Publications by authors named "Francesco Gaudio"

32 Publications

Inflammatory Cells in Diffuse Large B Cell Lymphoma.

J Clin Med 2020 Jul 28;9(8). Epub 2020 Jul 28.

Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy.

Diffuse large B cell lymphoma (DLBCL), known as the most common non-Hodgkin lymphoma (NHL) subtype, is characterized by high clinical and biological heterogeneity. The tumor microenvironment (TME), in which the tumor cells reside, is crucial in the regulation of tumor initiation, progression, and metastasis, but it also has profound effects on therapeutic efficacy. The role of immune cells during DLBCL development is complex and involves reciprocal interactions between tumor cells, adaptive and innate immune cells, their soluble mediators and structural components present in the tumor microenvironment. Different immune cells are recruited into the tumor microenvironment and exert distinct effects on tumor progression and therapeutic outcomes. In this review, we focused on the role of macrophages, Neutrophils, T cells, natural killer cells and dendritic cells in the DLBCL microenvironment and their implication as target for DLBCL treatment. These new therapies, carried out by the induction of adaptive immunity through vaccination or passive of immunologic effectors delivery, enhance the ability of the immune system to react against the tumor antigens inducing the destruction of tumor cells.
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http://dx.doi.org/10.3390/jcm9082418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463675PMC
July 2020

Relapsing/refractory HL after autotransplantation: which treatment?

Acta Biomed 2020 05 25;91(S-5):30-40. Epub 2020 May 25.

Haematology Unit and Bone Marrow Transplant Unit, San Camillo Forlanini Hospital, Rome, Italy.

For advanced-stage Hodgkin lymphoma (HL), front-line chemotherapy, alone or in combination with radiotherapy, leads to 5-year progression-free survival (PFS) rates and freedom-from-treatment failure (FFTF) rates of 70-85%, regardless of the chemotherapy regimen applied. Patients with HL experiencing disease progression during or within 3 months of front-line therapy (primary refractory) and patients whose disease relapses after a complete response have a second chance of treatment. The standard of care for relapsed or refractory HL is second-line chemotherapy followed by autologous stem cell transplantation (ASCT), which can induce long-term remission in approximately 40-50% of patients. However, HL recurrence occurs in about 50% of patients after ASCT, usually within the first year, and represents a significant therapeutic challenge. Allogeneic transplantation from HLA-matched donors represents the standard of care for patients with HL relapsing after- or refractory to ASCT.
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http://dx.doi.org/10.23750/abm.v91iS-5.9912DOI Listing
May 2020

Long-term Hodgkin Lymphoma Survivors: A Glimpse of What Happens 10 Years After Treatment.

Clin Lymphoma Myeloma Leuk 2020 08 20;20(8):e506-e512. Epub 2020 Mar 20.

Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy. Electronic address:

Introduction: This retrospective study was focused on 96 patients (median age at diagnosis, 35 years) with newly diagnosed Hodgkin lymphoma (HL) treated at the University Hospital of Bari (Italy) between 2005 and 2008, to evaluate the outcome and the long-term toxicity.

Patients And Methods: First-line chemotherapy was ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in all patients; 49 (51%) patients had undergone radiotherapy. At the end of treatment, 75 (78%) patients were in complete remission (CR); 18 (24%) of 75 patients relapsed after first-line treatment; 20 (21%) underwent autologous hematopoietic stem cell transplantation, and 3 (3%) underwent allogeneic stem cell transplantation.

Results: After a median follow-up of 12 years, 85 (88%) patients are alive in CR, and 11 (14%) have died (2 of a second neoplasia, 1 of infection, and 8 of the disease). The 140-month Kaplan-Meier survival estimates were 86%. Three women became pregnant and each gave birth to a healthy child. The most prevalent chronic conditions at last follow-up were: a reduction in lung transfer factor for carbon monoxide (40%), fatigue (31%), hypothyroidism (30%), and infertility (16%).

Conclusions: Results of this study offer indications about how long after the initial treatment excess deaths from causes other than HL begin to occur. However, challenges remain, namely establishing the optimal time to begin screening for potential late complications and developing better surveillance guidelines. Further work is needed to identify risk factors that may predict specific late effects.
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http://dx.doi.org/10.1016/j.clml.2020.03.006DOI Listing
August 2020

STAT3, tumor microenvironment, and microvessel density in diffuse large B cell lymphomas.

Leuk Lymphoma 2020 03 17;61(3):567-574. Epub 2019 Oct 17.

Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy.

Constitutively activated STAT3 is correlated with more advanced clinical stage and overall poor survival of diffuse large B-cell lymphoma (DLBCL). The aim of this study was to evaluate STAT3 and Ki67 tumor cell expression, inflammatory cell infiltration, microvascular density in DLBCL bioptic specimens. RNA-scope showed that activated B cell (ABC) tissue samples contained a significant higher number of STAT3+ cells as compared to germinal center B (GCB) tissue samples. Immunohistochemical analysis showed a significant increased levels of CD3, CD8, CD68, CD163, CD34, and Ki67 positive cells in ABC patients. A positive correlation between STAT3 and CD3, CD8, CD68, and CD163 was evidenced in ABC group. In ABC group, we found also a positive correlation between CD8 and CD34 and a positive correlation between Ki67 and, CD68, and CD163. These data indicate that in ABC-as compared to GCB-DLBCL, a higher STAT3 expression is associated with a higher CD163+ TAM and CD8+ cell infiltration which induces a strong angiogenic response.
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http://dx.doi.org/10.1080/10428194.2019.1678154DOI Listing
March 2020

Pregnancy rate and outcome of pregnancies in long-term survivors of Hodgkin's lymphoma.

Ann Hematol 2019 Aug 17;98(8):1947-1952. Epub 2019 Apr 17.

Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy.

Thanks to the increased number of young survivors of Hodgkin's lymphoma (HL), management of the pregnancies of women who have a history of exposure to chemotherapies and radiation therapy is becoming increasingly common. Many patients and clinicians are worried that pregnancy after the diagnosis of HL may increase the risk of relapse, despite a lack of empirical evidence to support such concerns. In the present study, we included 89 women diagnosed with HL between 2006 and 2015 under the age of 50 years, who were in complete remission and alive without relapse > 1 year after treatment. We determined the pregnancy rate, time to pregnancy, and the disease-free survival. We found no evidence of significant impairment of the fertility of female HL long-term survivors and no evidence that a pregnancy increases the relapse rate among women in remission from HL. Survivors of HL need to consider a range of factors when deciding on future reproduction.
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http://dx.doi.org/10.1007/s00277-019-03684-0DOI Listing
August 2019

Lenalidomide in Pretreated Patients with Diffuse Large B-Cell Lymphoma: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice.

Oncologist 2019 09 2;24(9):1246-1252. Epub 2019 Apr 2.

Institute of Hematology, University of Bologna, Bologna, Italy

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma subtype, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis with currently available treatments. Lenalidomide is available in Italy for patients with rrDLBCL based on a local disposition of the Italian Drug Agency.

Subjects, Materials, And Methods: An observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use for rrDLBCL in real practice.

Results: One hundred fifty-three patients received lenalidomide for 21/28 days with a median of four cycles. At the end of therapy, there were 36 complete responses (23.5%) and 9 partial responses with an overall response rate (ORR) of 29.4%. In the elderly (>65 years) subset, the ORR was 33.6%. With a median follow-up of 36 months, median overall survival was reached at 12 months and median disease-free survival was not reached at 62 months. At the latest available follow-up, 29 patients are still in response out of therapy. Median progression-free survivals differ significantly according to age (2.5 months vs. 9.5 in the younger vs. elderly group, respectively) and to disease status at the latest previous therapy (15 months for relapsed patients vs. 3.5 for refractory subjects). Toxicities were manageable, even if 30 of them led to an early drug discontinuation.

Conclusion: Lenalidomide therapy for patients with rrDLBCL is effective and tolerable even in a real-life context, especially for elderly patients.

Implications For Practice: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis, reflected by the remarkably short life expectancy of 12 months with currently available treatments. The rrDLBCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for patients with rrDLBCL is effective and tolerable even in a real-life context, especially for elderly patients.
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http://dx.doi.org/10.1634/theoncologist.2018-0603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738312PMC
September 2019

Brentuximab vedotin prior to allogeneic stem cell transplantation increases survival in chemorefractory Hodgkin's lymphoma patients.

Ann Hematol 2019 Jun 14;98(6):1449-1455. Epub 2019 Mar 14.

Haematology, "Policlinico" Hospital, Bari, Italy.

This study reports a retrospective multicenter experience by the Rete Ematologica Pugliese (REP) over the past 16 years, aiming to compare the patients characteristics and outcomes of 21 brentuximab vedotin (BV)-pre-treated patients to 51 patients who received reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT) without prior BV. In total, 72 patients with classical Hodgkin's lymphomas who received allogeneic SCT were retrospectively studied. Prior use of BV had no effect on either engraftment or the incidence and severity of acute graft versus host disease (GVHD). Indeed, a lower incidence of chronic GVHD was observed in the BV group, with a 43% cumulative incidence at 3 years versus 47% in the no BV group, although this was not statistically significant. Despite the low incidence of chronic GVHD, survival was not worse in the BV-treated group: 3-year progression-free survival (PFS) was 53%, 3-year overall survival (OS) was 62%, 3-year non-relapse mortality (NRM) was 24%. In the no BV group, the 3-year PFS was 33%, 3-year OS was 44%, and 3-year NRM was 14%. In chemorefractory patients at the time of transplant, we found a statistically significant difference in PFS between the BV and no BV groups (51% vs. 10%, p = 0.013).
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http://dx.doi.org/10.1007/s00277-019-03662-6DOI Listing
June 2019

STAT-3 RNAscope Determination in Human Diffuse Large B-Cell Lymphoma.

Transl Oncol 2019 Mar 9;12(3):545-549. Epub 2019 Jan 9.

Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy. Electronic address:

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription with many important functions, including regulation of cell proliferation, differentiation, survival, angiogenesis, and immune response.

Materials And Methods: In this study, we have compared by means of RNAscope technology STAT3 RNA expression in human DLBCL in a selected group of activated B-cell-like DLBCL (ABC-DLBCL) patients with another group of germinal center B-cell-like DLBCL (GBC-DLBCL) patients.

Results: The results have shown that ABC DLBCL tissue samples contained a significantly higher number of STAT3-positive cells as compared with GCB tissue samples. Moreover, by means of confocal immunofluorescence analysis, we have observed that tumor vessels in ABC samples appeared lined by endothelial cells expressing both FVIII and STAT3 signals, while in GCB samples, only few vessels coexpressed FVIII and STAT3.

Conclusions: These data confirm other reports showing that STAT3 is highly expressed and activated in ABC-DLBCL and our previously published data demonstrating that, in primary central nervous system lymphoma, tumor vessels appeared lined by endothelial cells expressing both FVIII and STAT3.
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http://dx.doi.org/10.1016/j.tranon.2018.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370997PMC
March 2019

Bone Involvement in Hodgkin's Lymphoma: Clinical Features and Outcome.

Acta Haematol 2018 9;140(3):178-182. Epub 2018 Oct 9.

Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy.

Hodgkin's lymphoma (HL) is now a highly curable disease, with an improving 5-year survival rate that has now reached 86%. At the time of presentation, HL is usually almost entirely confined to the lymph nodes. We performed a retrospective single-institution study of 384 cases with a median follow-up of 44 months, with the aim of identifying clinical and radiological characteristics and outcomes of patients with bone HL; 32 patients (8%) had primary bone involvement, always with concurrent nodal disease. These included 22 men (69%) and 10 women (31%) with the median age as 41 years. Advanced stages and nodular sclerosis histology prevailed among the subgroup. Radiographic features of bone HL are not specific but indicate a destructive malignant process with osteosclerosis and/or osteolysis. With current chemotherapeutic regimens, the long-term prognosis of patients with osseous HL appears good. The presence of bone lesions in HL should not be interpreted as implying a worse prognosis than without bone involvement.
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http://dx.doi.org/10.1159/000490489DOI Listing
June 2019

Outcomes of Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Hodgkin Lymphomas: A Retrospective Multicenter Experience by the Rete Ematologica Pugliese (REP).

Clin Lymphoma Myeloma Leuk 2019 01 12;19(1):35-40. Epub 2018 Sep 12.

Haematology, "G.Panico" Hospital, Tricase (LE), Italy.

Background: Hodgkin lymphoma (HL) is a potentially curable disease, and modern therapy is expected to successfully cure more than 80% of the patients. However, patients progressing after intensive treatments, such as autologous stem cell transplantation (SCT), have a very poor outcome. Allogeneic SCT offers the only strategy with a curative potential for these patients. This study reports a retrospective multicenter experience of the Rete Ematologica Pugliese (REP) over the past 17 years, aiming to define the impact of each patient's disease and transplant-related characteristics on outcomes.

Patients And Methods: We retrospectively studied 72 patients with HL who received allogeneic SCT from 2000 to 2017. At the time of allogeneic SCT, 33 (46%) patients had chemosensitive disease, and 39 (54%) were chemo-refractory. All patients received reduced-intensity conditioning, 50% received grafts from a matched sibling donor, and 50% from a matched-unrelated donor.

Results: With a median follow-up of 48 months (range, 3-195 months), 30 patients are alive, and 42 have died. The Kaplan-Meier estimates of overall survival and progression-free survival at 5 years were 35% and 34%, respectively. Following transplantation, 12 (17%) patients died of non-relapse mortality at a median of 90 days (range, 1 day-20 months). The causes of death included infection (n = 7), graft-versus-host disease (n = 3), and multi-organ failure (n = 2).

Conclusions: Allogeneic SCT results extend survival in selected patients with relapsed/refractory HL, showing low treatment-related mortality. Patients with active disease at the time of allogeneic transplantation have poor outcomes. Allogeneic SCT may be an effective salvage strategy for patients who relapse after an autologous SCT.
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http://dx.doi.org/10.1016/j.clml.2018.08.012DOI Listing
January 2019

Brentuximab vedotin as salvage treatment in Hodgkin lymphoma naïve transplant patients or failing ASCT: the real life experience of Rete Ematologica Pugliese (REP).

Ann Hematol 2018 Oct 27;97(10):1817-1824. Epub 2018 Jul 27.

Department of Hematology, Hospital University Riuniti, Foggia, Italy.

Brentuximab vedotin (BV) shows a high overall response rate (ORR) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) after autologous transplant (ASCT). The aim of this multicenter study, conducted in nine Hematology Departments of Rete Ematologica Pugliese, was to retrospectively evaluate the efficacy and safety of BV as salvage therapy and as bridge regimen to ASCT or allogeneic transplant (alloSCT) in R/R HL patients. Seventy patients received BV. Forty-five patients (64%) were treated with BV as bridge to transplant:16 (23%) patients as bridge to ASCT and 29 (41%) as bridge to alloSCT. Twenty-five patients (36%), not eligible for transplant, received BV as salvage treatment. The ORR was 59% (CR 26%). The ORR in transplant naïve patients was 75% (CR 31%). In patients treated with BV as bridge to alloSCT, the ORR was 62% (CR 24%). In a multivariate analysis, the ORR was lower in refractory patients (p < 0.005). The 2y-OS was 70%. The median PFS was 17 months. Ten of the 16 (63%) naïve-transplant patients received ASCT, with 50% in CR before ASCT. In the 29 patients treated with BV as bridge to alloSCT, 28 (97%) proceeded to alloSCT with 25% in CR prior to alloSCT. The most common adverse events were peripheral neuropathy (50%), neutropenia (29%) and anemia (12%). These data suggest that BV is well tolerated and very effective in R/R HL, producing a substantial level of CR. BV may also be a key therapeutic agent to achieve good disease control before transplant, improving post- transplant outcomes, also in refractory and heavily pretreated patients, without significant overlapping toxicities with prior therapies.
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http://dx.doi.org/10.1007/s00277-018-3379-5DOI Listing
October 2018

Extralymphatic Disease Is an Independent Prognostic Factor in Hodgkin Lymphoma.

Clin Lymphoma Myeloma Leuk 2018 06 14;18(6):e261-e266. Epub 2018 Apr 14.

Hematology Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, Bari, Italy.

Purpose: To identify the characteristics and outcomes of patients with extralymphatic Hodgkin lymphoma.

Patients And Methods: We performed a retrospective single-institution study of 341 cases comprising 207 male (61%) and 134 female (39%) subjects with a median follow-up of 44 months.

Results: Fifty-five patients (16%) had extralymphatic disease. The sites were lung in 29 patients (44%), bone in 22 (33%), liver in 12 (18%), and kidney in 3 (5%). In 46 patients (86%) only one organ was involved, while in 7 patients (13%) extralymphatic disease was present in 2 sites and in 2 patients (3%) in 3 sites. The extralymphatic disease group had a poorer prognosis than the lymphatic disease group. Complete remission rates in the extralymphatic and lymphatic patient subsets were 65% and 82% (P = .043), respectively.

Conclusion: Extralymphatic disease in patients with Hodgkin lymphoma is a rare occurrence (16%) associated with poor clinical outcome.
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http://dx.doi.org/10.1016/j.clml.2018.04.001DOI Listing
June 2018

Computer-driven quantitative image analysis in the assessment of tumor cell and T cell features in diffuse large B cell lymphomas.

Ann Hematol 2018 Apr 23;97(4):663-668. Epub 2018 Jan 23.

Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, Bari, Italy.

Diffuse large B cell lymphoma (DLBCL) is recognized as the most common non-Hodgkin lymphoma subtype. Advanced high-resolution digital scans of pathology slides have enabled the development of computer-based image analysis algorithms that may assist pathologists in quantifying immunohistochemical stains. In this retrospective study, we reviewed data from 29 patients affected by DLBCL. In order to evaluate the number of tumor cells and microenvironment T cells, we performed an analysis of CD20, Ki67, and CD3 counts, assessed with the Positive Pixel Count algorithm embedded in the Aperio ImageScope software. A lower tumor cell count was observed in patients with a non-germinal center immunophenotype, high LDH, splenomegaly and an IPI ≥ 3. A lower number of CD3 was observed in patients with bulky disease, an IPI ≥ 3 and disease stage 3-4. Overall, these data confirm that quantitative analysis of the tumor cells and of the tumor microenvironment by means of computer-driven quantitative image analysis may add new information in DLBCL diagnosis.
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http://dx.doi.org/10.1007/s00277-017-3212-6DOI Listing
April 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

Risk of lymphoma subtypes by occupational exposure in Southern Italy.

J Occup Med Toxicol 2017 23;12:31. Epub 2017 Nov 23.

Department of Public Health, Clinical & Molecular Medicine, Occupational Health Section, University of Cagliari, 09100 Cagliari, Italy.

Background: Occupational exposure is known to play a role in the aetiology of lymphomas. The aim of the present work was to explore the occupational risk of the major B-cell lymphoma subtypes using a case-control study design.

Methods: From 2009 to 2014, we recruited 158 lymphoma cases and 76 controls in the provinces of Bari and Taranto (Apulia, Southern Italy). A retrospective assessment of occupational exposure based on complete work histories and the Carcinogen Exposure (CAREX) job-exposure matrix was performed.

Results: After adjusting for major confounding factors, farmers showed an increased risk of diffuse large B-cell lymphoma (DLBCL) [odds ratio (OR) = 10.9 (2.3-51.6)] and multiple myeloma (MM) [OR = 16.5 (1.4-195.7)]; exposure to the fungicide Captafol was significantly associated with risk of non-Hodgkin lymphoma (NHL) [OR = 2.6 (1.1-8.2)], particularly with the risk of DLBCL [OR = 5.3 (1.6-17.3)].

Conclusions: Agricultural activity seems to be a risk factor for developing lymphoma subtypes, particularly DLBCL, in the provinces of Bari and Taranto (Apulia Region, Southern Italy). Exposure to the pesticides Captafol, Paraquat and Radon might be implicated.

Trial Registration: Protocol number UNIBA 2207WEJLZB_004 registered 22/09/2008.
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http://dx.doi.org/10.1186/s12995-017-0177-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701427PMC
November 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

Romidepsin in relapsed/refractory T-cell lymphomas: Italian experience and results of a named patient program.

Leuk Lymphoma 2016 10 17;57(10):2370-4. Epub 2016 Feb 17.

a Institute of Hematology "L. E A. Seràgnoli", University of Bologna , Bologna , Italy ;

Clinical trial results indicate that romidepsin, a histone deacetylase inhibitor, is a promising treatment in relapsed/refractory T-cell lymphomas (TCLs). This retrospective multicenter study was conducted in patients with relapsed/refractory TCL treated with romidepsin monotherapy through a Named Patient Program (NPP) in Italy. Principal endpoints were overall response rate (ORR), safety, and overall survival (OS). The ORR in 33 evaluable patients was 24.2% with an ORR in the cutaneous TCL of 35.7%. Global OS was 39.3% at 30 months. There were not any specific differences on hematological and extrahematological adverse events. Data from patients treated with romidepsin outside a controlled clinical trial give additional information about the clinical use, efficacy, and toxicity of the drug given to relapsed or refractory TCL patients in a real life context as TCLs are rare diseases and more information is needed. These findings suggest that romidepsin is effective and safe for heavily pretreated TCL patients.
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http://dx.doi.org/10.3109/10428194.2015.1137292DOI Listing
October 2016

T cells, mast cells and microvascular density in diffuse large B cell lymphoma.

Clin Exp Med 2016 Aug 10;16(3):301-6. Epub 2015 May 10.

Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Piazza Giulio Cesare, 11, 70124, Bari, Italy.

Diffuse large B cell lymphoma (DLBCL) is recognized as the most common form of non-Hodgkin lymphoma (NHL), accounting for about 40 % of all cases of NHL. Among the cellular components of the tumor inflammatory infiltrate, T cells and mast cells have been demonstrated to be correlated with tumor angiogenesis. In this report, we have investigated CD3 and tryptase expression and their relationship with microvascular density (MVD) in DLBCL patients. Moreover, we determined the significance of CD3 expression in bulky and non-bulky disease. CD3 expression was significantly lower in bulky disease patients when compared to non-bulky ones. CD3 showed a positive correlation with tryptase and MVD, while multiple regression analysis efficaciously predicted MVD depending on CD3 and tryptase as predictors, supporting a complex interplay between these cells in sustaining tumor angiogenesis in DLBCL patients.
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http://dx.doi.org/10.1007/s10238-015-0354-5DOI Listing
August 2016

Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a retrospective analysis.

Leuk Res 2014 Dec 22;38(12):1446-50. Epub 2014 Oct 22.

Hematology and Bone Marrow Transplantation Unit, Antonio Perrino Hospital, Brindisi, Italy.

For patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are not eligible for intensive chemotherapy because of comorbidities, advanced age, or relapse after heavy salvage regimens, treatment options are very limited and prognosis is poor. We retrospectively analyzed 29 patients with relapsed/refractory DLBCL treated with combination bendamustine plus rituximab (BR) between July 2010 and January 2014 to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and treatment safety. Twenty-eight patients were available for this analysis. ORR was 50% (14 patients), with 39.3% CR (11 patients), and 10.7% PR (3 patients). SD was reported in 2 patients (7.2%) and PD in 12 patients (42.8%). At the median follow up of 8 months (range 1-37.4 months), the median PFS was 8 months for all patients (95% CI 5.5-26.6). The median DOR was 24.7 months (95% CI 3.2-24.7). Grade 3/4 toxicity observed included hematologic events: lymphopenia (42.8%), neutropenia (32.1%), anemia (17.2%), and thrombocytopenia (14.2%). BR can be considered to have a role in the treatment of patients with relapsed/refractory DLBCL with limited therapeutic options, in that it can induce long-term remission in some patients with an acceptable toxicity profile.
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http://dx.doi.org/10.1016/j.leukres.2014.10.001DOI Listing
December 2014

Microvascular density, CD68 and tryptase expression in human diffuse large B-cell lymphoma.

Leuk Res 2014 Nov 22;38(11):1374-7. Epub 2014 Sep 22.

Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy; National Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address:

Diffuse Large B-cell Lymphoma (DLBCL) is the most common form of Non-Hodgkin lymphoma characterized by clinical and biological heterogeneity attributable both to the tumor cells and the complex tumor-microenvironment surrounding them. Tumor-associated macrophages (TAMs) and mast cells are two major components of the tumor inflammatory infiltrate with a definite role in enhancing tumor angiogenesis. In this study, we have investigated CD68 and tryptase expression and their relationship with microvascular density (MVD) in chemo-resistant and chemosensitive patients affected by DLBCL. CD68 and tryptase expression as well as MVD were increased in chemo-resistant patients when compared with chemosensitive patients. Tryptase expression showed a positive correlation with MVD, supporting a role for mast cell in DLBCL tumor angiogenesis, while CD68 correlation with MVD was not significant, indicating a different role for TAMs than angiogenesis in DLBCL.
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http://dx.doi.org/10.1016/j.leukres.2014.09.007DOI Listing
November 2014

CT-guided needle biopsy performed with modified coaxial technique in patients with refractory or recurrent lymphomas.

Ann Hematol 2014 Sep 24;93(9):1559-64. Epub 2014 Apr 24.

Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari Medical School, Bari, Italy,

The aim of this study was to evaluate the role of computed tomography (CT)-guided core needle biopsy (CNB) performed by modified coaxial technique as an alternative tool to surgical biopsy in patients with refractory or recurrent lymphomas. Between May 2005 and May 2012, 57 CT-guided CNB of deep lesions were performed in patients with a previous diagnosis of lymphoma and suspected for refractory or recurrent disease. A modified coaxial technique was used in all cases and multiple samples were obtained for histological and immunohistochemical studies. A diagnosis of lymphoma with specification of subtype according to the World Health Organization (WHO) classification was established in 30/57 cases (52.6 %). The previous diagnosis of lymphoma was confirmed in 27/57 patients (47.4 %), whereas histological progression in 3/57 (5.3 %) and other malignant neoplasms in 17/57 (29.8 %) were found. Lymphoma without subtype specification was diagnosed in 6/57 (10.5 %), and no conclusive diagnosis could be established in 4/57 cases (7 %). Overall diagnostic accuracy was 82.5 %. In patients with a final diagnosis of malignant lymphoma, accuracy was 75 %. No complications occurred. Percutaneous CT-guided CNB is a safe, effective and reliable tool in the management of patients with refractory or recurrent lymphomas without superficial lymphadenopathy and can be considered as alternative to surgical sampling.
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http://dx.doi.org/10.1007/s00277-014-2078-0DOI Listing
September 2014

Computed tomography-guided needle biopsy performed with modified coaxial technique in patients with suspected lymphoma.

Leuk Lymphoma 2014 Aug 28;55(8):1949-51. Epub 2014 Jan 28.

Hematology Section, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari Medical School , Bari , Italy.

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http://dx.doi.org/10.3109/10428194.2013.867488DOI Listing
August 2014

Peripheral blood CD4/CD19 cell ratio is an independent prognostic factor in classical Hodgkin lymphoma.

Leuk Lymphoma 2014 Jul 4;55(7):1596-601. Epub 2014 Feb 4.

Hematology Section, Department of Emergency and Organ Transplantation, University of Bari Medical School , Bari , Italy.

Classical Hodgkin lymphoma (cHL) is characterized by the presence of tumoral cells in a rich background of T and B cells, macrophages and other inflammatory cells. The contribution of these non-tumoral cells to the pathogenesis of HL is still poorly understood. In our study we evaluated the prognostic significance of peripheral blood B, T and natural killer (NK) cells at diagnosis in 118 immunocompetent patients with cHL treated at our institution between January 2006 and December 2010. Fifty-four (46%) were male and 64 (54%) female. Median age at diagnosis was 33 years (range 15-82), and 71 patients (60%) presented an advanced stage (IIB-IV), 54 (46%) had bulky disease and 55 (47%) presented B symptoms. At the end of treatment, 94 patients (80%) had a complete response (CR) and 24 (20%) had a partial response. After a median follow-up of 54 months, 18 patients (15%) had relapsed. The variables that had a negative impact on progression-free survival (PFS) at univariate analysis were advanced stage, bone marrow involvement, International Prognostic Score (IPS) ≥ 3, positive interim positron emission tomography (int-PET), NK cells < 200/μL, CD19 cells < 85/μL, CD3/CD19 ratio ≥ 13 and CD4/CD19 ratio ≥ 10. At multivariate analysis, advanced stage, positive int-PET and CD4/CD19 ratio ≥ 10 were independent prognostic factors of PFS. New biological markers could be predictive of the response to treatment and survival in cHL. A CD4/CD19 ratio ≥ 10 seems to be associated with a worse outcome.
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http://dx.doi.org/10.3109/10428194.2013.854889DOI Listing
July 2014

Outcome of allogeneic peripheral blood stem cell transplantation by donor graft CD3+/Tregs ratio: a single-center experience.

Biol Blood Marrow Transplant 2013 Mar 27;19(3):495-9. Epub 2012 Nov 27.

Hematology Section, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11,Bari, Italy.

The therapeutic efficacy of allogeneic peripheral blood stem cell transplantation (PBSCT) for hematological malignancies relies largely on the graft-versus-leukemia (GVL) effects exerted by the donor CD3 cells, but there is a risk of onset of uncontrolled graft-versus-host disease (GVHD). Regulatory T cells (Tregs) (CD4+CD25(high) Foxp3+) are believed to maintain tolerance and to inhibit acute GVHD (aGVHD) after allogeneic PBSCT. Nevertheless, when looking at post-allotransplantation patient outcomes, although the impact of aGVHD on survival is amply documented, so far there is no evidence that the donor graft CD3/Tregs ratio may affect overall survival (OS), nonrelapse mortality (NRM), disease-free survival (DFS), and relapse rates. Our aim was to study the possible impact of the gCD3/Tregs ratio on survival after myeloablative allogeneic PBSCT. We analyzed 74 consecutive patients diagnosed with acute myeloid leukemia (n = 62), acute lymphoblastic leukemia (n = 10), and chronic myeloid leukemia (n = 2) who underwent transplantation with unmanipulated PBSCs from a human leukocyte antigen-identical related donor (n = 48) or a human leukocyte antigen-identical unrelated donor (n = 26). Patients were subdivided into a high gCD3/Tregs ratio (≥36) group (HR group, n = 30) and a low gCD3/Tregs ratio (<36) group (LR group, n = 44). The OS, DFS, NRM, and relapse rates at 3 years were 53%, 51%, 29%, and 34%, respectively. Comparing the LR and HR groups, a statistically significant difference was demonstrated for the 3-year OS, DFS, and NRM rates (65% vs 31%, P = .0001; 67 versus 26%, P = .0001; 5% versus 71%, P < .0001, respectively) but not for relapse (30% vs 25%, P = ns). By multivariate analysis, LR significantly predicted better OS (P = .019), DFS (P = .003), and NRM (P = .05), whereas there was no statistically significant association between LR and relapse (P = .155). Overall, our data may suggest that LR preserves GVL effects but is also protective against aGVHD in allotransplantation patients.
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http://dx.doi.org/10.1016/j.bbmt.2012.11.015DOI Listing
March 2013

CD3+/Tregs ratio in donor grafts is linked to acute graft-versus-host disease and immunologic recovery after allogeneic peripheral blood stem cell transplantation.

Biol Blood Marrow Transplant 2012 Jun 4;18(6):887-93. Epub 2011 Nov 4.

Hematology Section, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Graft-versus-host disease (GVHD), mediated by mature T cells present in the donor graft, remains a major complication after allogeneic peripheral blood stem cell transplantation (PBSCT). Regulatory T cells (Tregs) (CD4(+)CD25(high)Foxp3(+)) are believed to maintain tolerance and to inhibit GVHD after allogeneic PBSCT (allo-PBSCT). In this study, we analyzed the graft CD3(+)/Tregs ratio (gCD3/Tregs R) and evaluated its impact on acute GVHD (aGVHD) and immunologic recovery after myeloablative allo-PBSCT. We analyzed 65 consecutive patients who underwent transplantation with unmanipulated peripheral blood stem cells from an HLA-identical related donor (n = 45) or an HLA-identical unrelated donor (n = 20). The median CD3(+) and Tregs doses administered were 256 × 10(6)/kg of body weight (range, 67-550 × 10(6)/kg) and 12 × 10(6)/kg (range, 2-21 × 10(6)/kg), respectively; the median gCD3/Tregs R value was 18 (range, 8-250). Patients were subdivided into a high gCD3/Tregs R (≥36) group (HR; n = 26) and a low gCD3/Tregs R (<36) group (LR; n = 39). The incidence of aGVHD (grade II-IV) was lower in the LR group compared with the HR group (8/39 [20%] versus 22/26 [84%]; P < .001). Median cytomegalovirus-specific CD8(+) T lymphocytes were significantly higher in the LR group than in the HR group at 1 month (2 cells/μL versus 0 cells/μL; P < .001), 2 months (6 cells/μL versus 1 cell/μL; P < .001), and 3 months (15 cells/μL versus 3 cells/μL; P < .001) months. Moreover, cytomegalovirus infection/disease was observed in 15% of patients in the LR group versus 69% of patients in the HR group (P < .001). At multivariate logistic regression, gCD3/Tregs R was correlated both with aGVHD (odds ratio, 2.50; 95% confidence interval, 1.30-4.50; P = .05) and with cytomegalovirus infection/disease (odds ratio, 2.35; 95% confidence interval, 0.9-5.00; P = .05). Taken together, our data may suggest that the balance in favor of graft Tregs content is able to mediate protective effects against aGVHD and to maintain an optimal microenviroment for the reconstitution of functional immunity.
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http://dx.doi.org/10.1016/j.bbmt.2011.10.039DOI Listing
June 2012

BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients.

Blood 2011 Sep 3;118(12):3419-25. Epub 2011 Aug 3.

Hematology and Stem Cell Transplant Center, Marche Nord Hospital, Pesaro, Italy.

We designed a phase 1-2 study to evaluate the safety and the efficacy of increasing doses of bendamustine (160 mg/m², 180 mg/m², and 200 mg/m² given on days -7 and -6) coupled with fixed doses of etoposide, cytarabine, and melphalan (BeEAM regimen) as the conditioning regimen to autologous stem cell transplantation for resistant/relapsed lymphoma patients. Forty-three patients (median age, 47 years) with non-Hodgkin (n = 28) or Hodgkin (n = 15) lymphoma were consecutively treated. Nine patients entered the phase 1 study; no patients experienced a dose-limiting toxicity. Thirty-four additional patients were then treated in the phase 2. A median number of 6 × 10⁶ CD34(+) cells/kg (range, 2.4-15.5) were reinfused. All patients engrafted, with a median time to absolute neutrophil count > 0.5 × 10⁹/L of 10 days. The 100-day transplantation-related mortality was 0%. After a median follow-up of 18 months, 35 of 43 patients (81%) are in complete remission, whereas 6 of 43 relapsed and 2 of 43 did not respond. Disease type (non-Hodgkin lymphomas vs Hodgkin disease) and disease status at transplantation (chemosensitive vs chemoresistant) significantly influenced DFS (P = .01; P = .007). Remarkably, 4 of 43 (9%) patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell transplantation. In conclusion, the new BeEAM regimen is safe and effective for heavily pretreated lymphoma patients. The study was registered at European Medicines Agency (EudraCT number 2008-002736-15).
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http://dx.doi.org/10.1182/blood-2011-04-351924DOI Listing
September 2011

High Ki67 index and bulky disease remain significant adverse prognostic factors in patients with diffuse large B cell lymphoma before and after the introduction of rituximab.

Acta Haematol 2011 24;126(1):44-51. Epub 2011 Mar 24.

Section of Hematology, Department of Pathology and Hematology, University of Bari, Bari, Italy.

The aim of this study was to evaluate the impact of clinical variables and biologic features on response rate (RR), overall survival (OS) and progression-free survival (PFS) in 111 patients with de novo diffuse large B cell lymphoma (DLBCL). Fifty-three patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and 58 patients were treated with R-CHOP (rituximab + CHOP). The variables predictive of RR in the CHOP group were B symptoms, age, clinical stage, bone marrow involvement, bulky disease, International Prognostic Index (IPI) and Bcl-2; in the R-CHOP group, these variables were bulky disease, bone marrow involvement, IPI and Ki67 expression >80%. Multivariate analysis showed that in patients treated with CHOP, the independent prognostic factors associated with PFS were age, bulky disease, IPI and Bcl-2 and those associated with OS were performance status, clinical stage, IPI and bone marrow involvement. In contrast, in patients treated with R-CHOP, the variable shown by multivariate analysis to be an independent prognostic factor associated with PFS was bulky disease, whereas Ki67 expression >80% was associated with OS and PFS. Our data show that a high Ki67 expression and bulky disease could represent possible predictive factors of poor prognosis, which would help to identify a high-risk subgroup of newly diagnosed DLBCL.
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http://dx.doi.org/10.1159/000324206DOI Listing
August 2011