Associations between statin use and non‐Hodgkin lymphoma (NHL) risk and survival: a meta‐analysis

Evidence on the effect of statin use on non‐Hodgkin lymphoma (NHL) is not clear. We conducted a systematic review and meta‐analysis to examine the associations between statin use and NHL risk and survival. We searched multiple literature sources up to October 2014 and identified 10 studies on the risk of diagnosis with NHL and 9 studies on survival. Random effects model was used to calculate pooled odds ratio (PORs) for risk and pooled hazard ratio (PHR) for survival. Heterogeneity among studies was examined using the Tau‐squared and the I‐squared (I²) tests. Statin use was associated with reduced risk for total NHL (POR = 0.82, 95% CI 0.69–0.99). Among statin users, there was a lower incidence risk for marginal zone lymphoma (POR = 0.54, 95% CI 0.31–0.94), but this was not observed for other types of NHL. However, statin use did not affect overall survival (PHR = 1.02, 95% CI 0.99–1.06) or event‐free survival (PHR = 0.99, 95% CI 0.87–1.12) in diffuse large B‐cell lymphoma. There is suggestive epidemiological evidence that statins decrease the risk of NHL, but they do not influence survival in NHL patients. Copyright © 2015 John Wiley & Sons, Ltd.     

Health‐related quality of life among survivors of aggressive non‐Hodgkin lymphoma

BACKGROUND:

Non‐Hodgkin lymphoma (NHL) is the fifth most common cancer among men and women. Patients with aggressive NHL receive intense medical treatments that can significantly compromise health‐related quality of life (HRQOL). However, knowledge of HRQOL and its correlates among survivors of aggressive NHL is limited.

METHODS:

Self‐reported data on HRQOL (physical and mental function, anxiety, depression, and fatigue) were analyzed for 319 survivors of aggressive NHL. Survivors 2 to 5 years postdiagnosis were selected from the Los Angeles County Cancer Registry. Bivariate and multivariable methods were used to assess the influence of sociodemographic, clinical, and cognitive health‐appraisal factors on survivors' HRQOL.

RESULTS:

After accounting for other covariates, marital status was associated with all HRQOL outcomes (P < .05). Younger survivors reported worse mental function and higher levels of depression, anxiety, and fatigue (P < .01). Survivors who had more comorbid conditions or lacked private health insurance reported worse physical and mental function and higher levels of depression and fatigue (P < .05). Survivors who experienced a recurrence reported worse physical function and higher levels of depression and fatigue (P < .05). With the exception of a nonsignificant association between perceived control and physical function, greater perceptions of personal control and health competence were associated significantly with more positive HRQOL outcomes (P < .01).

CONCLUSIONS:

The current results indicated that survivors of aggressive NHL who are younger, are unmarried, lack private insurance, or experience greater illness burden may be at risk for poorer HRQOL. Cognitive health‐appraisal factors were strongly related to HRQOL, suggesting potential benefits of interventions focused on these mutable factors for this population. Cancer 2013. © 2012 American Cancer Society.     

GBV‐C/hepatitis G virus infection and non‐Hodgkin lymphoma: a case control study

We investigated whether there was an association between GBV‐C viremia and the development of non‐Hodgkin lymphoma (NHL) in 553 NHL cases and 438 controls from British Columbia, Canada. Cases were aged 20–79, diagnosed between March 2000 and February 2004, and resident in Greater Vancouver or Victoria. Cases and controls were tested for GBV‐C RNA by RT‐PCR and positive samples were genotyped. Overall, GBV‐C RNA was detected in 4.5% of NHL cases vs. 1.8% of controls [adjusted odds ratio (OR) = 2.72, 95% confidence interval (CI) = 1.22–6.69]. The association between GBV‐C RNA detection and NHL remained even after individuals with a history of prior transfusion, injection drug use and hepatitis C virus sero‐positivity were excluded. GBV‐C viremia showed the strongest association with diffuse large B cell lymphoma (adjusted OR = 5.18, 95% CI = 2.06–13.71). Genotyping was performed on 29/33 GBV‐C RNA positive individuals; genotypes 2a (n = 22); 2b (n = 5) and 3 (n = 2) were identified, consistent with the distribution of genotypes found in North America. This is the largest case‐control study to date associating GBV‐C viremia and NHL risk. As GBV‐C is known to be transmitted through blood products this may have important implications for blood safety.     

Periodontal disease and risk of non‐Hodgkin lymphoma in the Health Professionals Follow‐Up Study

Periodontal disease is a chronic inflammatory condition that has been associated with chronic diseases, including cancer. In an earlier prospective cohort analysis within the Health Professionals Follow‐Up Study (HPFS), we observed a 31% higher risk of non‐Hodgkin lymphoma (NHL) among participants with severe periodontal disease at baseline. Here, we extend the study with an additional 8 years of follow‐up, and conduct analyses with updated periodontal disease status and NHL subtypes. The HPFS is an ongoing prospective cohort study of 51,529 men in the USA Between baseline in 1986 and 2012, 875 cases of NHL were diagnosed, including 290 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 85 diffuse large B‐cell lymphomas and 91 follicular lymphomas. We performed multivariable Cox proportional hazards regression to evaluate associations of interest. History of periodontal disease at baseline was positively associated with risk of NHL overall (hazard ratio (HR) = 1.26, 95% confidence interval (CI): 1.06–1.49) and CLL/SLL (HR = 1.41, 95% CI: 1.04–1.90). With updated periodontal status, HRs were 1.30 (95% CI: 1.11–1.51) for NHL overall and 1.41 (95% CI: 1.08–1.84) for CLL/SLL. In contrast, after adjusting for periodontal disease, tooth loss was inversely associated with NHL, suggesting that other causes or consequences of tooth loss may have different implications for NHL etiology. Our findings suggest that periodontal disease is a risk factor for NHL. Whether periodontal disease is a direct or indirect cause of NHL, or is a marker of underlying systemic inflammation and/or immune dysregulation, warrants further investigation.     

Smoking,alcohol use,obesity, and overall survival from non‐Hodgkin lymphoma

BACKGROUND:

Smoking, alcohol use, and obesity appear to increase the risk of developing non‐Hodgkin lymphoma (NHL), but to the authors' knowledge, few studies to date have assessed their impact on NHL prognosis.

METHODS:

The association between prediagnosis cigarette smoking, alcohol use, and body mass index (BMI) and overall survival was evaluated in 1286 patients enrolled through population‐based registries in the United States from 1998 through 2000. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox regression, adjusting for clinical and demographic factors.

RESULTS:

Through 2007, 442 patients had died (34%), and the median follow‐up for surviving patients was 7.7 years. Compared with never smokers, former (HR, 1.59; 95% CI, 1.12‐2.26) and current (HR, 1.50; 95% CI, 0.97‐2.29) smokers had poorer survival, and poorer survival was found to be positively associated with smoking duration, number of cigarettes smoked per day, pack‐years of smoking, and shorter time since quitting (all P <0.01). Alcohol use was associated with poorer survival (P = 0.03); compared with nonusers. Those drinking >43.1 g/week (median intake among drinkers) had poorer survival (HR, 1.55; 95% CI, 1.06‐2.27), whereas those drinkers consuming less than this amount demonstrated no survival disadvantage (HR, 1.13; 95% CI, 0.75‐1.71). Greater BMI was associated with poorer survival (P = 0.046), but the survival disadvantage was only noted among obese individuals (HR, 1.32 for BMI ≥30 vs BMI 20‐24.9; 95% CI, 1.02‐1.70). These results held for lymphoma‐specific survival and were broadly similar for diffuse large B‐cell lymphoma and follicular lymphoma.

CONCLUSIONS:

NHL patients who smoked, consumed alcohol, or were obese before diagnosis were found to have a poorer overall and lymphoma‐specific survival. Cancer 2010. © 2010 American Cancer Society.     

Cardiovascular mortality among patients with non‐Hodgkin lymphoma: Differences according to lymphoma subtype

Survival rates of patients with non‐Hodgkin lymphoma (NHL) have improved over the last decade. However, cardiotoxicities remain important adverse consequences of treatment with chemotherapy and radiation, although the burden of cardiovascular mortality (CVM) in such patients remains unknown. We conducted a retrospective cohort study of patients greater than or equal to 20 years of age diagnosed with diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) between 2000 and 2013 using data extracted from the United States Surveillance, Epidemiology, and End Results (SEER) database. Our primary endpoint was CVM. The association between NHL and CVM was evaluated using multivariable Cox regression analysis after adjusting for other patient characteristics. We calculated standardized mortality ratios (SMRs) for CVM, comparing NHL patients with the general population. We identified 153 983 patients who met the inclusion criteria (69 329 with DLBCL, 48 650 with CLL/SLL, and 36 004 with FL). The median follow‐up was 37 months (interquartile range, 10‐78 months); the mean patient age was 66.24 (±14.69) years; 84 924 (55.2%) were men; 134 720 (87.5%) were White, and 131 912 (85.7%) did not receive radiation therapy. Overall, 9017 patients (5.8%) died from cardiovascular disease, and we found that NHL patients had a higher risk of CVM than the general population, after adjusting for age (SMR 15.2, 95% confidence interval: 14.89‐15.52). The rates of CVM were 5.1%, 8%, and 4.4% in patients with DLBCL, CLL/SLL, and FL, respectively. Furthermore, across all NHL subtypes, older age, higher stage at the time of diagnosis (particularly stage 4), male sex, and living in the south were associated with higher risks of CVM. Our data suggest that risk assessment and careful cardiac monitoring are recommended for NHL patients, particularly those with the CLL/SLL subtypes.     

Presence of autoimmune disease affects not only risk but also survival in patients with B‐cell non‐Hodgkin lymphoma

Although autoimmune diseases (AIDs) are known to predispose to non‐Hodgkin lymphoma (NHL), their association with NHL prognosis has rarely been investigated. We examined associations between autoimmunity and B‐cell NHL onset by comparing AID history (determined by self‐report and medication review and supplemented by chart review where possible) among 435 adult B‐NHL patients in Hadassah‐Hebrew University Medical Center, diagnosed 2009‐2014, and 414 age‐and‐sex frequency‐matched controls. We examined AIDs as a whole, B‐ and T‐cell–mediated AIDs, and autoimmune thyroid diseases. Among cases, we used Kaplan‐Meier and Cox regression models to assess the association of AID with overall survival and relapse‐free survival, adjusting for prognostically important patient and disease characteristics such as Ki67% staining, International Prognostic Index, rituximab treatment, and histological subgroup. Autoimmune diseases were associated with B‐NHL (odds ratio [OR] = 1.95; 95% confidence interval (CI), 1.31‐2.92), especially AIDs mediated by B‐cell activation (OR = 5.20; CI, 1.90‐14.3), which were particularly associated with marginal zone lymphoma (OR = 19.3; CI, 4.59‐80.9). We found that time to relapse for all B‐NHL patients with AIDs was significantly shorter (mean of 49.21 mo [±3.22]) than among patients without AID (mean of 59.74 mo [±1.62]), adjusted hazard ratio [HR_adj] = 1.69 (CI, 1.03‐2.79). Specifically, in patients with diffuse large B‐cell lymphoma, of whom 91.8% had received rituximab, a history of B‐cell–mediated AIDs was associated with shorter relapse‐free survival and overall survival, HR_adj = 8.34 (CI, 3.01‐23.1) and HR_adj = 3.83 (CI, 1.20‐12.3), respectively. Beyond confirming the well‐known association between AIDs and B‐NHL, we found that AID is an adverse prognostic factor in B‐cell lymphoma, associated with a shortened time to relapse, suggesting that there are specific therapeutic challenges in the subgroup of patients suffering from both these diseases. Further work is required to address mechanisms of resistance to standard treatment in the setting of AID‐associated B‐NHL. In the era of immunotherapy, these findings have particular relevance.     

Pretransplantation [18‐F]fluorodeoxyglucose positron emission tomography scan predicts outcome in patients with recurrent Hodgkin lymphoma or aggressive non‐Hodgkin lymphoma undergoing reduced‐intensity conditioning followed by allogeneic stem cell transplantation

BACKGROUND:

The use of positron emission tomography (PET) scanning in Hodgkin lymphoma (HL) and aggressive non‐Hodgkin lymphoma (HG‐NHL) has recognized prognostic value in patients who are receiving chemotherapy or undergoing autologous stem cell transplantation (SCT). In contrast, the role of PET before reduced‐intensity conditioning (RIC) and followed by allogeneic SCT has not been investigated to date.

METHODS:

PET was used to assess 80 patients who had chemosensitive disease (34 patients with HG‐NHL and 46 patients with HL) before they underwent allogeneic SCT: 42 patients had negative PET studies, and 38 patients had positive PET studies. Patients underwent allograft from matched related siblings (n = 41) or alternative donors (n = 39).

RESULTS:

At the time of the last follow‐up, 48 patients were alive (60%), and 32 had died. The 3‐year cumulative incidence of nonrecurrence mortality and disease recurrence was 17% and 40%, respectively. The cumulative incidence of disease recurrence was significantly lower in the PET‐negative patients (25% vs 56%; P = .007), but there was no significant difference between the patients with or without chronic graft‐versus‐host disease (P = .400). The patients who had negative PET studies before undergoing allogenic SCT also had significantly better outcomes in terms of 3‐year overall survival (76% vs 33%; P = .001) and 3‐year progression‐free survival (73% vs 31%; P = .001). On multivariate analysis, overall survival was influenced by PET status (hazard ratio [HR], 3.35), performance status (HR, 5.15), and type of donor (HR, 6.26 for haploidentical vs sibling; HR, 1.94 for matched unrelated donor vs sibling).

CONCLUSIONS:

The current results indicated that PET scanning appears to be an accurate tool for assessing prognosis in patients who are eligible for RIC allografting. Cancer 2010. © 2010 American Cancer Society.     

Successful treatment of non‐Hodgkin lymphoma associated immune thrombocytopenia with involved field radiotherapy

Immune thrombocytopenia complicates the course and impacts the outcome of non‐Hodgkin lymphoma (NHL‐ITP, non‐Hodgkin lymphoma–immune thrombocytopenic purpura). The response to corticosteroids and/or intravenous immune globulins is usually short lasting, but NHL‐ITP usually responds to anti‐lymphoma chemotherapy. It is not clear if this success is due to the elimination of the lymphomatous tissue or to the immunosuppressor/immunomodulator effect of chemotherapy. Myelosuppressive anti‐lymphoma chemotherapy carries the risk of severe thrombocytopenia that may not respond adequately to platelet transfusion support. We report on a patient with recurrent diffuse large B‐cell lymphoma that coincided with immune thrombocytopenia. Both diseases completely responded to involved field radiation therapy. This supports the hypothesis that at least in some cases of NHL‐ITP, the lymphomatous clone secretes the anti‐platelet antibodies. This supports the therapeutic decision making for these patients. Copyright © 2013 John Wiley & Sons, Ltd.     

Bendamustine is effective therapy in patients with rituximab‐refractory,indolent B‐cell non‐Hodgkin lymphoma

BACKGROUND:

Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single‐agent bendamustine in patients with rituximab‐refractory, indolent B‐cell lymphoma.

METHODS:

Eligible patients (N = 100, ages 31‐84 years) received bendamustine at a dose of 120 mg/m² by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0‐6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression‐free survival (PFS).

RESULTS:

An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).

CONCLUSIONS:

Single‐agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab‐refractory indolent B‐cell lymphoma. Cancer 2010. © 2010 American Cancer Society.     

Use of non‐steroidal anti‐inflammatory drugs and risk of non‐Hodgkin lymphoma: a systematic review and meta‐analysis

Epidemiological study findings regarding the association between use of non‐steroidal anti‐inflammatory drugs (NSAIDs) and risk of non‐Hodgkin lymphoma (NHL) have been inconsistent. We aimed to systematically review epidemiological studies of the association and calculate pooled relative risks using meta‐analytic methods. We searched eight electronic literature databases and three clinical trial registers to identify all studies (including observational studies and randomized clinical trials) of the association published prior to October 2013. Identified studies were independently reviewed by two researchers. We used a random effects model to calculate pooled odds ratio (PORs). Heterogeneity amongst studies was examined using Cochran's Q and I‐squared (I²) tests; and sources of heterogeneity were explored using subgroup and meta‐regression analyses. A total of 17 studies (12 case‐control studies and five cohort studies), all adult studies, were included. Use of NSAIDs was not associated with overall risk of NHL [POR = 1.05, and 95% confidence interval (95% CI) 0.90–1.22] or NHL subtypes including B‐cell lymphoma, T‐cell lymphoma, follicular lymphoma, diffuse large B‐cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Aspirin use was associated with reduced risk of CLL/SLL (POR = 0.70, 95% CI 0.54–0.91) but not with the risk of all NHLs (POR = 1.02, 95% CI 0.89–1.17). Use of non‐aspirin NSAIDs was associated with increased risk of NHL (POR = 1.41, 95% CI 1.01–1.97) amongst females only. The epidemiologic evidence remains inconclusive. Effects of NSAIDs may differ by drug type, NHL subtype, and sex and more studies taking into consideration these differences are needed. Copyright © 2014 John Wiley & Sons, Ltd.     

Relationship between ambient ultraviolet radiation and non‐Hodgkin lymphoma subtypes: A U.S. population‐based study of racial and ethnic groups

Associations between ultraviolet radiation (UVR) exposure and non‐Hodgkin lymphoma (NHL) have been inconsistent, but few studies have examined these associations for specific subtypes or across race/ethnicities. We evaluated the relationship between ambient UVR exposure and subtype‐specific NHL incidence for whites, Hispanics and blacks in the United States for years 2001–2010 (n = 187,778 cases). Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for UVR quintiles using Poisson regression. Incidence was lower for the highest UVR quintile for chronic/small lymphocytic/leukemia (CLL/SLL) (IRR = 0.87, 95% CI: 0.77–0.97), mantle cell (IRR = 0.82, 95% CI: 0.69–0.97), lymphoplasmacytic (IRR = 0.58, 95% CI: 0.42–0.80), mucosa‐associated lymphoid tissue (MZLMALT) (IRR = 0.74, 95% CI: 0.60–0.90), follicular (FL) (IRR = 0.76, 95% CI: 0.68–0.86), diffuse large B‐cell (IRR = 0.84, 95% CI: 0.76–0.94;), peripheral T‐cell other (PTCL) (IRR = 0.76, 95% CI: 0.61–0.95) and PTCL not otherwise specified (PNOS) (IRR = 0.77, 95% CI: 0.61–0.98). Trends were significant for MZLMALT, FL, DLBCL, BNOS and PTCL, with FL and DLBCL still significant after Bonferroni correction. We found interaction by race/ethnicity for CLL/SLL, FL, Burkitt, PNOS and MF/SS, with CLL/SLL and FL still significant after Bonferroni correction. Some B‐cell lymphomas (CLL/SLL, FL and Burkitt) suggested significant inverse relationships in whites and Hispanics, but not in blacks. Some T‐cell lymphomas suggested the most reduced risk for the highest quintile of UVR among blacks (PNOS and MF/SS), though trends were not significant. These findings strengthen the case for an inverse association of UVR exposure, support modest heterogeneity between NHL subtypes and suggest some differences by race/ethnicity.     

The impact of cancer and quality of life for post‐treatment non‐Hodgkin lymphoma survivors

Objective: Recent work suggests that perceptions of the impact of cancer on survivors' lives are associated with physical and mental health and quality of life (QOL) outcomes. This study examines the association between the Impact of Cancer Version 2 Scales (IOCv2) and these outcomes in a large sample of survivors of adult non‐Hodgkin lymphoma (NHL). Methods: Participants completed a mailed survey to assess physical and mental health (SF‐36), cancer‐specific QOL (FACT‐G) and perceived impact of cancer (IOCv2). Hierarchical multiple regression models, in which demographic, clinical, psychosocial and IOCv2 measures were added sequentially, were employed to evaluate their contribution to explain variance in SF‐36 and FACT‐G scores. Results: A total of 652 post‐treatment NHL survivors participated. Survivors with comorbidities and negative appraisals of life threat and treatment intensity reported worse physical and mental health and QOL (all p<0.05). After controlling for demographic and clinical characteristics, younger respondents reported better physical but worse mental health and QOL (all p<0.01). Lower IOCv2 Negative Impact (all p<0.001) and higher Positive Impact (all p<0.05) scores were associated with better physical and mental health and QOL after controlling for demographic, clinical and psychosocial characteristics. Conclusions: Findings suggest that perceptions of cancer's impact on survivors' lives may influence or be influenced by health status and functioning and QOL. Longitudinal research is needed to establish causality, which could lead to the development of interventions targeting survivors' impact of cancer concerns, and ultimately to the enhancement of overall health and QOL. Copyright © 2010 John Wiley & Sons, Ltd.     

Cancer risks among relatives of children with Hodgkin and non-Hodgkin lymphoma

A role for genetic susceptibility in the aetiology of childhood lymphomas was investigated in 454 families of children with histologically confirmed Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) from Northwest England. Cancers in parents were obtained from the UK National Health Service Central Register and in other close relatives by interview with the parents. The cancer incidence among relatives was compared with expected incidence based on cancer registry data for England. There were 197 cancers in relatives (SIR 1.0 95% CI 0.8-1.1). In families of children with HL, there was an excess of HL in the first degree relatives (SIR 5.8 95% CI 1.2-16.9). Excesses of HL diagnosed under population median age (SIR 4.1 95% CI 1.1-10.6) were seen among all relatives and relatives of children who were below the median age at diagnosis (SIR 5.5 95% CI 1.1-16.0). In families of children with NHL, there were non-significant excesses of central nervous system (CNS) tumours in the first degree relatives (SIR 2.9 95% CI 0.8-7.4) and in the second and third degree relatives (SIR 1.5). There were significant excesses of CNS tumours diagnosed under the population median age (SIR 2.8 95% CI 1.1-5.8) in all relatives. Excess CNS tumours were also seen among relatives of children below the median age at diagnosis (SIR 3.2 95% CI 1.1-7.6). In conclusion, genetic susceptibility in some families of children with lymphoma might be operating, but aetiologies in HL and NHL appear to be different. Possible interpretations of our findings, in the context of putative genetic and infectious aetiologies, are discussed.