The impact of hepatitis B virus infection and vaccination on the development of non‐Hodgkin lymphoma

Hepatitis B virus (HBV) infection has been documented as a risk factor for non‐Hodgkin lymphoma (NHL). However, there are few large cohort studies, and there is no report about the impact of HBV vaccination. We conducted this study to evaluate these issues. We used the nationwide cohort of the Taiwan National Health Insurance Research Database for 1997–2013. We compared the incidence and the risk of developing NHL and CD20⁺ aggressive lymphoma between HBV and non‐HBV cohorts. The hazard ratios (HRs) were computed using Cox proportional hazards models. We matched these two large cohorts to reconfirm the data. We also compared the incidence of NHL between cohorts born before and after the inception of universal HBV vaccination. We found that HBV infection increased the risk for developing NHL and CD20⁺ aggressive lymphoma, with HRs of 4.14 and 5.52, with a higher incidence of 17.07 and 13.9 per 100 000 person‐years, respectively, compared to the non‐HBV cohort. The incidence of NHL in the cohort born in the era before universal HBV vaccination was higher with 1.85 per 100 000 person‐years compared to 0.74 in the cohort born later aged younger than 20. Our study confirms that HBV confers a greater risk for developing NHL, especially CD20⁺ aggressive lymphoma. The impact of HBV vaccination is protective against lymphoma development in the teenagers in an endemic area, but longer follow‐up is needed for older age.     

Use of rituximab in diffuse large B-cell lymphoma in the salvage setting

The addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy was a milestone in the development of front-line therapy for diffuse large B-cell lymphoma (DLBCL). R-CHOP and equivalent rituximab-containing anthracycline-based regimens are now widely accepted as the standard of care in this setting. However, the optimal treatment for patients with DLBCL relapsing or progressing after front-line therapy is not yet established. This review explores the role of rituximab in the treatment of DLBCL in the salvage setting, as monotherapy, in combination with chemotherapy or novel agents, and in the context of autologous stem cell transplantation (ASCT). Current evidence suggests that rituximab may improve outcomes in several ways: the higher response rates achieved with rituximab-based induction in the salvage setting optimize the number of patients who are able to proceed to high-dose therapy -ASCT; rituximab may improve outcomes following ASCT when used as post-transplantation consolidation/maintenance therapy; and addition of rituximab to salvage regimens may improve outcomes for patients ineligible for transplantation. However, patients refractory to or relapsing after first-line therapy (including rituximab-based regimens) still have a poor prognosis. In conclusion, rituximab in salvage therapy for DLBCL is effective and well tolerated. Ongoing studies will further clarify the optimal use of rituximab in the salvage setting.     

Decreasing mortality from non‐Hodgkin lymphoma in Australia

Based on the number of new cases (incidence), non‐Hodgkin lymphoma is an increasingly common cancer in Australia and many developed countries. Until recently, mortality trends have been stable or slightly increasing. However, since the year 2000, mortality has decreased every year by an average of 5.1% per year (95% confidence interval (CI) ?7.1 to ?3.1%), whereas incidence has continued to increase at 0.9% per year (95%CI 0.6 to 1.2%). It was not possible with the population‐based registry data available to us to untangle the causes of the decrease in mortality. The stable mortality rates during the 1990s (in the face of increasing incidence) might have been because of introduction of novel therapies such as autologous stem cell transplant for relapsed diffuse large cell lymphoma or the purine analogue‐based therapy for indolent lymphomas. A plausible explanation for the large decrease in mortality since 2000 is the introduction of the monoclonal antibody rituximab.     

Impact of prior rituximab on outcomes of autologous stem‐cell transplantation in patients with relapsed or refractory aggressive B‐cell lymphoma: a multicentre retrospective Spanish group of lymphoma/autologous bone marrow transplant study

The use of highly effective rituximab‐containing therapy for treating diffuse large B‐cell lymphoma (DLBCL) makes it more difficult to salvage relapsed or refractory patients. Autologous stem‐cell transplantation (ASCT) is the reference treatment for these patients, but the impact of previous exposure to rituximab on the subsequent results of ASCT remains unknown. We analysed 248 patients with relapsed or refractory DLBCL or grade 3B follicular lymphoma pre‐treated with rituximab as part of first‐line therapy (R+ group) who received ASCT, in comparison with a control group of 127 patients without previous exposure to rituximab (R? group). The complete remission (CR) rates were similar in both groups. Multivariate analysis identified age‐adjusted International Prognostic Index at diagnosis, extranodal involvement and disease status at transplant, and the number of previous chemotherapy lines as independent factors with a negative influence on CR rate. Compared with R? patients, those in the R+ group had a significantly better progression‐free survival (63% vs. 48% at 5 years) and overall survival (72% vs. 61% at 5 years). This observation was independent of other prognostic factors that affected these outcomes. In conclusion, ASCT is no less effective in patients with relapsed or refractory aggressive B‐cell lymphoma pre‐treated with first‐line rituximab‐containing therapy than in rituximab‐naive patients.     

A multicentre study of primary breast diffuse large B‐cell lymphoma in the rituximab era

Primary breast diffuse large B‐cell lymphoma (DLBCL) is a rare subtype of non‐Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow‐up of 4·5 years (range 0·6–20·6 years), the Kaplan–Meier estimated median progression‐free survival was 10·4 years (95% confidence interval [CI] 5·8–14·9 years), and the median overall survival was 14·6 years (95% CI 10·2–19 years). Twelve patients (16%) had CNS relapse. A low stage‐modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage‐modified IPI score is associated with survival.     

Diffuse large B‐cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era

The addition of rituximab has improved outcomes in diffuse large B‐cell lymphoma (DLBCL ), however, there remains limited information on the impact of rituximab in those with testicular involvement. All patients with diffuse large cell lymphoma and testicular involvement treated with curative intent were identified in the British Columbia Cancer Agency Lymphoid Cancer Database. In total, 134 patients diagnosed between 1982 and 2015 with diffuse large cell lymphoma involving the testis were identified: 61 received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)‐like chemotherapy and 73 received CHOP plus rituximab (R‐CHOP ). A greater proportion of R‐CHOP treated patients had higher International Prognostic Index (IPI , P  =  0·005). In multivariate analysis, the protective effect of rituximab on progression‐free survival (hazard ratio (HR ) 0·42, P  <  0·001), overall survival (HR 0·39, P  <  0·001) and cumulative incidence of progression (HR 0·46, P  =  0·014) were independent of the IPI . However, in a competing risk multivariate analysis including central nervous system (CNS ) prophylaxis and the CNS ‐IPI , rituximab was not associated with a decreased risk of CNS relapse. The addition of rituximab has reduced the risk of lymphoma recurrence in testicular DLBCL , presumably through improved eradication of systemic disease. However, CNS relapse risk remains high and further studies evaluating effective prophylactic strategies are needed.     

Guidelines for the management of diffuse large B‐cell lymphoma

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8–10 months. We conducted a phase II trial of standard CHOP‐21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2–6: 1000 mg day 1) (CHOP‐O) followed by 12 months ofatumumab maintenance (1000 mg given 8‐weekly for up to six cycles). Forty‐three patients were recruited of whom 37 were evaluable. Seventy‐three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide‐based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression‐free survival was 6·2 months (95% confidence interval [CI] 4·9–14·0 months) and median OS was 11·4 months (95% CI 6·4–25·6 months). Treatment‐naïve and TP53‐intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non‐neutropenic infections were observed. There were no treatment‐related deaths. Seven patients received platinum‐containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP‐O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.     

A phase 2 study of inotuzumab ozogamicin in patients with indolent B‐cell non‐Hodgkin lymphoma refractory to rituximab alone,rituximab and chemotherapy,or radioimmunotherapy

This phase 2 study evaluated the efficacy and safety of inotuzumab ozogamicin (InO) in patients with indolent B‐cell non‐Hodgkin lymphoma (NHL) refractory to rituximab alone, rituximab plus chemotherapy or anti‐CD20 radioimmunotherapy. Patients received InO 1·8 mg/m² intravenously on a 28‐d cycle for a planned 4–8 cycles. The initial InO dose and schedule could be adjusted for tolerability and patients were allowed to receive 2 additional cycles (up to 8 total) after achieving a complete response (CR). The primary endpoint was overall response. Eighty‐one patients were enrolled, among whom 48 (59%) received ≥3 InO cycles and 13 (16%) completed the treatment phase. The overall response rate was 67% (CR, 31%). Median (95% confidence interval) progression‐free survival was 12·7 (8·9–26·9) months; median overall survival was not reached. Haematological adverse events (AEs) were common, particularly thrombocytopenia (74%) and neutropenia (56%). These were also the most common AEs leading to treatment discontinuation (37% and 11%, respectively); 58% of patients reported AEs leading to treatment discontinuation. InO demonstrated robust activity in these heavily pretreated patients, although treatment duration was limited by haematological toxicities. Additional studies may determine dosing regimens that allow for reduced toxicity.     

Impact of rituximab on treatment outcomes of patients with diffuse large b-cell lymphoma: a population-based analysis

We conducted a multi-institutional population-based analysis of the survival and toxicity associated with the addition of rituximab to chemotherapy for patients with diffuse large B-cell lymphoma (DLBCL), including patients aged ≥ 80 years, who were excluded from published randomized trials. Using population-based registries in Ontario, we identified 4021 patients who received chemotherapy with or without rituximab (R-CHOP [rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone] or CHOP) for DLBCL between 1996 and 2007, including 397 patients aged ≥ 80 years. After propensity score matching, the overall survival (OS) and significant toxicities for R-CHOP and CHOP treatment groups were compared. R-CHOP was associated with a significant increase in 5-year OS compared to CHOP alone (62% vs. 54%; hazard of death = 0·78, P = 0·0004). Survival benefit was seen in all age groups, including those aged ≥ 80 years. Patients treated with rituximab did not have a significant increase in 1-year hospitalization rates for cardiac, pulmonary, gastrointestinal or neurological diagnoses compared to those treated with CHOP alone. The addition of rituximab to CHOP improves survival in the general population of patients with DLBCL and produces early survival benefit for very elderly patients, without any significant increase in the risk of serious toxicity.     

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.     

An audit of patients with mature T‐cell non‐Hodgkin lymphoma by transplant status in Tasmania

This retrospective audit of patients diagnosed with mature T‐cell lymphoma across a 10‐year period provides contemporary information on the outcomes and treatment patterns of an Australian cohort. Forty‐two patients diagnosed with mature T‐cell lymphoma were identified from the Tasmanian Cancer Registry and analysed using medical records and simple statistical analysis. The demographics and outcomes of patients in this cohort were comparable to large international studies with treatment patterns in line with the best available evidence.     

Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma: post‐hoc analyses from a phase III trial

This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28‐d cycles of 85 mg/m² pixantrone dimaleate (equivalent to 50 mg/m² in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2–6) with pixantrone and 3 (2–6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate (ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression‐free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26–1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B‐cell NHL in the 3rd or 4th line setting, independently of previous rituximab.     

Weekly rituximab consolidation following four cycles of R‐CHOP induction chemotherapy in very elderly patients with diffuse large B‐cell lymphoma: Consortium for improving survival of lymphoma study (CISL)

This study aimed to determine the objective response, toxicity, and clinical outcome of weekly rituximab consolidation after four cycles of R‐CHOP21 in very elderly patients with DLBCL. A prospective, multi‐institutional phase II trial was conducted on patients with previously untreated CD20⁺ DLBCL who were older than 70 yr. Patients were treated with four cycles of R‐CHOP21 followed by weekly consolidation with rituximab (375mg/m², four times infusion) (NCT01181999). We also compared the clinical outcomes with an historical case‐matched control group treated conventionally with six cycles of R‐CHOP21. A total of 51 patients with newly diagnosed DLBCL were enrolled at 15 institutes between June 2010 and September 2013 . The median age was 76 yr (range: 70–89). Forty‐one of the 51 patients completed the planned rituximab consolidation (R‐consolidation). The overall response rate was 78.4%, comprising 74.5% with a complete response and 3.9% with a partial response. After a median follow‐up of 20.3 months, 2‐yr progression‐free survival and overall survival were 63.9% and 68.7%, respectively. No serious toxicities were reported during rituximab consolidation. Weekly rituximab consolidation following four cycles of R‐CHOP21 resulted in an acceptable response with high tolerability and could be a good compromise between efficacy and safety for elderly patients with DLBCL.     

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.     

Addition of lenalidomide to rituximab,ifosfamide, carboplatin,etoposide (RICER) in first‐relapse/primary refractory diffuse large B‐cell lymphoma

Relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) is associated with a poor prognosis. Outcomes are particularly poor following immunochemotherapy failure or relapse within 12 months of induction. We conducted a Phase I/II trial of lenalidomide plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) (RICER) as a salvage regimen for first‐relapse or primary refractory DLBCL. Dose‐escalated lenalidomide was combined with RICE every 14 d. After three cycles of RICER, patients with chemosensitive disease underwent stem cell collection and consolidation with BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan] followed by autologous stem cell transplantation (autoSCT). Patients who recovered from autoSCT toxicities within 90 d initiated maintenance treatment with lenalidomide 25 mg daily for 21 d every 28 d for 12 months. No dose‐limiting or unexpected toxicities occurred with lenalidomide 25 mg plus RICE. Grade 3/4 haematological toxicities resolved appropriately, and planned dose density and dose intensity of RICER were preserved. No lenalidomide or RICE dose reductions were required in any of the three cycles. After two cycles of RICER, nine of 15 patients (60%) achieved a complete response, and two achieved a partial response (13%). Combining lenalidomide with RICE is feasible, and results in promising response rates (particularly complete response rates) in high‐risk DLBCL patients.     

Rituximab,cyclophosphamide, doxorubicin,vincristine and prednisolone (R‐CHOP) in the management of primary mediastinal B‐cell lymphoma: a subgroup analysis of the UK NCRI R‐CHOP 14 versus 21 trial

We performed a subgroup analysis of the phase III UK National Cancer Research Institute R‐CHOP‐14 versus R‐CHOP‐21 (two‐ versus three‐weekly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) trial to evaluate the outcomes for 50 patients with World Health Organization 2008 classified primary mediastinal B‐cell lymphoma identified from the trial database. At a median follow‐up of 7·2 years the 5‐year progression‐free survival and overall survival was 79·8% and 83·8%, respectively. An exploratory analysis raised the possibility of a better outcome in those who received R‐CHOP‐14 and time intensification may still, in the rituximab era, merit testing in a randomised trial in this subgroup of patients.     

Classification of non‐Hodgkin lymphoma in South‐eastern Europe: review of 632 cases from the international non‐Hodgkin lymphoma classification project

The distribution of non‐Hodgkin lymphoma (NHL) subtypes varies around the world, but a systematic study of South‐eastern Europe (SEEU) has never been done. Therefore, we evaluated the relative frequencies of NHL subtypes in three SEEU countries – Croatia, Romania and Macedonia. Five expert haematopathologists reviewed 632 consecutive cases of newly diagnosed NHL from the three SEEU countries using the World Health Organization classification. The results were compared to 399 cases from North America (NA) and 580 cases from Western Europe (WEU). The proportions of B‐ and T‐cell NHL and the sex distribution in SEEU were similar to WEU and NA. However, the median ages of patients with low‐ and high‐grade B‐NHL in SEEU (60 and 59 years, respectively) were significantly lower than in NA (64 and 68 years, respectively; P < 0·05). SEEU had a significantly lower proportion of low‐grade B‐NHL (46·6%) and higher proportion of high‐grade B‐NHL (44·5%) compared to both WEU (54·5% and 36·4%, respectively) and NA (56·1% and 34·3%, respectively). There were no significant differences in the relative frequencies of T‐NHL subtypes. This study provides new insights into differences in the relative frequencies of NHL subtypes in different geographic regions. Epidemiological studies are needed to better characterize and explain these differences.