Le Cellule Endoteliali Circolanti nelle Neoplasie Ematologiche

Accumulating evidences showed that bone marrow endothelial cells play a key role in neoplastic angiogenesis. In neoplastic progression they are more circulating endothelial cells than in remission or in health volunteers. Some circulating endothelial cells are characterized by a mature well differentiated phenotype while other entothelial cell show antigens of progenitor cells indicating that these circulating endothelial progenitor cells (EPC) might be inside in angiogenic tissues and take active part in angiogenesis of new vessels, in particular in neoplasia. It is demonstrated that circulating endothelial cells (CEC) are characterized by a limited proliferating capacity, while EPC, coming from bone marrow, have got a elevated proliferating capacity. Bone marrow endothelial cells can contribute to neoplastic angiogenesis. Increasing evidences suggest that angiogenesis is involved in pathology of hematological malignant diseases included Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL). Taken together these findings suggest that angiogenesis plays a role in progression of oncohematological disease by synthesis of pro angiogenetic factors and neoplastic cells, mimicking a endothelial activity, taking part in synthesis of new vascular net-works by a autocrine loop, promoting leukemic progression. To clarify whether CEC in MM, in AML and in CLL originate from cancer, we evaluated 8 patients with deletion of 13q (5 with MM and 3 with Monoclonal Uncertain Gammopathy), 7 patients with AML and 74 patients with CLL with known cytogenetic abnormalities; we extracted CEC by immunomagnetic sorting from circulating cells and we characterized CEC by immunophenotype analysis and by Fluorescence In Situ Hybridization (FISH). In CLL we performed also a gene expression profile of 12 samples of CEC from patients with CLL using microarrays of 33.000 genes and comparing the results with gene expression profile of 2 health volunteers. The findings of these studies have shown that CEC levels both in MM and in AML and in CLL are increased compared to CEC levels in health volunteers or to CEC levels of patients in remission. Entothelial cell are in part endothelial progenitor cell (EPC) characterized by CD133 surface expression, a early endothelial marker lost during maturation of endothelial cell. FISH analysis highlighted that endothelial cells are positive for know cytogenetic abnormalities of MM, AML and CLL. Gene expression profiling in CEC of CLL has showed a well defined genetic pattern whose genes are involved in neoplastic progression and in neo-vasulogenesis identifying a cellular population co-expressing endothelial and lymphatic genes (CD19, von Willebrand Factor, VEGFR2). In conclusion our findings suggest that in MM, AML and in CLL, CEC are increased, are tumor related, show a EPC immuno phenotype and have a gene expression profile not only of endothelial cells but also of hematological malignance; in particular we find a increased expression of genes involved in proliferation, progression and angiogenesis. CEC can contribute to neoplastic angiogenesis and to progression acting as a sort bridgehead on which more numerous and possibly more specialized and functional active non clonal bone marrow derived EPCs could actively differentiate in mature vessels and contribute to tumor neovascularization and spreading. The results presented in this study, by showing a subset of CEC harbors cytogenetic abnormalities, suggest several theories. First, ECs and hematologic malignancies may derive from the same multipotent hemangioblast precursor cell; alternatively we may advocate theory about dedifferentiation, trans differentiation or theory of cellular fusion even if the last seems unlikely. Findings about CEC might play a key role non only in understanding of hematological malignancies biological specific features of but also in translation of new anti-angiogenic therapies to the clinic

Hepatitis C virus- related cryoglobulinemic vasculitis: A review of the role of the new direct antiviral agents (DAAs) therapy

Hepatitis C virus (HCV) infection affects about 70 million people worldwide. HCV is responsible for both hepatitis and extra-hepatic manifestations. Chronic infection has been shown to develop in about 70% of cases and can progress to cirrhosis or hepatocellular carcinoma. Ten percent of HCV patients may develop extra-hepatic manifestations, including mixed cryoglobulinemia (MC) and non-Hodgkin lymphomas. Many studies have demonstrated that, after antiviral therapy, MC can disappear along with HCV eradication. After the introduction of the new direct antiviral agents (DAAs), the combination of pegylated interferon and ribavirin has been abandoned. Several studies on new DAAs have reported remarkable 90% to 100% eradication rates, regardless of HCV genotype. Treatment with DAAs has comparable efficacy on viral eradication in patients with MC, but definite clinical improvements of vasculitis can be observed only in half the patients. On the contrary, the regression of renal disease and lympho-proliferative disorders, induced by HCV, appears to have a lower remission rate after viral eradication with DAAs and most cases need immunosuppressive treatments. In HCV related CV, the main clinical goal must be early eradication of HCV, to avoid organ complication and manifestation of lympho-proliferative diseases. This review focuses on the role of DAAs in treatment of HCV-related cryoglobulinemic vasculitis

Efficacy and safety of venetoclax plus hypomethylating agents in relapsed/refractory acute myeloid leukemia: a multicenter real-life experience

Venetoclax (VEN) has been shown to play a synergistic effect in combination with hypomethylating agents (HMAs) in the frontline treatment of acute myeloid leukemia (AML). However, the potential role of this therapy in the relapsed/refractory (R/R) AML setting, still needs to be further unveiled. The aim of the current study was to retrospectively outline the safety profile, response and survival outcomes of R/R AML patients treated with VEN in association with HMAs. Clinical, biological, and molecular data were collected from 57 patients with R/R AML treated with VEN combined with azacitidine or decitabine between 2018 and 2023. The median age of patients was 63 years, 38 (66.7%) received treatment for relapsed disease while 19 (33.3%) for refractory disease, 5 (8.7%) were treated for molecular relapse. A consistent proportion of the cohort was represented by patients with unfavorable prognostic factors such as complex karyotype (36.8%), secondary AML (29.8%), previous exposure to HMAs (38.6%), and relapse after allogeneic stem cell transplant (22.8%). A total of 14 patients achieved CR (24.6%), 3 (5.3%) CRi, 3 (5.3%) MLFS, and 3 (5.3%) PR, accounting for an ORR of 40.4%. The CR/CRi rate was higher in the group treated with azacitidine than in the group treated with decitabine (37.8% vs. 15%). The median OS was 8.2 months, reaching 20.1 months among responding patients. VEN-HMAs treatment allowed to bridge to allogeneic stem cell transplantation 11 (23.9%) of eligible patients, for which a median OS of 19.8 months was shown. On multivariate analysis, ECOG performance status ≥2, complex karyotype and not proceeding to allogeneic stem cell transplantation after therapy with VEN-HMAs were the factors independently associated with shorter OS. Patients treated with the azacitidine rather than the decitabine containing regimen generally displayed a trend toward superior outcomes. The major toxicities were prolonged neutropenia and infections. In conclusion, this study showed how VEN-HMAs could represent an effective salvage therapy in patients with R/R AML, even among some of those patients harboring dismal prognostic features, with a good toxicity profile. Further prospective studies are thus warranted

Venetoclax in combination with hypomethylating agents in previously untreated patients with acute myeloid leukemia ineligible for intensive treatment: a real-life multicenter experience

The addition of venetoclax to hypomethylating agents (HMA-V) improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive treatment. The aim of our study was to confirm data reported in literature, in a real-life multicenter experience. We retrospectively evaluated 56 naive AML patients who received HMA-V at 8 different collaborating Hematology Units in the North-East of Italy, from September 2018 to October 2020. Patients received azacitidine or decitabine at standard dose, adding venetoclax starting from cycle 1-3. The median time-to-response was 2 cycles and composite complete remission rate (CCR) was 67.9%. Thirteen out of 38 responders (34.2%) relapsed, with a median response duration of 13.7 months. Transfusion independence (TI) was obtained in 27 (87.0%) and 28 (90.3%) out of 31 patients for red blood cells and platelets, respectively. Median OS was 12.3 months (95% CI, 8.1-16.5), and median PFS was 11.3 months (95% CI, 4.6-17.9). Cytogenetic risk was the only variable impacting on survival, while no differences were observed stratifying patients by age, bone marrow blasts, WHO classification or type of HMA. In conclusion, our real-life multicenter experience indicates that HMA-V treatment allows achieving good response rates in naive AML patients, ineligible for intensive chemotherapy

Efficacy and safety of pegylated interferon plus ribairin for the treatment of hepatitis C virus-positive cryoglobulinemic glomerulonephritis

Background: The most frequent form of renal involvement in patients with hepatitis C infection is cryoglobulinemic membrano-proliferative glomerulonephritis. Nonetheless, some reports indicate that the eradication of the hepatitis C virus may also lead to the remission of this renal disease. Methods: The virological, immunological and nephrological response to pegylated interferon \u3b1 plus ribavirin (48 weeks in patients infected with genotype 1, and 24 weeks for patients infected with genotypes 2 and 3) was evaluated retrospectively in 10 patients with cryoglobulinemic glomerulonephritis. Results: 6 patients obtained end of treatment virological response (60%); during follow-up, 2 relapsed, and 4 patients maintained a sustained virological response (40%). At the end of follow-up, three patients obtained a significant nephrological response and decrease in cryoglobulin levels (p< 0.05). No significant changes in clinical and biological parameters were observed in non-responders/relapsers. Conclusions: Eradication of hepatitis C may be associated with the regression of cryoglobulinemic glomerulonephriti

Survival and Prognostic Factors in Mixed Cryoglobulinemia: Data from 246 Cases

Introduction: The clinical and therapeutic management of mixed cryoglobulinemia (MC) remains a subject of controversy. In addition, most studies have not recorded the long-term follow-up and the outcome of these cases. Material and Methods: We enrolled 246 patients affected by MC who were consecutively admitted to our Department from January 1993 to February 2013. Clinical and biological data had been recorded until June 2014. Results: The median age (at diagnosis) was 60 years (range 26&ndash;83). The aetiology was HCV in 95% of patients, HBV in 3% and &ldquo;essential&rdquo; in 2%. HCV genotype was 1b in 57%, genotypes 2&ndash;3 in 43%. MC was Type II in 203 of the cases (87%) and Type III in 52 (13%). The most frequent clinical manifestations were purpura (72%), chronic liver disease (70%), glomerulonephritis (35%), arthralgias (58%), peripheral neuropathy (21%), non-Hodgkin lymphoma (15%) and cutaneous ulcers (3%). Purpura, arthralgias, peripheral neuropathy, glomerulonephritis and non-Hodgkin lymphoma were more frequently observed in Type II than in Type III MC (p &lt; 0.05). Treatments were interferon (IFN) or Pegilated-IFN (PEG-IFN) alone or plus Ribavirin (RIBA) in 101 cases, steroids with or without alkylating agents in 33 cases, Rituximab in 8 patients. The complete clinical, virological and immunological responses were associated with PEG-IFN plus RIBA. Severe infections were associated with renal failure. At 10 years, the overall survival rate was 71% in Type II MC and 84% in Type III (p &lt; 0.053). Conclusions: From our data, antiviral therapy is the first-line therapy in HCV-related MC, whereas steroids, alkylating agents and Rituximab should be considered as a second-line therapy. Given the heterogeneity of the disease, the role of these different therapeutic strategies should be checked in randomized controlled trials

Hepatitis B virus related cryoglobulinemic vasculitis: A multicentre open label study from the Gruppo Italiano di Studio delle Crioglobulinemie - GISC

Background: Cryoglobulinemic vasculitis (CV) related to Hepatitis-B Virus (HBV) is rare and its treatmentis ill-defined.Aims: To describe clinical and treatment characteristics of HBV-related CV patients. In addition, the effi-cacy of treatment with antiviral agent nucleotide (NUC), including Entecavir, Adefovir, and Lamivudine,was explored.Methods: In four Italian centres, 17 HBV-positive CV patients (median age 56 years, range 45\u201370) wereenrolled.Results: The extrahepatic manifestations were: purpura (100%), arthralgias (71%), peripheral neuropathy(29%), chronic hepatitis (47%), liver cirrhosis (29%), and glomerulonephritis (18%). Mixed cryoglobuline-mias were type II (88%) and type III (12%). The median cryocrit was 3% (range 1\u201314), rheumatoid factor was200 U/L (range 20\u20135850), C4 was 12 mg/dl (range 2\u201331), ALT 71 U/L (range 36\u2013114). All patients wereHBsAg-positive and 80% anti-HbeAg-positive. At enrollment, they were treated with steroids (eight),Entecavir (five), Alpha-IFN (two), Adefovir and Lamivudine (one each). After NUC treatment, no diseaseprogression was observed and, in all patients, HBV-DNA became undetectable. Moreover, a regressionof purpura and a reduction of cryocrit were observed. Four patients died during therapy, two of kidneyfailure and two of liver cirrhosis.Conclusion: NUC therapy appeared to be safe and effective in CV-related HBV

Bendamustine plus rituximab versus R-CHOP as first-line treatment for patients with indolent non-Hodgkin\u2019s lymphoma: evidence from a multicenter, retrospective study

The optimal first-line treatment for advanced low-grade non-Hodgkin lymphomas (LG-NHL) is still highly debated. Recently, the StiL and the BRIGHT trials showed that the combination of rituximab and bendamustine (R-B) is non-inferior to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with a better toxicity profile. Utilizing a retrospective analysis, we compared the efficacy and safety of both regimens in clinical practice. From November 1995 to January 2014, 263 LG-NHL patients treated with either R-B or R-CHOP were retrospectively assessed in seven European cancer centers. Ninety patients were treated with R-B and 173 with R-CHOP. Overall response rate was 94 and 92 % for the R-B and the R-CHOP group, respectively. The percentage of complete response was similar for both groups (63 vs. 66 % with R-B and R-CHOP, respectively; p = 0.8). R-B was better tolerated and less toxic than R-CHOP. The median follow-up was 6.8 and 5.9 years for the R-CHOP and the R-B group, respectively. Overall, no difference in progression-free survival (PFS) (108 vs. 110 months; p = 0.1) was observed in the R-B group compared to the R-CHOP cohort. Nevertheless, R-B significantly prolonged PFS in FL patients (152 and 132 months in the R-B and R-CHOP group, respectively; p = 0.05). However, this result was not verified in multivariate analysis probably due to the limits of the present study. We confirm that the R-B regimen administered in patients with LG-NHL is an effective and less toxic therapeutic option than R-CHOP in clinical practice. \ua9 2016, Springer-Verlag Berlin Heidelberg