance of such protective BM responses after myeloablative therapy could contribute to the increased risk of IFI in hematologic patients.
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http://dx.doi.org/10.1093/mmy/myv107DOI Listing
March 2016

Chronic and recurrent benign lymphadenopathy without constitutional symptoms associated with human herpesvirus-6B reactivation.

Br J Haematol 2016 Feb 18;172(4):561-72. Epub 2015 Dec 18.

Dipartimento di Scienze Mediche e Chirurgiche Materno Infantili e dell'Adulto, Università di Modena e Reggio Emilia, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy.

Chronic/recurrent behaviour may be encountered in some distinct atypical or malignant lymphoproliferations, while recurrences are not generally observed in reactive/benign lymphadenopathies. We retrospectively analysed a consecutive series of 486 human immunodeficiency virus-negative adults, who underwent lymphadenectomy. Neoplastic and benign/reactive histopathological pictures were documented in 299 (61·5%) and 187 (38·5%) cases, respectively. Of note, seven of the 111 (6·3%) patients with benign lymphadenopathy without well-defined aetiology, showed chronic/recurrent behaviour, without constitutional symptoms. Enlarged lymph nodes were round in shape and hypoechoic, mimicking lymphoma. Reactive follicular hyperplasia and paracortical expansion were observed. Human herpesvirus (HHV)-6B positive staining in follicular dendritic cells (FDCs) was documented in all seven patients. Serological, molecular and immunological examinations suggested HHV-6B reactivation. Among the remaining 104 cases with reactive lymphoid hyperplasia in the absence of well-known aetiology and without recurrences, positivity for HHV-6B on FDCs was found in three cases, whereas in seven further patients, a scanty positivity was documented in rare, scattered cells in inter-follicular regions. Immunohistochemistry for HHV-6A and HHV-6B was invariably negative on 134 lymph nodes, with either benign pictures with known aetiology or malignant lymphoproliferative disorders, tested as further controls. Future studies are warranted to investigate a potential association between HHV-6B reactivation and chronic/recurrent benign lymphadenopathy.
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http://dx.doi.org/10.1111/bjh.13871DOI Listing
February 2016

Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia.

Haematologica 2015 Feb 14;100(2):253-62. Epub 2014 Nov 14.

Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Lenalidomide is an immunomodulatory agent clinically active in chronic lymphocytic leukemia patients. The specific mechanism of action is still undefined, but includes modulation of the microenvironment. In chronic lymphocytic leukemia patients, nurse-like cells differentiate from CD14(+) mononuclear cells and protect chronic lymphocytic leukemia cells from apoptosis. Nurse-like cells resemble M2 macrophages with potent immunosuppressive functions. Here, we examined the effect of lenalidomide on the monocyte/macrophage population in chronic lymphocytic leukemia patients. We found that lenalidomide induces high actin polymerization on CD14(+) monocytes through activation of small GTPases, RhoA, Rac1 and Rap1 that correlated with increased adhesion and impaired monocyte migration in response to CCL2, CCL3 and CXCL12. We observed that lenalidomide increases the number of nurse-like cells that lost the ability to nurture chronic lymphocytic leukemia cells, acquired properties of phagocytosis and promoted T-cell proliferation. Gene expression signature, induced by lenalidomide in nurse-like cells, indicated a reduction of pivotal pro-survival signals for chronic lymphocytic leukemia, such as CCL2, IGF1, CXCL12, HGF1, and supported a modulation towards M1 phenotype with high IL2 and low IL10, IL8 and CD163. Our data provide new insights into the mechanism of action of lenalidomide that mediates a pro-inflammatory switch of nurse-like cells affecting the protective microenvironment generated by chronic lymphocytic leukemia into tissues.
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http://dx.doi.org/10.3324/haematol.2014.113217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803140PMC
February 2015

Endothelin-1 promotes survival and chemoresistance in chronic lymphocytic leukemia B cells through ETA receptor.

PLoS One 2014 5;9(6):e98818. Epub 2014 Jun 5.

Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.

The endothelin axis, comprising endothelins (ET-1, ET-2 and ET-3) and their receptors (ET(A)R and ETBR), has emerged as relevant player in tumor growth and metastasis. Here, we investigated the involvement of ET-1/ET(A)R axis in chronic lymphocytic leukemia (CLL). CLL cells expressed higher levels of ET-1 and ETA receptor as compared to normal B cells. ET-1 peptide stimulated phosphoinositide-3-kinase and mitogen-activated protein kinase signaling pathways, improved survival and promoted proliferation of leukemic cells throughout ET(A)R triggering. Moreover, the blockade of ET(A)R by the selective antagonist BQ-123 inhibited the survival advantage acquired by CLL cells in contact with endothelial layers. We also found that blocking ET(A)R via BQ-123 interferes with ERK phosphorylation and CLL pro-survival effect mediated by B-cell receptor (BCR) activation. The pro-apoptotic effect of phosphoinositide-3-kinase δ inhibitor idelalisib and mitogen-activated protein kinase inhibitor PD98059 was decreased by the addition of ET-1 peptide. Then, ET-1 also reduced the cytotoxic effect of fludarabine on CLL cells cultured alone or co-cultured on endothelial layers. ET(A)R blockade by BQ-123 inhibited the ET-1-mediated protection against drug-induced apoptosis. Lastly, higher plasma levels of big ET-1 were detected in patients (n = 151) with unfavourable prognostic factors and shorter time to first treatment. In conclusion, our data describe for the first time a role of ET-1/ET(A)R signaling in CLL pathobiology. ET-1 mediates survival, drug-resistance, and growth signals in CLL cells that can be blocked by ET(A)R inhibition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098818PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046988PMC
August 2015

Ruxolitinib for pulmonary extramedullary hematopoiesis in myelofibrosis.

Leuk Lymphoma 2014 Sep 28;55(9):2207-8. Epub 2014 Jan 28.

Department of Medical and Surgical Sciences, UNIMORE, UO-C Ematologia, AOU Policlinico , Modena , Italy.

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http://dx.doi.org/10.3109/10428194.2013.873538DOI Listing
September 2014

Characterization of specific immune responses to different Aspergillus antigens during the course of invasive Aspergillosis in hematologic patients.

PLoS One 2013 4;8(9):e74326. Epub 2013 Sep 4.

Section of Hematology, Department of Surgical and Medical Sciences, University of Modena and Reggio Emilia, Azienda Ospedaliera Policlinico, Modena, Italy.

Several studies in mouse model of invasive aspergillosis (IA) and in healthy donors have shown that different Aspergillus antigens may stimulate different adaptive immune responses. However, the occurrence of Aspergillus-specific T cells have not yet been reported in patients with the disease. In patients with IA, we have investigated during the infection: a) whether and how specific T-cell responses to different Aspergillus antigens occur and develop; b) which antigens elicit the highest frequencies of protective immune responses and, c) whether such protective T cells could be expanded ex-vivo. Forty hematologic patients have been studied, including 22 patients with IA and 18 controls. Specific T cells producing IL-10, IFN-γ, IL-4 and IL-17A have been characterized through enzyme linked immunospot and cytokine secretion assays on 88 peripheral blood (PB) samples, by using the following recombinant antigens: GEL1p, CRF1p, PEP1p, SOD1p, α1-3glucan, β1-3glucan, galactomannan. Specific T cells were expanded through short term culture. Aspergillus-specific T cells producing non-protective interleukin-10 (IL-10) and protective interferon-gamma (IFN-γ) have been detected to all the antigens only in IA patients. Lower numbers of specific T cells producing IL-4 and IL-17A have also been shown. Protective T cells targeted predominantly Aspergillus cell wall antigens, tended to increase during the IA course and to be associated with a better clinical outcome. Aspergillus-specific T cells could be successfully generated from the PB of 8 out of 8 patients with IA and included cytotoxic subsets able to lyse Aspergillus hyphae. Aspergillus specific T-cell responses contribute to the clearance of the pathogen in immunosuppressed patients with IA and Aspergillus cell wall antigens are those mainly targeted by protective immune responses. Cytotoxic specific T cells can be expanded from immunosuppressed patients even during the infection by using the above mentioned antigens. These findings may be exploited for immunotherapeutic purposes in patients with IA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074326PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762751PMC
April 2014

Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study.

Blood 2013 Jun 12;121(25):5055-63. Epub 2013 Mar 12.

Department of Medicine, Karolinska Institute at Huddinge and Solna, Stockholm,

Long-term follow-up of prospective studies comparing allogeneic transplantation to autologous transplantation in multiple myeloma is few and controversial. This is an update at a median follow-up of 96 months of the European Group for Blood and Marrow Transplantation Non-Myeloablative Allogeneic stem cell transplantation in Multiple Myeloma (NMAM)2000 study that prospectively compares tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation alone (auto). There are 357 myeloma patients up to age 69 years enrolled. Patients with an HLA-identical sibling were allocated to auto/RICallo (n = 108) and those without to auto alone (n = 249). At 96 months progression-free survival (PFS) and overall survival (OS) were 22% and 49% vs 12% (P = .027) and 36% (P = .030) with auto/RICallo and auto respectively. The corresponding relapse/progression rate (RL) was 60% vs 82% (P = .0002). Non-relapse mortality at 36 months was 13% vs 3% (P = .0004). In patients with the del(13) abnormality corresponding PFS and OS were 21% and 47% vs 5% (P = .026), and 31% (P = .154). Long-term outcome in patients with multiple myeloma was better with auto/RICallo as compared with auto only and the auto/RICallo approach seemed to overcome the poor prognostic impact of del(13) observed after autologous transplantation. Follow up longer than 5 years is necessary for correct interpretation of the value of auto/RICallo in multiple myeloma.
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http://dx.doi.org/10.1182/blood-2012-11-469452DOI Listing
June 2013

The monocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation.

Haematologica 2013 Jul 24;98(7):1115-23. Epub 2013 Jan 24.

Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Macrophages reside in tissues infiltrated by chronic lymphocytic leukemia B cells and the extent of infiltration is associated with adverse prognostic factors. We studied blood monocyte population by flow cytometry and whole-genome microarrays. A mixed lymphocyte reaction was performed to evaluate proliferation of T cells in contact with monocytes from patients and normal donors. Migration and gene modulation in normal monocytes cultured with CLL cells were also evaluated. The absolute number of monocytes increased in chronic lymphocytic leukemia patients compared to the number in normal controls (792 ± 86 cells/μL versus 485 ± 46 cells/μL, P=0.003). Higher numbers of non-classical CD14(+)CD16(++) and Tie-2-expressing monocytes were also detected in patients. Furthermore, we performed a gene expression analysis of monocytes in chronic lymphocytic leukemia patients, showing up-regulation of RAP1GAP and down-regulation of tubulins and CDC42EP3, which would be expected to result in impairment of phagocytosis. We also detected gene alterations such as down-regulation of PTGR2, a reductase able to inactivate prostaglandin E2, indicating immunosuppressive activity. Accordingly, the proliferation of T cells in contact with monocytes from patients was inhibited compared to that of cells in contact with monocytes from normal controls. Finally, normal monocytes in vitro increased migration and up-regulated CD16, RAP1GAP, IL-10, IL-8, MMP9 and down-regulated PTGR2 in response to leukemic cells or conditioned media. In conclusion, altered composition and deregulation of genes involved in phagocytosis and inflammation were found in blood monocytes obtained from chronic lymphocytic leukemia patients, suggesting that leukemia-mediated "education" of immune elements may also include the establishment of a skewed phenotype in the monocyte/macrophage population.
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http://dx.doi.org/10.3324/haematol.2012.073080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696616PMC
July 2013