Bacterial infection-driven lymphomagenesis.

PURPOSE OF REVIEW: The first convincing evidence for a causal relationship between bacterial infection and lymphomagenesis came from the link between gastric lymphoma and chronic Helicobacter pylori gastritis. This review will summarize the current epidemiological, clinical, and biological evidence of a causative role of bacteria in the development of malignant lymphomas, particularly, the extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type. RECENT FINDINGS: Other microorganisms have been associated with specific extranodal lymphoma sites with variable and not always definitive, evidence, including Chlamydia psittaci , Borrelia burgdorferi , Campylobacter jejuni and, most recently, Coxiella Burnetii . According to most plausible models, lymphoma growth is a consequence of continuous antigenic stimulation induced by chronic infection. However, some evidence of a direct oncogenic role of H. pylori has been provided, too. SUMMARY: Lymphomas are not the result of a single cause but multifactorial diseases, influenced by a variety of genetic and environmental elements. Hence, ascertaining the specific contribution of bacterial infections is not always easy. Nevertheless, the eradication of the associated chronic infection may result in sustained lymphoma regression. Moreover, the association between infections and lymphoma may offer opportunities for reducing lymphoma incidence by preventing the predisposing infections or treating them early.

Enhanced Expression of miR-181b in B Cells of CLL Improves the Anti-Tumor Cytotoxic T Cell Response.

The clinical progression of B cell chronic lymphocytic leukemia (CLL) is associated with immune cell dysfunction and a strong decrease of miR-181b-5p (miR-181b), promoting the death of CLL cells. Here we investigated whether the reduction of miR-181b impairs the immune response in CLL. We demonstrate that activated CD4+ T cells increase miR-181b expression in CLL through CD40-CD40L signaling, which enhances the maturation and activity of cytotoxic T cells and, consequently, the apoptotic response of CLL cells. The cytotoxic response is facilitated by a depletion of the anti-inflammatory cytokine interleukin 10, targeted by miR-181b. In vivo experiments in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice confirmed that miR-181b promotes the apoptotic death of CLL cells only when functional T cells are restored. Overall, our findings suggest that the reinstatement of miR-181b in CLL cells could be an exploitable adjuvant therapeutic option for the treatment of CLL.

A phase II trial of bendamustine in combination with ofatumumab in patients with relapsed or refractory marginal zone B-cell lymphomas.

Marginal zone lymphomas (MZLs) are indolent yet incurable lymphomas with frequent relapses following therapy. For patients with relapsed/refractory disease, no standard therapies exist. Here we report results of an exploratory phase II study aimed at assessing the efficacy and safety of the alkylator agent bendamustine in combination with the second-generation anti-CD20 monoclonal antibody, ofatumumab, in patients with relapsed or refractory MZL. Patients with MZL and previously treated with at least one line of systemic therapy were eligible. Treatment consisted in bendamustine (90 mg/m2 on days 1 and 2) and ofatumumab (1000 mg on day 1) in 28-day cycles for up to six cycles. Sixteen patients were included in the trial. In one patient, the diagnosis was revised after two cycles of treatment and was excluded from the efficacy analysis. Among 15 patients with MZL, 14 were evaluable for response: the overall and complete response rates were 92.9% and 57.1%, respectively. The median duration of response was 30.4 months (95% confidence interval [CI], 15.5 -not estimable) and 2-years progression-free survival 77% (95% CI, 43%-92%). Fifteen patients (94%) experienced grade 3-4 adverse events. Toxicity was mostly hematological. Neutropenia grade ≥3 was recorded in 27% of patients, lymphocytopenia in 93%, and infections and febrile neutropenia each in 13%. One patient discontinued treatment due to myocardial infarction; no treatment-related deaths occurred. The combination of bendamustine with ofatumumab was active with an acceptable toxicity profile in this small phase II trial and can be considered for further investigation in relapsed/refractory MZL patients.

Late relapse in patients with diffuse large B-cell lymphoma: impact of rituximab on their incidence and outcome.

Diffuse large B-cell lymphoma (DLBCL) constitutes 25-35% of all non-Hodgkin lymphomas in Western countries. Approximately two thirds of the patients can be cured with standard immuno-chemotherapy. Most relapses occur within 1-2 years from diagnosis, however, the occurrence of relapses after 5 years or more has been described. We aimed at defining the incidence and clinical features of late relapses. Data of 1113 DLBCL patients were analysed. Among the 196 patients relapsing after a first complete remission, 36 (18% of relapses and 3% of all DLBCLs) experienced a recurrence more than 5 years from diagnosis. Late relapsing patients, in comparison with those relapsing earlier, showed a more favourable risk profile at presentation: normal lactate dehydrogenase levels (P = 0·002), early Ann Arbor stage (P = 0·006) and low International Prognostic Index (P = 0·003). The risk of late relapse was lowered by the introduction of rituximab as part of the front-line treatment (P < 0·001). Cause-specific survival (CSS) from the time of relapse was significantly better for late relapsing patients compared to those relapsing early: 5-year CSS rates were 53% and 31%, respectively (P = 0·033). A trend toward a better overall survival was also observed, with 5-year rates after relapse of 47% and 25%, respectively (P = 0·054).

Hepatitis C virus-associated B-cell non-Hodgkin's lymphomas: what do we know?

Epidemiological studies have shown an increased risk of developing B-cell lymphomas in patients with chronic hepatitis C virus (HCV) infection. There is, however, a great geographic variability and it remains unclear whether additional environmental and genetic factors are involved or whether the international discrepancies represent simply a consequence of the variable prevalence of HCV infection in different countries. Other confounding factors may affect the comparability of the different studies, including the method of HCV assessment, the selection of normal controls, the lymphoma classification used and the year of publication. The most convincing evidence for a causal relationship comes from the observation, mainly limited to some indolent subtypes, of B-cell lymphoma regressions after successful HCV eradication with antiviral treatment. Yet, the molecular mechanism of HCV-induced lymphomagenesis are mainly hypothetical. According to most plausible models, lymphoma growth is a consequence of continuous antigenic stimulation induced by the chronic viral infection. This review will summarize the current knowledge on HCV-associated lymphomas and their management.

Bendamustine in combination with rituximab for elderly patients with previously untreated B-cell chronic lymphocytic leukemia: A retrospective analysis of real-life practice in Italian hematology departments.

The front-line therapy for CLL young and fit patients is chemo-immunotherapy with fludarabine-cyclophosphamide-rituximab (FCR). FCR regimen results in a significant myelosuppression and high rates of early and late infections especially in elderly patients. German CLL study group compared FCR vs. bendamustine-rituximab (BR) in fit untreated patients. The response rates with BR or FCR were comparable, BR could be an alternative 1st-line treatment for elderly patients. Here we report retrospective data of 70 elderly (≥65 years) CLL patients from 12 Italian centers treated with BR as front-line therapy. The primary end points were overall response rate (complete remission/partial remission) and safety. Forty-seven males and 23 females, with a median age of 72 years, were included in the study. Eight patients were unfit for CIRS. The OR rate was 88.6% (31.4% CR and 57.2% PR). Progression free survival, treatment free survival and overall survival rates at 2-years were 79%, 90.3% and 89.6%, respectively. Only del17 was independent unfavorable parameter on the response rate and PFS. Our results indicate that BR front-line at standard dose provides a high response rate with a good safety profile, even if more than 50% of patients experienced a bendamustine dose reduction until 70 mg/m2.

Primary extranodal B-cell lymphoma: current concepts and treatment strategies.

Around 30% of all non-Hodgkin lymphoma (NHL) cases arise from extranodal sites. Often the primary extranodal presentation requires site-specific strategies either for diagnosis or therapy. However, several issues remain controversial such as the definition itself of primary extranodal lymphoma, and the most appropriate staging system to characterize the disease extent. Moreover, the specific presenting sites may have per se prognostic implications. The vast majority of the published reports on primary extranodal lymphomas are represented by single-institution retrospective studies. In most clinical trials the primary extranodal lymphomas are often included together with the nodal ones and only a few studies have investigated the peculiarity of extranodal lymphomas. This review summarizes the recent advances in B-cell extranodal lymphomas, addressing the critical points in the management of the more frequently involved sites.

Management of the marginal zone lymphomas.

Marginal zone lymphomas (MZL) represent around 8 % of all non-Hodgkin lymphomas. During the last decades a number of studies have addressed the mechanisms underlying the disease development. Extranodal MZL lymphoma usually arises in mucosal sites where lymphocytes are not normally present from a background of either autoimmune processes, such as Hashimoto thyroiditis or Sjögren syndrome or chronic infectious conditions. In the context of a persistent antigenic stimulation, successive genetic abnormalities can progressively hit a B-cell clone among the reactive B-cells of the chronic inflammatory tissue and give rise to a MALT lymphoma. The best evidence of an etiopathogenetic link is available for the association between Helicobacter pylori-positive gastritis and gastric MALT lymphoma. Indeed, a successful eradication of this micro-organism with antibiotics can be followed by gastric MALT lymphoma regression in more than 2/3 of cases. Other microbial agents have been implicated in the pathogenesis of MZL arising in the skin (Borrelia burgdorferi), in the ocular adnexa (Chlamydophila psittaci), and in the small intestine (Campylobacter jejuni). The prevalence of hepatitis C virus (HCV) has also been reported higher in MZL patients (particularly of the splenic type) than in the control population, suggesting a possible causative role of the virus. In non-gastric MALT lymphoma and in splenic MZL the role of the antimicrobial therapy is, however, less clear. This review summarizes the recent advances in Marginal Zone Lymphomas, addressing the critical points in their diagnosis, staging and clinical management.

Prevalence, characteristics and management of occult hepatitis B virus infection in patients with chronic lymphocytic leukemia: a single center experience.

Several reports have emphasized the risk of hepatitis B virus (HBV) reactivation in patients with lymphoproliferative disorders undergoing cytotoxic treatment. To determine the prevalence of occult B infection (OBI) in a population with chronic lymphocytic leukemia (CLL) and management with universal prophylaxis (UP) in all patients undergoing chemoimmunotherapy or targeted prophylaxis (TP) in patients experiencing seroreversion during therapy, we analyzed 397 patients with CLL from our database. The prevalence of OBI in our patients with CLL was 8.6% (34 patients). When comparing patients with OBI/CLL with those with CLL, we did not find any statistical difference among clinical-biological parameters and time dependent endpoints except for a lower peripheral blood lymphocyte count in the OBI/CLL group (p = 0.036). From 2000 to 2010 careful follow-up and TP were adopted; two out of 10 patients (20%) showed seroreversion. From June 2010 we adopted UP during and 12 months after immunosuppressive treatment in all patients with CLL with OBI; no evidence of seroreversion was detected.

Emerging role of infectious etiologies in the pathogenesis of marginal zone B-cell lymphomas.

Extranodal marginal zone B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) arise from lymphoid populations that are induced by chronic inflammation in extranodal sites. The most frequently affected organ is the stomach, where MALT lymphoma is incontrovertibly associated with a chronic gastritis induced by a microbial pathogen, Helicobacter pylori. Gastric MALT lymphoma therefore represents a paradigm for evaluating inflammation-associated lymphomagenesis, which may lead to a deeper understanding of a possible etiologic association between other microorganisms and nongastric marginal zone lymphomas. Besides infectious etiology, chronic inflammation caused by autoimmune diseases, such as Sjögren syndrome or Hashimoto thyroiditis, can also carry a significant risk factor for the development of marginal zone lymphoma. In addition to the continuous antigenic drive, additional oncogenic events play a relevant role in lymphoma growth and progression to the point at which the lymphoproliferative process may eventually become independent of antigenic stimulation. Recent studies on MALT lymphomas have in fact demonstrated genetic alterations affecting the NF-κB) pathway, a major signaling pathway involved in many cancers. This review aims to present marginal zone lymphoma as an example of the close pathogenetic link between chronic inflammation and tumor development, with particular attention to the role of infectious agents and the integration of these observations into everyday clinical practice. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma."

Hepatitis C virus-associated B-cell non-Hodgkin lymphomas.

Epidemiological studies have demonstrated an increased risk of developing B-cell lymphomas in patients with chronic hepatitis C virus (HCV) infection. However, the strength of the association shows great geographic discrepancies, with higher relative risk in countries with high HCV prevalence. It remains unclear whether additional environmental and genetic factors are involved or if the international variability is simply a consequence of the variable infection prevalence. Therefore, a causal relationship remains controversial. Other confounding factors may affect the comparability of the different studies, including the method of HCV assessment, the selection of normal controls, the lymphoma classification used, and the year of publication. The most convincing proof is the observation, mainly limited to some indolent subtypes, of B-cell lymphoma regressions after HCV eradication with IFN and ribavirin. However, the molecular mechanisms of the HCV-induced lymphomagenesis are mainly hypothetical. According to the model considered to be most plausible, lymphoma growth is a consequence of the continuous antigenic stimulation of the B-cell immunologic response induced by the chronic viral infection. This review summarizes the current epidemiological and biological evidence of a role of HCV in lymphomagenesis, describing the putative mechanisms for a causative relationship. The clinical characteristics and management difficulties of the HCV-associated lymphomas are also discussed. HCV treatment with IFN cannot be given safely in concomitance with cytotoxic lymphoma treatment because of hematological and liver toxicity. However, novel and better tolerated antiviral regimens are under development and will hopefully make the treatment of both lymphoma and hepatitis easier in the future.

The use of monoclonal antibodies in the treatment of autoimmune complications of chronic lymphocytic leukemia.

Autoimmune cytopenias are a frequent complication in CLL, occurring in approximately 5-10% of the patients. The most common manifestation is autoimmune haemolytic anaemia, followed by immune thrombocytopenia and only rarely pure red blood cell aplasia or autoimmune granulocytopenia. Initial treatment is as for the idiopathic autoimmune cytopenias, with most patients responding to conventional corticosteroid therapy. Patients, who do not respond to conventional therapy after 4-6 weeks, should be considered for alternative immunosuppression, monoclonal antibody therapy or splenectomy. While randomized trials demonstrating the benefit of rituximab in CLL-related autoimmune diseases are still lacking, there are considerable data in the literature that provide evidence for its effectiveness. The monoclonal antibody alemtuzumab also displays considerable activity against both the malignant disease and the autoimmune complication in patients with CLL, although at the expense of greater toxicity. A number of new monoclonal antibodies, such as ofatumumab, GA-101, lumiliximab, TRU-016, epratuzumab, and galiximab, are currently investigated in CLL and their activity in CLL-related autoimmune cytopenias should be evaluated in future studies.

Chlorambucil plus Rituximab as Front-Line Therapy in Elderly/Unfit Patients Affected by B-Cell Chronic Lymphocytic Leukemia: Results of a Single-Centre Experience.

The current standard first line therapy for fit patients with B-CLL/SLL is based on combination of fludarabine-cyclophosphamide and rituximab. However, elderly patients or patients with comorbidities poorly tolerate purine analogue-based chemotherapy and they are often treated with Chlorambucil (Chl) only. However, complete response (CR) and overall response (OR) rates with Chl are relatively low. We now investigated whether the addition of Rituximab to Chl will improve the efficacy without impairing the tolerability in elderly and unfit patients. We included in our study 27 elderly or unfit patients that had not received prior therapy. All patients were treated with Chl (1mg/Kg per 28-day cycle for 8 cycles) plus Rituximab (375 mg/m(2) for the first course and 500 mg/m(2) for subsequent cycles until the 6(th) cycle). We obtained an OR rate of 74%. The most frequent adverse effect was grade 3-4 neutropenia, which occurred in 18.5% of the patients. Infections or grade 3-4 extra-hematological side effects were not recorded. None of the patients required reduction of dose, delay of therapy or hospitalization. Overall, these data suggest that Chl-R is an effective and well tolerated regimen in elderly/unfit patients with CLL.

Mantle cell lymphoma relapsing at the lymphedematous arm.

Lymphedema (LE) is a chronic medical condition characterized by lymphatic fluid retention, resulting in tissue swelling. Cancer treatments involving lymph nodes can damage lymph drainage routes, causing accumulation of lymph fluid in the interstitial tissue of related limbs and body areas and secondary LE. Basically, the LE has a negative impact on physical and mental quality of life. Moreover, 0.07-0.04% of long term survivors (most patients undergoing mastectomy) can develop the Stewart-Treves syndrome, a rare and aggressive multifocal lymphangiosarcoma arising within the LE region. Here we describe the case of a 45-year-old woman with a massive LE of the left arm, as a consequence of previous breast cancer, who was diagnosed after 4 years of stage IV mantle cell lymphoma (MCL). The patient, after obtaining complete remission with chemotherapy and autologous hematopoietic stem cell transplant, had a relapse of MCL in the lymphedema site.

Regulatory T-cells in chronic lymphocytic leukemia and autoimmune diseases.

Regulatory T-cells (Tregs) constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL). Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosus, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in cancer and autoimmune disorders, as well.

Efficacy of lenalidomide plus dexamethasone for POEMS syndrome relapsed after autologous peripheral stem-cell transplantation.

POEMS syndrome is a rare paraneoplastic condition associated to an underlying plasmacellular dyscrasia. The pathogenesis of POEMS is poorly understood, but overproduction of VEGF, probably secreted by clonal plasma cells, is thought to be responsible for the signs and symptoms of the syndrome, and it seems to be useful for the monitoring of the response to therapy. At present, an effective therapeutic option for the patients is represented by autologous peripheral blood stem-cell transplantation (aPBSCT), although relapses have been described, and there is an important morbidity associated with this procedure. Before the implementation of aPBSCT, the clinical course of POEMS syndrome was characterized by progressive polyneuropathy potentially leading to death for respiratory failure. Given the high serum and plasma levels of VEGF observed in POEMS patients, the use of anti-angiogenetic drugs such as thalidomide and lenalidomide and other drugs with anti-VEGF and anti-TNF effect such as bortezomib have been considered to treat this syndrome. There are evidences of lenalidomide benefit in both front-line and previously treated patients, but scanty data are available about its use for relapse after aPBSCT. Here, we report the successful use of lenalidomide in a patient who relapsed after aPBSCT.

The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma.

PURPOSE: The Epstein-Barr virus (EBV) is present in the malignant Hodgkin/Reed-Sternberg (HRS) cells of 20% to 40% cases of Hodgkin lymphoma (HL) in Western countries. We were interested in the detection and quantification of cell-free plasma EBV-DNA as an indicator of biological and clinical characteristics in EBV-associated HL. EXPERIMENTAL DESIGN: EBV was detected in peripheral blood compartments (whole blood, plasma, and mononuclear cells) at diagnosis by real-time PCR for the EBNA (EB nuclear antigen) region (n = 93) and in HRS cells by in situ hybridization for EBV-encoded small RNAs (EBER; n = 63). These data were correlated to histological and clinical characteristics, EBV serology, circulating cell-free DNA, and interleukin (IL)-6 levels. RESULTS: Detection of EBV-DNA in plasma had a high specificity (90%), but a relatively low sensitivity (65%) to predict for EBV association. The viral load was higher in patients with advanced stage disease, older age in the presence of B-symptoms, and international prognostic score more than 2. The presence of EBV in HRS cells and higher plasma EBV-DNA copy numbers correlated to an increased frequency of tumor-infiltrating CD68+ macrophages in lymph node biopsies. Plasma EBV-DNA load correlated to circulating cell-free DNA and IL-6 levels, and inversely correlated to lymphocyte counts and EBNA1 antibody titers. CONCLUSION: Although the presence of EBV-DNA in peripheral blood cannot be regarded as a surrogate marker for EBER, the plasma EBV-DNA load at HL diagnosis is an indicator of disease activity and biological characteristics associated with negative prognosis. Moreover, the inverse correlation to EBNA1 antibody titers and lymphocyte counts may indicate a reduction in immunosurveillance, favoring the expansion of EBV-HRS cells in HL.