Follicular lymphoma (FL) has variable progression and survival, and improved identification of patients at high risk for progression would aid in identifying patients most likely to benefit from alternative therapy. In a sample of 244 FL cases identified during a population-based case-control study of non-Hodgkin lymphoma (NHL), we examined 6,679 tag SNPs in 488 gene regions for associations with overall FL survival. Over a median follow-up of 89 months with 65 deaths in this preliminary study, we identified 5 gene regions (BMP7, GALNT12, DUSP2, GADD45B, and ADAM17) that were associated with overall survival from FL. Results did not meet the criteria for statistical significance after adjustment for multiple hypothesis testing. These results, which support a role for host factors in determining the variable progression of FL, serve as an initial examination that can inform future studies of genetic variation and FL survival. However, they require replication in independent populations, as well as assessment in rituximab-treated patients.
follicular lymphoma; genetic variation; survival; tag SNP; case-control study
Antioxidants, primarily from fruits and vegetables, have been hypothesized to protect against non-Hodgkin lymphoma (NHL). The Oxygen Radical Absorbance Capacity (ORAC) assay, which measures total antioxidant capacity of individual foods and accounts for synergism, can be estimated using a food-frequency questionnaire (FFQ). We tested the hypothesis that higher intake of antioxidant nutrients from foods, supplements, and FFQ-based ORAC values are associated with a lower risk of NHL in a clinic-based study of 603 incident cases and 1007 frequency-matched controls. Diet was assessed with a 128-item FFQ. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals adjusted for age, sex, residence and total energy. Dietary intake of α-tocopherol (OR=0.50; p-trend=0.0002), β-carotene (OR=0.58; p-trend=0.0005), lutein/zeaxanthin (OR=0.62; p-trend=0.005), zinc (OR=0.54; p-trend=0.003) and chromium (OR=0.68; p-trend=0.032) were inversely associated with NHL risk. Inclusion of supplement use had little impact on these associations. Total vegetables (OR=0.52; p-trend<0.0001), particularly green leafy (OR=0.52; p-trend<0.0001) and cruciferous (OR=0.68; p-trend=0.045) vegetables, were inversely associated with NHL risk. NHL risk was inversely associated with both hydrophilic ORAC (OR=0.61, p-trend=0.003) and lipophilic ORAC (OR=0.48, p-trend=0.0002), although after simultaneous adjustment for other antioxidants or total vegetables only the association for lipophilic ORAC remained significant. There was no striking heterogeneity in results across the common NHL subtypes. Higher antioxidant intake as estimated by the FFQ-ORAC, particularly the lipophilic component, was associated with a lower NHL risk after accounting for other antioxidant nutrients and vegetable intake, supporting this as potentially useful summary measure of total antioxidant intake.
Diet; non-Hodgkin lymphoma; vegetables; antioxidants; ORAC
While standard clinical prognostic factors predict outcome in diffuse large B-cell lymphoma (DLBCL), predicting the outcome of patients might be further refined using biological factors. We tested whether serum cytokines could provide prognostic information in DLBCL patients. Thirty cytokines were measured in pre-treatment samples from newly diagnosed DLBCL patients using a multiplex ELISA. Sixty-nine patients treated with R-CHOP plus epratuzumab were used in an initial cohort and 185 patients treated with standard R-CHOP served as a subsequent validation cohort. In the initial cohort, elevated serum IL-10 (interleukin-10; HR=6.6, p=0.022), GM-CSF (granulocyte macrophage colony-stimulating factor; HR=10.8, p=0.027) and IP-10 (interferon-inducible protein-10, CXCL10; HR=3.32, p=0.015) were associated with event-free survival (EFS). An identical analysis of the subsequent validation cohort confirmed that elevated serum levels of IP-10 were strongly associated with a poor EFS (HR=2.42, p= 0.0007); and also identified IL-8 (interleukin-8; HR=3.40, p= 0.00002) and IL-2R (interleukin-2 receptor, CD25; HR=2.59, p= 0.0012) as significantly associated with prognosis. The prognostic significance of elevated IP-10 remained significant after adjustment for the International Prognostic Index (IPI; EFS – HR 1.99, p=0.009, overall survival- HR 1.93, p=0.021). Elevated pretreatment serum IP-10 levels are therefore associated with an increased likelihood of disease relapse and an inferior survival in patients with DLBCL.
IP-10; CXCL10; cytokines; diffuse large B-cell lymphoma; prognosis
The complement pathway plays a central role in innate immunity, and also functions as a regulator of the overall immune response. We evaluated whether polymorphisms in complement genes are associated with event-free survival (EFS) in follicular (FL) and diffuse large B-cell (DLBCL) lymphoma. We genotyped 167 single nucleotide polymorphisms (SNPs) from 30 complement pathway genes in a prospective cohort study of newly diagnosed FL (N=107) and DLBCL (N=82) patients enrolled at the Mayo Clinic from 2002–2005. Cox regression was used to estimate Hazard Ratios (HRs) for individual SNPs with EFS, adjusting for FLIPI or IPI and treatment. For gene-level analyses, we used a principal components based gene-level test. In gene-level analyses for FL EFS, CFH (p=0.009), CD55 (p=0.006), CFHR5 (p=0.01), C9 (p=0.02), CFHR1 (p=0.03), and CD46 (p=0.03) were significant at p<0.05, and these genes remained noteworthy after accounting for multiple testing (q<0.15). SNPs in CFH, CFHR1, and CFHR5 showed stronger associations among patients receiving any rituximab, while SNPs from CD55 and CD46 showed stronger associations among patients who were observed. For DLBCL, only CLU (p=0.001) and C7 (p=0.03) were associated with EFS, but did not remain noteworthy after accounting for multiple testing (q>0.15). Genes from the Regulators of Complement Activation (CFH, CD55, CFHR1, CFHR5, CD46) at 1q32-q32.1, along with C9, were associated with FL EFS after adjusting for clinical variables, and if replicated, these findings add further support for the role of host innate immunity in FL prognosis.
non-Hodgkin lymphoma; complement pathway; SNPs; prognosis; prospective cohort
Both LMO2 mRNA and protein expression in diffuse large B-cell lymphoma (DLBCL) have been associated with superior survival; however, a role for germline genetic variation in LMO2 has not been previously reported. Immunohistochemistry (IHC) for LMO2 was conducted on tumor tissue from diagnostic biopsies, and 20 tag single nucleotide polymorphisms (SNPs) from LMO2 were genotyped from germline DNA. LMO2 IHC positivity was associated with superior survival (HR=0.55; 95% CI 0.31–0.97). Four LMO2 SNPs (rs10836127, rs941940, rs750781, rs1885524) were associated with survival after adjusting for LMO2 IHC and clinical factors (p<0.05), and one of these SNPs (rs941940) was also associated with IHC positivity (p=0.02). Compared to a model with clinical factors only (c-statistic=0.676), adding the 4 SNPs (c-statistic=0.751) or LMO2 IHC (c-statistic=0.691) increased the predictive ability of the model, while inclusion of all 3 factors (c-statistic=0.754) did not meaningfully add predictive ability above a model with clinical factors and the 4 SNPs. In conclusion, germline genetic variation in LMO2 was associated with DLBCL prognosis and provided slightly stronger predictive ability relative to LMO2 IHC status.
Diffuse large B-cell lymphoma; LMO2; prognosis; single nucleotide polymorphisms
The purpose of this study was to determine the activity of topotecan given by 21-day continuous infusion in patients previously treated with one prior therapy for a diffuse large cell lymphoma or immunoblastic lymphoma. Patients with appropriate histology and measurable disease who had been treated with one prior chemotherapy regimen were eligible for study. Slides of tumor biopsies were submitted for central review of pathology. Patients were required to have ECOG performance status of 0, 1, or 2 and adequate bone marrow function. Patients were treated with continuous infusion topotecan, 0.4 mg/m2/day × 21 days. Therapy could be escalated to 0.5 and then 0.6 mg/m2/day in subsequent cycles if there was no dose limiting toxicity at the initial dose level. Patients were treated with 2 cycles after achieving complete response or until disease progression or unacceptable toxicity occurred. Thirty seven patients were enrolled, however, only 26 cases were eligible due to performance status of > 2 (2), more than one prior chemotherapy (1), and wrong histology on review (8). Due to the unexpectedly high ineligibility rate, two sets of analysis were done for all the 37 patients enrolled and for the 26 eligible patients, respectively. Of the 37 patients (15 males and 22 females), international prognostic index included 11% low risk, 30% low-intermediate risk; 46% high-intermediate risk, and 8% high risk. The median follow up was 77 months. A total of 136 cycles of therapy were given with a median of 3 cycles per patient. Grade 4 toxicities included: 14% grade 4 thrombocytopenia; 14% grade 4 granulocytopenia, 8% leukopenia, 3% each anemia, hemorrhage, infection, vomiting, thrombosis, liver toxicity, and neuromotor toxicity. The response analysis including all 37 patients showed 5 complete remissions (CR) and 4 partial remissions (PR) for a total response rate of 24% (90% two-stage confidence interval 13–39%). Median progression free survival (PFS) was 3.7 months, with one and two year PFS of 21% and 6% respectively (90% confidence interval 11–34% and 2–15%). Median overall survival (OS) was 10.5 months, with one and two year OS 41% and 27% respectively (90% confidence interval 27–53% and 16–39%). Analysis including only eligible patient showed similar response rates and survival outcomes. Single agent topotecan has moderate activity for previously treated high grade lymphoma equivalent to that of several newer agents, and should be considered for incorporation into multi-drug salvage chemotherapy programs.
Background & Aims
Celiac disease (CD) is associated with an increased risk of lymphoma. However, relatively few studies have assessed the outcome of patients diagnosed with both CD and lymphoma. We evaluated the temporal association between lymphoma and CD, along with clinical presentation, response to therapy, and prognosis.
Patients diagnosed with both CD and lymphoma were identified retrospectively in a tertiary referral center. Clinical characteristics and survival were analyzed.
Sixty-three patients (36 men) were identified who had been diagnosed with lymphoma and CD. Thirty-six (57%) were diagnosed with CD before they were diagnosed with lymphoma. The most common histologic entity was diffuse, large, B-cell lymphoma, which affected 18 (29%) patients. Complete information for staging was available in 59 patients; 24 (38%) had stage IV disease. Only chemotherapy or only radiation therapy was used for 43 (68%) and 11 (17%) patients, respectively. The 5- and 10-year cumulative survival rates for the entire cohort were 58% and 39%, respectively. Survival of patients with T-cell lymphoma was shorter than for all other lymphomas (119.4 vs 22.8 mo; P = .02).
CD is associated with B- and T-cell lymphomas. Patients with B-cell lymphomas had a better prognosis than those with T-cell lymphoma. Therapy is unsatisfactory for enteropathy-type T-cell lymphoma.
Cancer; Enteropathy; GI Disease; Gluten
The serum free light chain (FLC) assay quantitates free immunoglobulin kappa and lambda light chains, which has prognostic value in plasma cell dyscrasias. However, there is limited data on serum FLC in lymphoid malignancies. We analyzed the association of pretreatment FLC with event-free survival (EFS) and overall survival (OS) in 100 patients with Hodgkin lymphoma (HL). Elevated polyclonal FLC were present in 30% of patients; these patients had an inferior EFS (HR = 4.84; 95% CI: 1.84–12.7) and OS (HR = 8.87; 95% CI: 2.35–33.52) compared to patients with normal FLC. Further studies of FLC in HL are warranted.
The serum free light chain (FLC) assay quantitates free kappa (κ) and free lambda (λ) immunoglobulin light chains. This assay has prognostic value in plasma cell proliferative disorders. There are limited data on serum FLC in B-cell malignancies.
Patients and Methods
The association of pretreatment FLC with event-free survival (EFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) was evaluated in 76 patients from the North Central Cancer Treatment Group trial N0489 (NCT00301821) and 219 patients from the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER). Published reference ranges were used to define an elevated FLC or an abnormal κ:λ FLC ratio.
Elevated FLC or abnormal κ:λ FLC ratio was present in 32% and 14% of patients, respectively. Patients with elevated FLC had an inferior OS and EFS in both cohorts compared with patients with normal FLC (N0489: EFS hazard ratio [HR], 3.06; OS HR, 3.16; both P < .02; MER: EFS HR, 2.42; OS HR, 3.40; both P < .001; combined EFS HR, 2.57; OS HR, 3.74; both P < .001). All associations remained significant for EFS and OS after adjusting for the International Prognostic Index (IPI). Abnormal κ:λ FLC ratio was modestly associated with outcome in the combined group (EFS HR, 1.61; OS HR, 1.67; both P = .07), but not in patients without corresponding elevated κ or λ. Elevated FLC was the strongest predictor of outcome in multivariable models with the IPI components.
Increased serum FLC is an independent, adverse prognostic factor for EFS and OS in DLBCL and warrants further evaluation as a biomarker in DLBCL.
Non-Hodgkin lymphoma (NHL) is a malignancy of lymphocytes, and there is growing evidence for a role of germline genetic variation in immune genes in NHL etiology.
To identify susceptibility immune genes, we conducted a 2-stage analysis of single nucleotide polymorphisms (SNPs) from 1,253 genes using the Immune and Inflammation Panel. In Stage 1, we genotyped 7,670 SNPs in 425 NHL cases and 465 controls, and in Stage 2 we genotyped the top 768 SNPs on an additional 584 cases and 768 controls. The association of individual SNPs with NHL risk from a log-additive model was assessed using the Odds Ratios (ORs) and 95% confidence intervals (CI).
In the pooled analysis, only the TAP2 coding SNP rs241447 (MAF=0.26; Thr655Ala) at 6p21.3 (OR=1.34, 95%CI 1.17-1.53) achieved statistical significance after accounting for multiple testing (p=3.1 × 10−5). The TAP2 SNP was strongly associated with follicular lymphoma (FL, OR=1.82, 95%CI 1.46-2.26; p=6.9 × 10−8), and was independent of other known loci (rs10484561 and rs2647012) from this region. The TAP2 SNP was also associated with diffuse large B-cell lymphoma (DLBCL, OR=1.38, 95% CI 1.08-1.77; p=0.011), but not chronic lymphocytic leukemia (OR=1.08; 95% CI 0.88-1.32). Higher TAP2 expression was associated with the risk allele in both FL and DLBCL tumors.
Genetic variation in TAP2 was associated with NHL risk overall, and FL risk in particular, and this was independent of other established loci from 6p21.3.
Genetic variation in antigen presentation of HLA class I molecules may play a role in lymphomagenesis.
genetics; non-Hodgkin lymphoma; immune function; single nucleotide polymorphisms
The t(14;18)(q32;q21) is the most commonly observed chromosomal translocation in non-Hodgkin lymphoma (NHL), resulting in constitutive Bcl-2 expression and apoptosis inhibition. In addition, germline variation in both BCL2L11 (BIM) and CASP9, known regulators of apoptosis, have recently been linked to NHL risk. We conducted a comprehensive evaluation of 36 apoptosis pathway genes with risk of NHL.
We genotyped 226 single nucleotide polymorphisms (SNPs) from 36 candidate genes in a clinic-based study of 441 newly diagnosed NHL cases and 475 frequency matched controls. We used principal components analysis to assess gene-level associations, and logistic regression to assess SNP-level associations. MACH was used for imputation of SNPs in BCL2L11 and CASP9.
In gene level analyses, BCL2L11 (p=0.0019), BCLAF1 (p=0.0097), BAG5 (p=0.026) and CASP9 (p=0.0022) were associated with NHL risk after accounting for multiple testing (tail strength 0.38; 95% CI 0.05, 0.70). Two of the 5 BCL2L11 tagSNPs (rs6746608 and rs12613243), both genotyped BCLAF1 tagSNPs (rs797558 and rs703193), the single genotyped BAG5 tagSNP (rs7693), and 3 of the 7 genotyped CASP9 tagSNPs (rs6685648, rs2020902, rs2042370) were significant at p<0.05. We successfully imputed BCL2L11 and CASP9 SNPs previously linked to NHL, and replicated all 4 BCL2L11 and 2 of 3 CASP9 SNPs.
We replicated the association of BCL2L11 and CASP9 with NHL risk at the gene and SNP-level, and identified novel associations with BCLAF1 and BAG5.
Closer evaluation of germline variation of genes in the apoptosis pathway with risk of NHL and its subtypes is warranted.
Bcl-2 pathways; caspases; molecular epidemiology; non-Hodgkin lymphoma
Vitamin D insufficiency is common in the United States, with low levels linked in some studies to higher cancer incidence, including non-Hodgkin's lymphoma (NHL). Recent data also suggest that vitamin D insufficiency is related to inferior prognosis in some cancers, although there are no data for NHL.
Patients and Methods
We tested the hypothesis that circulating 25-hydroxyvitamin D [25(OH)D] levels are predictive of event-free survival (EFS) and overall survival (OS) in a prospective cohort of 983 newly diagnosed patients with NHL. 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels were measured by liquid chromatography-tandem mass spectrometry.
Mean age at diagnosis was 62 years (range, 19 to 94 years); 44% of patients had insufficient 25(OH)D levels (< 25 ng/mL) within 120 days of diagnosis. Median follow-up was 34.8 months; 404 events and 193 deaths (168 from lymphoma) occurred. After adjusting for known prognostic factors and treatment, 25(OH)D insufficient patients with diffuse large B-cell lymphoma (DLBCL) had inferior EFS (hazard ratio [HR], 1.41; 95% CI, 0.98 to 2.04) and OS (HR, 1.99; 95% CI, 1.27 to 3.13); 25(OH)D insufficient patients with T-cell lymphoma also had inferior EFS (HR, 1.94; 95% CI, 1.04 to 3.61) and OS (HR, 2.38; 95% CI, 1.04 to 5.41). There were no associations with EFS for the other NHL subtypes. Among patients with DLBCL and T-cell lymphoma, higher 1,25(OH)2D levels were associated with better EFS and OS, suggesting that any putative tumor 1-α-hydroxylase activity did not explain the 25(OH)D associations.
25(OH)D insufficiency was associated with inferior EFS and OS in DLBCL and T-cell lymphoma. Whether normalizing vitamin D levels in these patients improves outcomes will require testing in future trials.
No published survey has specifically addressed the beliefs, knowledge, and usage of complementary and alternative medicine (CAM) in long-term (5 to 20 years) lymphoma survivors alone. In this pilot project, 95 subjects were randomly selected from a population of 2,475 long-term lymphoma survivors and mailed a questionnaire. The median time from lymphoma diagnosis to completion of the questionnaire was 11 years (range 6-20). Overall, 68% (95% CI: 54-80%) of the long-term lymphoma survivors reported that they have used CAM, a rate higher than the estimated usage rate reported for the general population The most commonly used modalities were chiropractic (39%, 95% CI: 27-53%) and massage therapy (21%, 95% CI: 12-34%). Less than 10% used meditation (5%, 95% CI: 1-15%) and relaxation (7%, 95% CI: 2-17%). In terms of common herbal usage, 5% (95% CI: 1-15%) had used St. John’s Wort and 7% (95% CI: 2-17%) had used shark cartilage. While none of the patients reported that CAM usage was directed specifically towards treating their lymphoma, 4% (95% CI: 0-12%) of patients reported that CAM could cure cancer, and 14% (95% CI: 6-26%) reported that CAM could increase their feeling of control over their health. This pilot study suggests that long-term lymphoma survivors appear to use CAM at a rate higher than the general population. The use of potential agents of risk by the survivors and the lack of access to potentially beneficial modalities highlights the need for further study of CAM in this population.
complementary medicine; Hodgkin lymphoma; non-Hodgkin lymphoma
This study evaluates the predictive value of post-therapy FDG-PET, including indeterminate studies, following curative intent therapy in Diffuse Large B-cell Lymphoma (DLBCL).
Consecutive, patients from September 2002-December 2005 were prospectively offered enrollment in an observational registry. Available FDG-PET reports after primary therapy were interpreted by hematologists-oncologists as positive, negative or indeterminate.
125 DLBCL patients had median follow-up of 35.2 months. Ninety-three percent were treated with R-CHOP-like therapy. Twenty percent of PET reports were judged indeterminate. EFS at 3 years for the negative and indeterminate groups was 85% and 71% respectively (p=0.28 by log-rank). OS at 3 years for negative, indeterminate, and positive groups was 89%, 88%, and 48%. Combining pre-therapy International Prognostic Index (IPI) with the post-therapy FDG-PET result added to the predictive value of the study for patients. Three-year EFS for patients with low or low-intermediate IPI risk and an indeterminate FDG-PET report was 93% while high or high-intermediate pre-therapy IPI patients had a 3 year EFS of 45%(p<0.02). Interpreting FDG-PET reports following curative intent chemotherapy in patients is informative but imprecise, and incorporation of pre-therapy prognosis can improve predictive utility.
Diffuse large B-cell lymphoma; FDG-PET; prognosis
Smoking, alcohol use, and obesity appear to increase the risk of developing non-Hodgkin lymphoma (NHL), but few studies have assessed their impact on NHL prognosis.
We evaluated the association of pre-diagnosis cigarette smoking, alcohol use, and body mass index (BMI) on overall survival in 1,286 patients enrolled through population-based registries in the United States from 1998–2000. Hazard Ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression, adjusting for clinical and demographic factors.
Through 2007, 442 patients died (34%), and the median follow-up on living patients was 7.7 years. Compared to 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 positively associated with smoking duration, number of cigarettes smoked per day, pack-years of smoking, and shorter time since quitting (all p-trend<0.01). Alcohol use was associated with poorer survival (p-trend=0.03); compared to non-users, those drinking more than 43.1 grams/week (median of intake among drinkers) had poorer survival (HR=1.55; 95% CI 1.06–2.27) while those drinkers consuming less than this amount showed no survival disadvantage (HR=1.13; 95% CI 0.75–1.71). Greater body mass index was associated with poorer survival (p-trend=0.046), but the survival disadvantage was only seen among obese individuals (HR=1.32 for BMI ≥30 versus 20–24.9 kg/m2; 95% CI 1.02–1.70). These results held for lymphoma-specific survival and were broadly similar for DLBCL and follicular lymphoma.
NHL patients who smoked, consumed alcohol or were obese prior to diagnosis had a poorer overall and lymphoma-specific survival.
alcohol; non-Hodgkin lymphoma; obesity; smoking; survival
Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) often have chemotherapy resistant disease resulting in a poor prognosis. The aim of this study was to learn if inhibition of the mammalian target of rapamycin (mTOR) would produce tumor responses.
This was a phase II study of oral single-agent everolimus (10 mg/day) for relapsed/refractory indolent lymphoid malignancies including CLL.
Four of 22 patients with CLL (18%, 95% CI: 5–40%) achieved a partial remission to therapy. An unanticipated finding in this study was an increase in the absolute lymphocyte count (ALC) associated with a decrease in lymphadenopathy in 8 (36%) patients. The ALC increased a median of 4.8 fold (range, 1.9 – 25.1), and the clinically measurable lymphadenopathy decreased a median of 75.5% (range, 38 – 93) compared to baseline measurements.
Everolimus has modest anti-tumor activity against CLL and can mobilize malignant cells from nodal masses into the peripheral circulation in a subset of CLL patients. Because CLL cells in lymphatic tissue and bone marrow can be more resistant to therapy than circulating CLL cells, the ability of everolimus to mobilize CLL cells into the circulation could be utilized in combination therapeutic regimens.
CLL; mTOR; inhibitor; everolimus; rapamycins; mobilization
To prospectively investigate the prognostic significance of p21 and p53 expression in diffuse large B cell lymphoma (DLBCL) in the context of the US Intergroup trial comparing conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy to rituximab (R)-CHOP induction, with or without maintenance rituximab (MR).
Immunohistochemical staining of 197 paraffin-embedded biopsy specimens was scored by an independent panel of experts.
The cyclin-dependent kinase inhibitor, p21, was expressed in 55% of cases examined. In a multivariable analysis adjusting for International Prognostic Index score and BCL2 status, p21 expression was a significant, independent, favorable predictive factor for failure free survival and overall survival (FFS: relative risk 0.3; P = 0.001; OS: relative risk 0.3; P = 0.003) for patients treated with R-CHOP. Expression of p21 was not predictive of outcome for CHOP-treated patients.
Only p21-positive cases benefited from the addition of rituximab to CHOP. Among p21-positive patients, treatment with R-CHOP was associated with a higher FFS rate at 5 years compared to CHOP (61% versus 24%; P = 0.01). In contrast, no significant differences were detected in FFS according to treatment arm for p21-negative patients. Expression of p53, alone or in combination with p21, did not predict for outcome in uni- or multivariable analyses.
In this study, p21 protein expression emerged as an important independent predictor of a favorable clinical outcome when rituximab was added to CHOP therapy. These data suggest that rituximab-related effects on lymphoma survival pathways may be functionally linked to p21 activity.
We present the design features and implementation of a clinic-based case-control study on the molecular epidemiology of lymphoma conducted at the Mayo Clinic (Rochester, Minnesota, USA), and then assess the internal and external validity of the study. Cases were newly diagnosed lymphoma patients from Minnesota, Iowa and Wisconsin seen at Mayo and controls were patients from the same region without lymphoma who had a pre-scheduled general medical examination, frequency matched on age, sex and residence. Overall response rates were 67% for cases and 70% for controls; response rates were lower for cases and controls over age 70 years, cases with more aggressive disease, and controls from the local area, although absolute differences were modest. Cases and controls were well-balanced on age, sex, and residence characteristics. Demographic and disease characteristics of NHL cases were similar to population-based cancer registry data. Control distributions were similar to population-based data on lifestyle factors and minor allele frequencies of over 500 SNPs, although smoking rates were slightly lower. Associations with NHL in the Mayo study for smoking, alcohol use, family history of lymphoma, autoimmune disease, asthma, eczema, body mass index, and single nucleotide polymorphisms in TNF (rs1800629), LTA (rs909253), and IL10 (rs1800896) were at a magnitude consistent with estimates from pooled studies in InterLymph, with history of any allergy the only directly discordant result in the Mayo study. These data suggest that this study should have strong internal and external validity. This framework may be useful to others who are designing a similar study.
Case-control study; etiology; lymphoma; molecular epidemiology; validity
Antioxidant nutrients found in fruits, vegetables, and other foods are thought to inhibit carcinogenesis and to influence immune status. We evaluated the association of these factors with risk of NHL overall and for diffuse large B-cell (DLBCL) and follicular lymphoma specifically in a prospective cohort of 35,159 Iowa women aged 55–69 years when enrolled at baseline in 1986. Diet was ascertained using a validated semi-quantitative food frequency questionnaire. Through 2005, 415 cases of NHL (including 184 DLBCL and 90 follicular) were identified. Relative risks (RRs) and 95% confidence intervals (CI) were estimated using Cox regression, adjusting for age and total energy. The strongest associations of antioxidants with risk of NHL (RR for highest versus lowest quartile; p for trend) were observed for dietary vitamin C (RR=0.78; p=0.044), α-carotene (RR=0.71; p=0.015), proanthocyanidins (RR=0.70; p=0.0024), and dietary manganese (RR=0.62; p=0.010). There were no associations with multivitamin use or supplemental intake of vitamins C, E, selenium, zinc, copper or manganese. From a food perspective, greater intake of total fruits and vegetables (RR=0.69; p=0.011), yellow/orange (RR=0.72; p=0.015) and cruciferous (RR=0.82; p=0.017) vegetables, broccoli (RR=0.72; p=0.018), and apple juice/cider (RR=0.65; p=0.026) were associated with lower NHL risk; there were no strong associations for other antioxidant-rich foods, including whole grains, chocolate, tea or nuts. Overall, these associations were mainly observed for follicular lymphoma, and were weaker or not apparent for DLBCL. In conclusion, these results support a role for vegetables and perhaps fruits, and associated antioxidants from food sources, as protective factors against the development of NHL and follicular lymphoma in particular.
antioxidants; cohort studies; fruits; non-Hodgkin lymphoma; vegetables
Statins have antilymphoma properties but have also been shown to inhibit the binding of rituximab to the CD20 antigen, resulting in reduced antitumor activity of rituximab in vitro. The clinical impact of statin use on the outcome of lymphoma patients treated with a rituximab-containing regimen is unknown.
Patients and Methods
Consecutive patients with newly diagnosed, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were enrolled onto a registry and observed prospectively. The impact of statin use on patients' outcomes was analyzed.
Two hundred twenty-eight patients with DLBCL and 293 patients with FL were enrolled from September 2002 through June 2007; 21% of patients with DLBCL and 19% of patients with FL were on statins at diagnosis, and 20% and 17% remained on statins during lymphoma treatment, respectively. All patients with DLBCL and 39% of patients with FL received initial therapy containing rituximab. The median follow-up time was 47 months (range, 13 to 80 months). Statin use had no impact on the overall response rate (P = .67), overall survival (P = .76), or event-free survival (EFS) in patients with DLBCL (hazard ratio [HR] = 0.85; 95% CI, 0.43 to 1.68). Statin use at diagnosis was associated with improved EFS in patients with FL (HR = 0.45; 95% CI, 0.26 to 0.77), including subgroups treated with rituximab or a rituximab-containing regimen (HR = 0.38; 95% CI, 0.14 to 1.07) and patients who were observed only (HR = 0.38; 95% CI, 0.17 to 0.84).
The concurrent use of statins during the treatment of patients with DLBCL and FL in the rituximab era did not adversely affect outcome. The apparent benefit of statin therapy on FL outcome requires further studies.
The growth of Non-Hodgkin lymphomas can be influenced by tumor-immune system interactions. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell activation that serves to dampen anti-tumor immune responses. Blocking anti-CTLA-4 monoclonal antibodies improve host resistance to immunogenic tumors, and the anti-CTLA-4 antibody ipilimumab (MDX-010) has clinical activity against melanoma, prostate, and ovarian cancers.
We performed a phase I trial of ipilimumab in patients with relapsed/refractory B-cell lymphoma to evaluate safety, immunologic activity and potential clinical efficacy. Treatment consisted of ipilimumab at 3 mg/kg, then monthly at 1 mg/kg × 3 months (dose level 1), with subsequent escalation to 3 mg/kg monthly × 4 months (dose level 2).
Eighteen patients were treated - 12 at the lower dose and 6 at the higher dose level. Ipilimumab was generally well tolerated, with common adverse events attributed to ipilimumab including diarrhea, headache, abdominal pain, anorexia, fatigue, neutropenia and thrombocytopenia. Two patients had clinical responses, 1 patient with diffuse large B-cell lymphoma had an ongoing complete response (31+ months) and 1 with follicular lymphoma had a partial response lasting 19 months. In 5 of 16 cases tested (31%), T cell proliferation to recall antigens was significantly increased (>2-fold) after ipilimumab therapy.
Blockade of CTLA-4 signaling using ipilimumab is well tolerated at the doses used, and has anti-tumor activity in patients with B-cell lymphoma. Further evaluation of ipilimumab alone or in combination with other agents in B-cell lymphoma patients is therefore warranted.
Waldenström macroglobulinemia is a B-cell malignancy with lymphoplasmacytic infiltration in the bone marrow or lymphatic tissue and a monoclonal immunoglobulin M protein (IgM) in the serum. It is incurable with current therapy, and the decision to treat patients as well as the choice of treatment can be complex. Using a risk-adapted approach, we provide recommendations on timing and choice of therapy. Patients with smoldering or asymptomatic Waldenström macroglobulinemia and preserved hematologic function should be observed without therapy. Symptomatic patients with modest hematologic compromise, IgM-related neuropathy that requires therapy, or hemolytic anemia unresponsive to corticosteroids should receive standard doses of rituximab alone without maintenance therapy. Patients who have severe constitutional symptoms, profound hematologic compromise, symptomatic bulky disease, or hyperviscosity should be treated with the DRC (dexamethasone, rituximab, cyclophosphamide) regimen. Any patient with symptoms of hyperviscosity should first be treated with plasmapheresis. For patients who experience relapse after a response to initial therapy of more than 2 years' duration, the original therapy should be repeated. For patients who had an inadequate response to initial therapy or a response of less than 2 years' duration, an alternative agent or combination should be used. Autologous stem cell transplant should be considered in all eligible patients with relapsed disease.
It has been hypothesized that vitamin D mediates the inverse relationship between sun exposure and non-Hodgkin lymphoma (NHL) risk reported in several recent studies. We evaluated the association of self-reported sun exposure at ages <13, 13–21, 22–40, and 41+ years and 19 single nucleotide polymorphisms (SNPs) from 4 candidate genes relevant to vitamin D metabolism (RXR, VDR, CYP24A1, CYP27B1) with NHL risk.
This analysis included 1,009 newly diagnosed NHL cases and 1,233 frequency-matched controls from an ongoing clinic-based study. Odds ratios (OR), 95 % confidence intervals (CI), and tests for trend were estimated using unconditional logistic regression.
There was a significant decrease in NHL risk with increased sun exposure at ages 13–21 years (OR≥15 vs. ≤3 h/week = 0.68; 95 % CI, 0.43–1.08; ptrend = 0.0025), which attenuated for older ages at exposure. We observed significant main effect associations for 3 SNPs in VDR and 1 SNP in CYP24A1: rs886441 (ORper-allele = 0.82; 95 % CI, 0.70–0.96; p = 0.016), rs3819545 (ORper-allele = 1.24; 95 % CI, 1.10–1.40; p = 0.00043), and rs2239186 (ORper-allele = 1.22; 95 % CI, 1.05–1.41; p = 0.0095) for VDR and rs2762939 (ORper-allele = 0.85; 95 % CI, 0.75–0.98; p = 0.023) for CYP24A1. Moreover, the effect of sun exposure at age 13–21 years on overall NHL risk appears to be modified by germline variation in VDR (rs4516035; pinteraction = 0.0066). Exploratory analysis indicated potential heterogeneity of these associations by NHL subtype.
These results suggest that germline genetic variation in VDR, and therefore the vitamin D pathway, may mediate an association between early life sun exposure and NHL risk.
Ultraviolet radiation; Vitamin D; VDR; Molecular epidemiology; Non-Hodgkin lymphoma
Germline mutations in complement genes have been associated with susceptibility to infections and autoimmune diseases, conditions that are associated with non-Hodgkin lymphoma (NHL) risk. To test the hypothesis that common genetic variation in complement genes affect risk of NHL, we genotyped 167 single nucleotide polymorphisms (SNPs) from 31 genes in 441 NHL cases and 475 controls. Principal components (PC) and haplotype analyses were used for gene-level tests of NHL risk, while individual SNPs were modeled as having a log-additive effect. In gene level PC analyses, C2 (p=0.023), C5 (p=0.0032) and C9 (p=0.020) were associated with NHL risk; haplotype analyses showed similar results, as well as a haplotype association for C7 (p=0.046). When all 4 genes were considered simultaneously, only C5 and C9 remained significant (p<0.05). In SNP level results from these genes, 10 SNPs had a p<0.05. However, after correcting for multiple testing, only the C5 SNPs rs7026551 (q=0.015; OR=1.54, 95% CI 1.21-1.95) and rs2416810 (q=0.015; OR=1.57; 95% CI 1.22-2.01), and the C9 SNP rs187875 (q=0.015; OR=0.68; 95% 0.56-0.84) remained noteworthy. Associations were similar for the common NHL subtypes. In summary, we provide evidence for a role of genetic variation in complement genes, particularly C5 and C9, and NHL risk.
non-Hodgkin lymphoma; genetic variation; complement genes; epidemiology