Obesity negatively impacts outcome in elderly female patients with aggressive B-cell lymphomas treated with R-CHOP: results from prospective trials of the German high grade non-Hodgkin's lymphoma trial group

PURPOSE: The incidence rates of non-Hodgkin’s lymphoma (NHL) unrelated to human immunodeficiency virus infection are lower for women than for men; yet, few factors have been identified that may account for this difference in risk. NHL is difficult to study epidemiologically because this disorder represents a group of malignancies that differ in terms of morphologic presentation, immunologic features, genetic characteristics, prognosis, and etiology. PATIENTS AND METHODS: We conducted a population-based case-control study in women to determine whether reproductive factors or hormonal exposures might be related to the risk of high- or intermediate-grade B-cell NHL. We interviewed 177 female residents of Los Angeles County who were diagnosed with high- or intermediate-grade B-cell NHL between 1989 and 1992; each case patient was individually matched on age and race to a control subject who lived in her neighborhood. RESULTS: Women who had used oral contraceptives had significantly lower risk of intermediate- or high-grade NHL (multivariate odds ratio [OR] = 0.47; 95% confidence interval [CI], 0.26 to 0.86) than women who had never used these compounds. Among parous women, those who had used lactation suppressants (which contain high levels of estrogen) had significantly lower risk of NHL (multivariate OR = 0.50; 95% CI, 0.29 to 0.85) than unexposed women. Postmenopausal women had a somewhat greater risk of NHL than premenopausal women, whereas those postmenopausal women who had used hormone replacement therapy (HRT) (primarily estrogen) had somewhat lower risk than those who had not used HRT. CONCLUSION: Exogenous estrogens seem to have a protective effect on the risk of high- and intermediate-grade B-cell NHL. Although the mechanisms for such protection are not known, alterations in immune reactivity, cytokine expression, or B-cell modulation may play a role.

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Methylenetetrahydrofolate Reductase and Methionine Synthase Polymorphism and Risk of Non-Hodgkin’s Lymphoma.

Blood ◽

10.1182/blood.v106.11.4691.4691 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4691-4691

Author(s):

Hee Nam ◽

Yeo-Kyeoung Kim ◽

Il-Kwon Lee ◽

Deok-Hwan Yang ◽

Kyeong-Soo Park ◽

...

Keyword(s):

B Cell ◽

Hodgkin’S Lymphoma ◽

Methylenetetrahydrofolate Reductase ◽

Methionine Synthase ◽

Hodgkin's Lymphoma ◽

B Cell Lymphomas ◽

Mthfr Polymorphism ◽

Non Hodgkin’S Lymphoma ◽

Increased Risk ◽

Non Hodgkin's Lymphoma

Abstract Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are key enzymes in folate metabolism, which is essential for DNA methylation and synthesis. It is known that polymorphisms in its genes have been associated with some forms of cancer including lymphoma. Previous studies have shown MTHFR 677TT was associated with decreased risk of non-Hodgkin’s lymphoma(NHL). However, recent two reports have shown MTHFR 677TT was associated with increased risk. To evaluate the association between the MTHFR C677T and MTR A2756G polymorphisms and risk of non-Hodgkin’s lymphoma, large-scale population-based case-control study was conducted in Chonnam University Hwasun Hospital between March 1997 and June 2005. Three hundreds sixty-five patients with histologically comfirmed lymphoma and 1,162 controls were evaluated. Genotyping was done using PCR-RFLP. The cases consisted of 203 diffuse large B-cell lymphomas(DLBCL), 77 T-cell lymphomas, 62 other B-cell lymphomas, and 23 unclassifiable lymphomas. The MTHFR 677CT and 677TT genotypes were inversely associated with NHL and DLBCL, respectively. Using subjects with the MTHFR 677CC as reference group, the odds ratio of MTHFR 677CT and 677TT were (0.70, 95% CI 0.54–0.90) and (0.46, 95% CI 0.32–0.68) for NHL. The association was more evident for DLBCL (OR 0.56, 95% CI 0.40–0.78 for 677CT; OR 0.40, 95% CI 0.24–0.65 for 677TT). Dose-response effect was evident for the MTHFR T-allele (p < 0.01). There was no significant association of MTR A2756G with NHL. These results suggest that the MTHFR polymorphism may play an important role in the pathogenesis of NHL, particularly DLBCL.

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Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) for Patients with Refractory or Relapsed Non-Hodgkin’s Lymphoma (NHL).

Blood ◽

10.1182/blood.v108.11.5356.5356 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5356-5356

Author(s):

Hugues de Lavallade ◽

Reda Bouabdallah ◽

Catherine Faucher ◽

Sabine Furst ◽

Jean El-Cheikh ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Cumulative Incidence ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

Cell Group ◽

High Grade ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

Abstract This study aimed to evaluate the role of RIC allo-SCT for relapsed or refractory non-Hodgkin’s lymphoma (NHL). We report here our experience in 25 consecutive patients transplanted in a single center for high grade (n=17) or follicular NHL (FL; n=8). In the high grade NHL group, median age was 46 (range, 24–63) years, and all 17 patients received 2 or more previous chemotherapy regimens prior to RIC allo-SCT. In addition, 12 patients (71%) had failed autologous SCT and 6 patients (35%) had chemoresistant disease at time of allo-SCT. Among the 8 patients transplanted for a heavily pretreated follicular NHL (FL), median age was 52 (range, 34–59) years and median number of prior lines of therapy was 3 (range, 2–5), with 3 patients (38%) having chemoresistant diseases and 4 patients (50%) relapsing after autologous SCT. Among the 17 patients with aggressive high grade NHL, we compared the outcome of T-cell and B-cell aggressive NHL. With a median follow-up of 15.4 (range, 3.4-65.2) months, the cumulative incidence of non-relapse mortality was 6%, (95%CI, 0.3%-31%) and the Kaplan-Meier estimate of progression-free survival (PFS) was significantly higher in the T-cell as compared to the B-cell group (P= 0.03; 100% vs. 40% at 3 years). In the FL group, the cumulative incidence of non-relapse mortality was 25% (95%CI, 3%–65%). Six patients (75%) showed objective disease response with complete remission (CR) occurring concomitantly to graft-versus-host disease, including one CR after donor lymphocytes infusion. With a median follow-up of 19 (range, 7–85) months, 6 patients from the FL group are still alive of whom 5 in CR. We conclude that a potent graft-vs.-lymphoma (GVL) may be achieved in FL patients, even those with chemoresistant disease or who have relapsed after autologous SCT. In the high grade NHL group, strategies aiming to enhance the GVL effect (Rituximab-based RIC and/or Rituximab maintenance therapy) in the B cell subtype are still needed. However, RIC allo-SCT is a feasible and promising strategy for aggressive NHL, with particularly low toxicity, and T-cell aggressive NHL benefiting most from a potent GVL effect, likely overcoming the poor prognosis usually associated with this phenotype.

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Genome-Wide Analysis of B Cell Non-Hodgkin’s Lymphoma Disclosed Frequent Involvement of Genes in NFkB Pathway

Blood ◽

10.1182/blood.v112.11.807.807 ◽

2008 ◽

Vol 112 (11) ◽

pp. 807-807

Author(s):

Motohiro Kato ◽

Kumi Nakazaki ◽

Yasuharu Sato ◽

Kengo Takeuchi ◽

Masashi Sanada ◽

...

Keyword(s):

B Cell ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

High Grade ◽

Genome Wide Analysis ◽

Non Hodgkin’S Lymphoma ◽

Genome Wide ◽

Non Hodgkin's Lymphoma ◽

Nfkb Pathway ◽

Homozygous Deletions

Abstract B cell non-Hodgkin’s lymphoma (B-NHL) consists of different pathological entities that are frequently characterized by distinct genetic alterations. However, the knowledge on these genetic lesions in B-NHL is still limited. In order to obtain a more comprehensive view of genetic lesions in B-NHL, we performed genome-wide analysis of copy number (CN) alterations as well as allelic imbalances using Affymetrix SNP arrays in 190 B-NHL cases, including 64 samples of diffuse large B-cell lymphoma (DLBCL), 62 of follicular lymphoma (FL), 64 of mucosa-associated lymphoid tissue lymphoma (MALT-L). SNP array data were analyzed with CNAG/AsCNAR software, which enabled sensitive detection of CN alterations in allele-specific manner, and thus allelic imbalances, without depending on availability of paired normal controls. Most frequent numerical abnormalities in B-NHL were gains of chromosomes 3 and 18, although gains of chromosome 3 were less prominent in FL. Chromosomal deletions that lead to loss of heterozygosity (LOH) were commonly found in 1p, 6q and 10q. However, the more chracteristic feature of B-NHL genomes was high frequency of CN netural LOH or uniparental disomy (UPD), which was found in 35 cases of DLBCL (55%), 32 cases of FL (52%) and 18 cases of MALT-L (28%). It is widely distributed in the genome, but more frequently found in 1p, 1q, 6p, 6q and 12q. High-grade amplifications and homozygous deletions frequently provide a clue to identify relevant gene targets. In our series, 12 loci of high-grade amplifications and 14 loci of homozygous deletions were identified, and helped to specify the candidate genes. These regions included, FCGR2B amplified in 5 cases of DLBCL, RERE amplified in 2 cases of FL and CDKN2A/CDKN2B deleted in 9 cases of DLBCL. The most notable finding in the current study was, however, the identification of common genomic alterations in genes that regulate activation of NFkB pathway in more than 50% of B-NHL cases. Eight lymphoma cases harbored high-grade amplification of cREL gene, and gain including cREL was detected in 28 samples (14.7%). Fourteen cases had gains or amplification of TRAF6, and another 16 cases had deletion at 10q including PTEN. These abnormalities were supposed to cause dysregulation of NFkB. Aberrant NFkB activity has long been implicated in the pathogenesis of B-NHL, and our study confirmed that dysregulation of NFkB pathway was main mechanism of lymphomagenesis, providing further rationale that he treatment against malignant lymphoma with inhibitor of NF kappa B pathway.

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