Prevalence of hepatitis B virus infection in non‐Hodgkin lymphoma: a systematic review and meta‐analysis

Background and aim: A recent meta‐analysis has demonstrated an association between hepatitis C virus and non‐Hodgkin lymphoma (NHL). There is also evidence on the association between hepatitis B virus (HBV) and NHL. The aim of this study was to evaluate this evidence using a meta‐analytic approach. Methods: We searched the MEDLINE database from 1962 to 2008 for case–control studies that have reported the association of HBV with NHL. We calculated the odds ratio (OR) and 95% confidence intervals (CI) to assess the prevalence of HBV infection and pooled the results using three different statistical models. Results: Our search yielded 12 studies with 11 studies (3262 NHL patients, 1 523 205 controls) evaluating HBV infection in NHL and one study (3888 HBV‐infected individuals, 205 203 controls) that had investigated for NHL in HBV infection. The OR of detecting HBV infection in NHL when compared with the control population was 2.56 (95% CI, 2.24–2.92) by the fixed effects model; 2.61 (95% CI, 2.29–2.98) by the exact method and 2.67 (95% CI, 2.04–3.49) by the random effects model suggesting a high prevalence of HBV carrier state in lymphoma. There was evidence of statistical heterogeneity which disappeared after exclusion of retrospective studies on sensitivity analysis. Conclusions: The results of this study suggest a possible causal relation between HBV infection and NHL which needs to be confirmed by experimental and epidemiological studies. In countries where prevalence of HBV infection is 1% or more, it may be prudent to screen patients with NHL for occult HBV infection.     

Hepatitis B virus and risk of non‐Hodgkin lymphoma: An updated meta‐analysis of 58 studies

Previous studies have focused on the relationship between hepatitis B virus (HBV) infection and non‐Hodgkin lymphoma (NHL). However, the results remain inconsistent and somehow conflicting in different subgroups. The aim of this study was to combine the findings of independent studies to comprehensively assess the association between HBV and NHL using a meta‐analysis. Relevant studies were identified through structured keyword searches in PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database, and 58 studies with a total of 53 714 NHL cases and 1 778 591 controls were finally included. Pooled estimates indicated a significantly increased NHL risk in HBV‐infected individuals (summary odds ratio [sOR]: 2.50; 95% confidence interval [CI]: 2.20‐2.83) regardless of the study design (case–control studies: sOR: 2.47; 95% CI: 2.16‐2.82; cohort studies: sOR: 2.64; 95% CI: 1.78‐3.91). Considerable heterogeneity was observed across studies that was primarily attributed to the NHL subtypes (meta‐regression: P < .05). Overall, B‐cell NHL (sOR: 2.46; 95% CI: 1.97‐3.07) presented a stronger association with HBV infection than T‐cell NHL (sOR: 1.67; 95% CI: 1.34‐2.10). Within the B‐cell NHL subtypes, HBV infection was significantly associated with diffuse large B‐cell lymphoma (DLBCL, sOR: 2.06; 95% CI: 1.48‐2.88) and follicular lymphoma (FL, sOR: 1.54; 95% CI: 1.11‐2.12), but not with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and Burkitt lymphoma. The results of this meta‐analysis support a positive link between HBV infection and NHL development. Further investigations for the mechanisms underlying HBV‐induced NHL are warranted.     

A national study on conditional survival,excess mortality and second cancer after high dose therapy with autologous stem cell transplantation for non‐Hodgkin lymphoma

This national population‐based study aimed to investigate conditional survival and standardized mortality ratios (SMR) after high‐dose therapy with autologous stem‐cell transplantation (HDT‐ASCT) for non‐Hodgkin lymphoma (NHL), and to analyse cause of death, relapses and second malignancies. All patients ≥18 years treated with HDT‐ASCT for NHL in Norway between 1987 and 2008 were included (n = 578). Information from the Cause of Death Registry and Cancer Registry of Norway were linked with clinical data. The 5‐, 10‐ and 20‐year overall survival was 61% (95% confidence interval [CI] 56–64%), 52% (95%CI 48–56%) and 45% (95%CI 40–50%), respectively. The 5‐year survival conditional on having survived 2, 5 and 10 years after HDT‐ASCT was 81%, 86% and 93%. SMRs were 12·3 (95%CI 11·0–13·9), 4·9 (95%CI 4·1–5·9), 2·4 (95%CI 1·8–3·2) and 1·0 (95%CI 0·6–1·8) for the entire cohort and for patients having survived 2, 5 and 10 years after HDT‐ASCT respectively. Of the 281 deaths observed, 77% were relapse‐related. Treatment‐related mortality was 3·6%. The 10‐year cumulative incidence of second malignancies was 7·9% and standardized incidence ratio was 2·0 (95%CI 1·5–2·6). NHL patients treated with HDT‐ASCT were at increased risk of second cancer and premature death. The mortality was still elevated at 5 years, but after 10 years mortality equalled that of the general population.     

Regression of fibrosis and portal hypertension in HCV‐associated cirrhosis and sustained virologic response after interferon‐free antiviral therapy

It is still controversial, whether and to what amount cirrhosis and portal hypertension are reversible in patients with hepatitis C virus (HCV)‐associated cirrhosis and sustained virologic response (SVR) after interferon‐free antiviral therapy. In this study, we prospectively evaluated dynamics of liver and spleen stiffness in HCV‐infected patients with advanced liver disease and SVR after interferon‐free treatment. A total of 54 patients with HCV‐associated cirrhosis and SVR were included. Liver and spleen stiffness was measured at therapy baseline (BL), end of treatment (EOT) and 24 weeks after EOT (FU24) by transient liver elastography (L‐TE) as well as by acoustic radiation force impulse of the liver (L‐ARFI) and spleen (S‐ARFI), as well as biochemical, virologic and clinical data. Improvement of liver and spleen stiffness was found in 44 of 50 (88%), 31 of 54 (57%) and 25 of 54 (46%) of patients assessed by L‐TE, L‐ARFI and S‐ARFI between baseline and FU24. Liver stiffness assessed by L‐TE improved between BL [median (range), 32.5 (9.1–75) kPa] and EOT [median (range), 21.3 (6.7–73.5) kPa; (P<.0001)], and between BL and FU24 [median (range), 21.2 (5.4–70) kPa; (P<.0001)]. Liver stiffness assessed by L‐ARFI improved between BL [median (range), 2.7 (1.2–4.1) m/s] and FU24 [median (range), 2.4 (1.2–3.9) m/s; P=.002), while spleen stiffness remained unchanged. Our data suggest that improvement of liver stiffness may be rather due to reduced necroinflammation and may be due to a less extent to regression of cirrhosis, as dynamics of liver stiffness improvement was more pronounced between BL and EOT than BL and FU24.     

Pretransplant FDG‐PET in aggressive non‐Hodgkin lymphoma: systematic review and meta‐analysis

This study aimed to systematically review and meta‐analyze the value of pretransplant FDG‐PET in predicting outcome after autologous stem cell transplantation in aggressive non‐Hodgkin lymphoma. MEDLINE was systematically searched; included studies were methodologically assessed and meta‐analyzed, when possible. Overall methodological quality of included studies (n = 11) was poor, with moderate risk of bias in the domains of study participation (n = 7) and prognostic factor measurement (n = 7), and high risk of bias in the domains of outcome measurement (n = 10), and study confounding (n = 11). In all aggressive non‐Hodgkin lymphomas, pooled sensitivity and specificity were 54.0% and 73.1% in predicting treatment failure, and 54.5% and 68.7% in predicting death. Because of interstudy heterogeneity, additional subgroup analyses were performed. In newly diagnosed aggressive non‐Hodgkin lymphoma, pooled sensitivity and specificity were 20.0% and 70.0% in predicting treatment failure, and 8.3% % and 30.5% in predicting death. In refractory/relapsed aggressive non‐Hodgkin lymphoma, pooled sensitivity and specificity were 68.1% and 72.1% in predicting treatment failure, and 77.3% and 69.6% in predicting death. At present, pretransplant FDG‐PET cannot be recommended in aggressive non‐Hodgkin lymphoma, because available studies suffer from major methodological flaws, and reported prognostic estimates are low (i.e., poor in newly diagnosed and moderate in refractory/relapsed aggressive non‐Hodgkin lymphoma).     

B‐cell lymphoma,unclassifiable, with features intermediate between diffuse large B‐cell lymphoma and burkitt lymphoma: study of 39 cases

B‐cell lymphoma, unclassifiable (B‐UCL), with features intermediate between diffuse large B‐cell lymphoma and Burkitt lymphoma, is a poorly characterized entity. Therefore, we investigated cases of B‐UCL treated by the Nebraska Lymphoma Study Group (NLSG). We searched the NLSG registry for years 1985–2010 for cases of B‐UCL. Immunohistochemical stains and fluorescence in situ hybridization studies for MYC, BCL2 and BCL6 gene rearrangements were performed. Among the 39 cases studied, 54% were male and 46% were female, with a median age of 69 years. The majority of patients presented with advanced‐stage disease (62%) and had high (3–5) International Prognostic Index (IPI) scores (54%). The median overall survival (OS) was only 9 months and the 5‐year OS was 30%. Patients with low IPI scores (0–2) had a better survival than those with high scores (3–5). The cases were genetically heterogeneous and included 11 ‘double‐hit’ lymphomas with rearrangements of both MYC and BCL2 or BCL6. None of the immunohistochemical or genetic features was predictive of survival. This B‐cell lymphoma is a morphologically‐recognizable entity with a spectrum of genetic abnormalities. New and better treatments are needed for this aggressive lymphoma.     

The molecular pathogenesis of B‐cell non‐Hodgkin lymphoma

The B‐cell non‐Hodgkin lymphomas (B‐NHL) are a diverse group of haematological malignancies which arise from the mature B‐lymphocyte compartment. Recently, our understanding of the molecular pathogenesis of these disorders has greatly increased due to technological advances such as high‐throughput DNA sequencing techniques. A paradigm of B‐NHL pathogenesis has emerged where the normal genetic processes that are central to generating B‐cell receptor diversity (somatic hypermutation and class switch/VDJ recombination) also drive the genesis of large‐scale, chromosomal‐level genetic lesions and smaller‐scale gene‐level mutations to produce the malignant phenotypes observed. Whilst a significant degree of genetic heterogeneity exists within each B‐NHL subtype, the genetic lesions present within each subtype show a degree of convergence on common intracellular signalling, epigenetic and cell cycle pathways. This convergence gives an insight into the key oncogenic drivers of specific B‐NHL subtypes and potential targets for therapeutic intervention. This review covers the current understanding of the causative genetic processes of B‐NHL, the associated driving molecular lesions and the implications of these findings for the treatment of this group of disorders.     

R‐CHOP versus dose‐adjusted R‐EPOCH in frontline management of primary mediastinal B‐cell lymphoma: a multi‐centre analysis

Primary mediastinal (thymic) large B‐cell lymphoma (PMBCL) is an uncommon subtype of non‐Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy ± involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose‐adjusted (DA) R‐EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged ≥18 years with PMBCL since January 2011. Patients were stratified by frontline regimen, R‐CHOP versus DA‐R‐EPOCH. 132 patients were identified from 11 contributing centres (56 R‐CHOP and 76 DA‐R‐EPOCH). The primary outcome was overall survival. Secondary outcomes included progression‐free survival, complete response (CR) rate, and rates of treatment‐related complications. Demographic characteristics were similar in both groups. DA‐R‐EPOCH use increased after April 2013 (79% vs. 45%, P < 0·001), and there was less radiation use after DA‐R‐EPOCH (13% vs. 59%, P < 0·001). While CR rates were higher with DA‐R‐EPOCH (84% vs. 70%, P = 0·046), these patients were more likely to experience treatment‐related toxicities. At 2 years, 89% of R‐CHOP patients and 91% of DA‐R‐EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R‐CHOP to DA‐R‐EPOCH for PMBCL.     

Pre‐diagnosis cigarette smoking and overall survival in non‐Hodgkin lymphoma

We examined whether smoking prior to non‐Hodgkin lymphoma (NHL) diagnosis was associated with overall survival (OS) and conducted a meta‐analysis to assess the evidence relating pre‐diagnosis cigarette smoking with OS. Among 523 NHL patients, worse OS was suggested for greater pre‐diagnostic smoking habits when compared to never smokers. In the meta‐analysis (n = 5 patient populations), inferior OS was observed for greater number of cigarettes smoked per day, years of cigarette smoking, and pack‐years of cigarette smoking. The inferior survival was more pronounced for follicular than for diffuse large B cell lymphoma. Pre‐diagnosis cigarette smoking may adversely impact the survival of NHL patients.     

Effect of hepatitis C virus on immunological and virological responses in HIV‐infected patients initiating highly active antiretroviral therapy: a meta‐analysis

Co‐infection of human immunodeficiency virus (HIV) with hepatitis C virus (HCV) is rather common. In the era of highly active antiretroviral therapy (HAART), viral hepatitis could result in adverse outcomes in HIV+ patients. The current meta‐analysis aims to evaluate the impact of HCV on immunological and virological responses after HAART initiation in HIV/HCV co‐infected individuals by synthesizing the existing scientific evidence. A comprehensive search of electronic databases was performed. Eligible studies were analysed using univariate and multivariate meta‐analytic methods. Totally, 21 studies involving 22533 individuals were eligible. The estimated summary difference in CD4 cell counts increase between HIV and HIV/HCV co‐infected subjects after 3–12 months on HAART was 34.86 cells/mm³ [95% confidence interval (CI): 16.82–52.89]. The difference was more prominent in patients with baseline CD4 counts below 350 cells/mm³ (38.97, 95% CI: 20.00–57.93) and attenuated 2 years later (13.43, 95% CI: 0.83–26.04). The analysis of ratio measures yielded similar findings. The virological control remained unaffected by the presence of HCV (adjusted Hazard Ratio for co‐infected patients vs those with HIV alone: 0.99, 95% CI: 0.91–1.07). The bivariate meta‐analytic method confirmed the results of the univariate approaches. This meta‐analysis supports the adverse effect of HCV on immune recovery of HIV+ patients initiating HAART, especially of those with initially impaired immunologic status. Although this effect diminishes over time, early administration of HAART in the setting of co‐infection seems to be justified.     

Oral anti‐CD3 immunotherapy for HCV‐nonresponders is safe,promotes regulatory T cells and decreases viral load and liver enzyme levels: results of a phase‐2a placebo‐controlled trial

Orally administered anti‐CD3 antibodies are biologically active in the gut through induction of regulatory T cells, exert an immune‐modulatory effect, and alleviate insulin resistance and liver damage in patients with NASH. Aims: To determine the safety of oral anti‐CD3 monoclonal antibody (MAb) immunotherapy in chronic HCV patients with associated immune dysfunction. Methods: Four groups (n = 9) of chronic HCV patients who were nonresponders to interferon plus ribavirin therapy received oral placebo (group A) or anti‐CD3 MAb at one of three dosage levels for 30 days. Patients were followed for safety parameters and serum levels of liver enzymes, virus, cytokines and regulatory T cells. Results: Oral anti‐CD3 immunotherapy was safe and well tolerated; no treatment‐related adverse events were noted. The following improvements were noted relative to pretreatment levels: HCV viral load and AST and ALT levels decreased in the low‐ and high‐dose groups following 30 days of therapy. In two of the treated groups, an increase in regulatory T cells (CD4⁺ CD25⁺) was noted. The positive effects were somewhat more apparent in subjects with initially elevated liver enzyme levels. Conclusions: Oral anti‐CD3 MAb immunotherapy for nonresponder HCV patients was safe and well tolerated. Trends and statistically significant improvements were observed as reductions in viral load and liver enzyme levels, along with an increase in regulatory T‐cell levels. These data support a role for the immune system in the pathogenesis of HCV infection and suggest that this immunotherapy is worthy of evaluation in combination with HCV antiviral drugs.     

Prognostic value of complete remission status at end‐of‐treatment FDG‐PET in R‐CHOP‐treated diffuse large B‐cell lymphoma: systematic review and meta‐analysis

This study systematically reviewed and meta‐analysed the prognostic value of complete remission status at end‐of‐treatment ¹⁸F‐fluoro‐2‐deoxy‐d ‐glucose positron emission tomography (FDG‐PET) in diffuse large B‐cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP). The systematic PubMed/MEDLINE search yielded seven suitable studies comprising a total of 737 R‐CHOP‐treated DLBCL patients who were in complete remission at end‐of‐treatment FDG‐PET. Overall, the methodological quality of included studies was reasonable. The disease relapse rate among all patients with complete remission status according to end‐of‐treatment FDG‐PET ranged from 7·0% to 20·0%, with a weighted summary proportion of 13·7%. Five of seven studies reported progression‐free survival (PFS) of these patients at various specific time points, i.e., 2‐year PFS (n = 1), estimated 3‐year PFS (n = 3) and 5‐year PFS (n = 1), which was 83%, 85–86·4% and 75%, respectively. Three of seven studies reported overall survival (OS) of these patients at various specific time points, i.e., estimated 3‐year OS (n = 2) and estimated 5‐year OS (n = 1), which were 90%, 93·6% and 83%, respectively. In conclusion, a non‐negligible proportion of R‐CHOP‐treated DLBCL patients who achieve complete remission according to end‐of‐treatment FDG‐PET experiences disease relapse during follow‐up.     

A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Although initial rituximab‐containing chemotherapies achieve high response rates, indolent B‐cell non‐Hodgkin lymphoma (B‐NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B‐NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21‐d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression‐free survival (PFS). Fifty‐six eligible patients were enrolled; 50 patients (39 with FL, seven with other B‐NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab‐containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.     

Rituximab extended schedule or retreatment trial for low tumour burden non‐follicular indolent B‐cell non‐Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402

The rituximab extended schedule or retreatment trial (RESORT; E4402) was a phase 3 randomized prospective trial comparing maintenance rituximab (MR) versus a retreatment (RR) dosing strategy in asymptomatic, low tumour burden indolent lymphoma. A planned exploratory sub‐study compared the two strategies for small lymphocytic (SLL) and marginal zone lymphomas (MZL). Patients responding to rituximab weekly × 4 were randomized to MR (single dose rituximab every 3 months until treatment failure) or RR (rituximab weekly × 4) at the time of each progression until treatment failure. The primary endpoint was time to treatment failure (TTTF). Patients with SLL (n = 57), MZL (n = 71) and unclassifiable small B‐cell lymphoma (n = 3) received induction rituximab. The overall response rate (ORR) was 40% [95% confidence interval (CI) 31–49%; SLL ORR 22·8%; MZL ORR 52·1%]; all 52 responders were randomized. At a median of 4·3 years from randomization, treatment failure occurred in 18/23 RR and 15/29 MR. The median TTTF was 1·4 years for RR and 4·8 years for MR (P = 0·012); median time to first cytotoxic therapy was 6·3 years for RR and not reached for MR (P = 0·0002). Survival did not differ (P = 0·72). In low tumour burden SLL and MZL patients responding to rituximab induction, MR significantly improved TTTF as compared with RR.