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All-trans-retinoic acid (ATRA) has greatly modified the prognosis of acute promyelocytic leukemia; however, the role of maintenance in patients in molecular complete remission after consolidation treatment is still debated. From July 1993 to May 2000, 807 genetically proven newly diagnosed acute promyelocytic leukemia patients received ATRA plus idarubicin as induction, followed by 3 intensive consolidation courses. Thereafter, patients reverse-transcribed polymerase chain reaction–negative for the PML-RARA fusion gene were randomized into 4 arms: oral 6-mercaptopurine and intramuscular methotrexate (arm 1); ATRA alone (arm 2); 3 months of arm1 alternating to 15 days of arm 2 (arm 3); and no further therapy (arm 4). Starting from February 1997, randomization was limited to ATRA-containing arms only (arms 2 and 3). Complete remission was achieved in 761 of 807 (94.3%) patients, and 681 completed the consolidation program. Of these, 664 (97.5%) were evaluated for the PML-RARA fusion gene, and 586 of 646 (90.7%) who tested reverse-transcribed polymerase chain reaction–negative were randomized to maintenance. The event-free survival estimate at 12 years was 68.9% (95% confidence interval, 66.4%-71.4%), and no differences in disease-free survival at 12 years were observed among the maintenance arms.

Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in >75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

PubMed ID: 12829583, Several studies have compared bone marrow (BM) and peripheral blood (PB) as stem cell sources in patients receiving allografts, but the cell doses infused have not been considered, especially for BM. Using the ALWP/EBMT registry, we retrospectively studied 881 adult patients with acute myelocytic leukemia (AML), who received a non-T-depleted allogeneic BM (n = 515) or mobilized PB (n = 366) standard transplant, in first remission (CR1), from an HLA-identical sibling, over a 5-year period from January 1994. The BM cell dose ranged from 0.17 to 29 × 10 8 /kg with a median of 2.7 × 10 8 /kg. The PB cell dose ranged from 0.02 to 77 × 10 8 /kg with a median of 9.3 × 10 8 /kg. The median dose for patients receiving BM (2.7 × 10 8 /kg) gave the greatest discrimination. In multivariate analyses, high-dose BM compared to PB was associated with lower transplant-related mortality (RR = 0.61; 95% CI, 0.39-0.98; P = .04), better leukemia-free survival (RR = 0.65; 95% CI, 0.46-0.91; P = .013), and better overall survival (RR = 0.64; 95% CI, 0.44-0. 92; P = .016). The present study in patients with AML receiving allografts in first remission indicates a better outcome with BM as compared to PB, when the dose of BM infused is rich. © 2003 by The American Society of Hematology.

Abstract 2928 Introduction. The recent development of a safe and efficient once daily oral iron chelator (Deferasirox, ExjadeÒ) made possible regular chelation therapy in transfusion dependent MDS patients. However in this category of patients the reported clinical experience is limited to selected populations. For this reason the GIMEMA group developed a phase IIIb prospective trial to test safety and efficacy of Deferasirox in a large population of patients comparable to general MDS population. Methods. One hundred and fifty-nine transfusion dependent IPSS low-intermediate1 risk MDS patients were enrolled. Analysis has been performed on 123 patients who had completed the planned year of treatment. Baseline characteristics were the following (data are expressed as median with upper and lower quartile unless specifically indicated): median age was 72 years (range 24 – 87); 48 were IPSS low risk and 75 Intermediate1; duration of transfusion dependency before treatment was 20 months (12-36) corresponding to 38 (22-70) packed red blood cells transfusions received. Baseline serum ferritin was 2000 ng/ml (1471-3000). Baseline Charlson and CIRS comorbity scores were 1 (0-1) and 0.2 (0.1-0.4), respectively. Patients started treatment with the standard 20 mg/kg Deferasirox dose but dose adjustments on clinical indications were allowed. Results. 61 patients (49%) prematurely interrupted the study (drop out), 62 (51%) patients completed the planned year of treatment. In logistic model for drop out rate high Charlson co-morbidity score showed a trend as significant risk factors (p=0.06). Drops out were related to: ten patients (8%) had progression to acute leukemia during the study; twenty patients (16%) experienced MDS related clinical problem (three had cardiac failure, seven had severe infectious diseases, four had severe bleeding, three died at home, three presented others MDS related problems); five patients underwent hemopoietic stem cell transplantation and thirteen discontinued treatment for unrelated problems. Drug related toxicity was drop out cause in 13 patients (11% of the entire population). Main causes of toxicity related drops out were increase of creatinine and gastro-intestinal disturbance. Out of 123 patients analyzed for adverse events only 4 (3%) presented grade 3–4 drug related adverse events. Severe adverse events with suspected relationship with study drug were diarrhea and increase of liver enzymes. Serum ferritin was monthly recorded in the 62 patients who completed the protocol with a statistically significant decrement during the 12 months follow up: median baseline value 2000 ng/ml (interquartile range 1471–3000), median final value 1550 ng/ml (interquartile range 775–2200) P < 0.001, Friedman test analyzing the entire study period. Analysis of quality of life is ongoing. One patient showed a complete erythroid response to Deferasirox treatment acquiring transfusion independence that is still ongoing after 18 months. Discussion. Preliminary results from the GIMEMA MDS0306 study confirmed feasibility of Deferasirox therapy in transfusion dependent MDS patients. Drop out rate, toxicity related drop out and severe side effects were similar to those reported in other trials even if the present population presented clinical characteristics of more advanced disease and age. The rate of progression is coherent with prolonged disease story. Serum ferritin behavior confirms Deferasirox efficacy. The serum ferritin reduction was more evident in the more heavily overloaded population indicating successful iron depletion in this group of patients as clinically requested. ClinicalTrial.gov identifier NCT00469560. Disclosures: Angelucci: Novartis: Honoraria. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

Abstract 2956 Poster Board II-932 Background. The B-cell leukemia 11A gene (BCL11A/Evi9/CTIP1) is essential for normal lymphoid development and genetic association studies have shown its potential regulator effect in blood related phenotypes. BCL11A encodes a Krüppel-like zinc-finger protein and functions as a transcriptional repressor through its interaction with several proteins including BCL6. The corresponding mouse gene is a common site of retroviral integration in myeloid leukemia, and may function as a leukemia oncogene. It is down-regulated during hematopoietic cell differentiation and abnormalities involving this gene have been detected in a variety of B-cell malignancies in humans. We genotyped SNP rs11886868 in the BCL11A gene, which has been previously associated with HbF production, in patients with hematological malignancies from Sardinia to investigate a possible contribution of this gene in determining genetic susceptibility to onco-hematological diseases. Patients and Methods. We screened a total of 325 patients with hematological malignancies for rs11886868 SNP at the BCL11A locus using the TaqMan allelic discrimination assay: 51 B-cell Non Hodgkin's lymphoma (NHL), 27 Hodgkin's disease (HD), 42 Chronic Lymphocytic Leukemia (CLL), 52 Multiple Myeloma, 35 Cutaneous T-cell Lymphomas (CTCL), 11 Acute Lymphoblastic Leukemia (ALL), 19 Myelodysplastic Syndromes (MDS), 31 Acute Non Lymphoblastic Leukemia (ANLL), 36 Philadelphia negative Myeloproliferative Disorders (MPD), 21 Chronic Myelogenous Leukemia. Fifty–four DNAs from healthy individuals were used as population controls. Both patients and controls originated from central Sardinia. The frequencies comparisons between controls and cases were performed using chi-square test and Odds Ratio (OR) analysis with Cornfield 95% confidence intervals (CI). Results. Allele frequencies for BCL11A rs11886868 were 22% for the “C” allele and 78% for the “T” allele. No statistically significant difference was observed between cases and controls. All genotypes were in Hardy-Weinberg equilibrium for both patients and controls groups. The genotype frequencies were 65% (T/T), 26% (C/T) and 9% (C/C) in controls and 53% (T/T), 40.5% (C/T), and 6.5% (C/C) in hematological malignancies. When compared with the genotype frequencies reported for Caucasian and healthy controls from Sardinia no statistically significant difference was observed (p=0.4). However, the C/T genotype was more frequent in cases than controls (41% vs 26%) conferring an increased risk for hematological malignancies with an estimated OR=1,9 (95%CI 1.08-3.6; p=0.03). In detail, statistically significant differences in genotype distribution were observed in CTCL (p< 0.0001), MPD (p=0.0006), NHL (p=0.008), HD (p=0.002) and ALL patients (p=0.02). The C/C genotype was not observed in CTCL and HD patients, while heterozygousity conferred an increased risk of 4.2 (2.3-7.7; p value Conclusions. We found genetic association of BCL11A gene in several blood disorders with the strongest association for Cutaneous T-cell Lymphomas and Myeloproliferative disorders suggesting a possible role of BCL11A in both lymphoid and myeloid lineages. Specific BCL11A genotypes have been associated with different BCL11A expression levels that influence HbF production. We speculate that BCL11A sequence variants may influence expression of different isoforms that may have effect on cell pathways involved in oncogenetic events as well as in globin gene regulation. This work was supported by Associazione Italiana contro le Leucemie e Linfomi (AIL) Disclosures: No relevant conflicts of interest to declare.

Aberrant methylation of CpG island of the promoter regions of genes is an important epigenetic mechanism, alternative to deletions or mutations, that cause the silencing of genes involved in carcinogenesis. We therefore investigated epigenetic events involved in multiple myeloma by screening 6 genes of interest for evidence of promoter hypermethylation. PATIENTS AND METHODS: The methylation patterns of the tumor suppressor genes p16INK4a (p16), E-cadherin (ECAD), FHIT and PTEN (negative regulator of AKT/PKB signalling pathway), Wnt signalling pathway antagonist genes WIF-1 and DKK-3 were determined in the bone marrow aspirates of 50 patients with Multiple Myeloma (MM) (37 at diagnosis; male 22; female 28; 68.8 median age. ISS stage: 47% stage I, 8% stage II and 45% stage III.), using the methylation-specific polymerase chain reaction after DNA bisulphite modification. Ten patients with monoclonal gammopathy of undetermined significance (MGUS) and 4 peripheral blood from controls were also evaluated. For statistical analysis Student t and Chi squared or Fisher exact tests were used. RESULTS: We found at least one hypermethylated gene in all MM patients. Gene methylation frequencies varied from 6% to 74%. ECAD, FHIT and p16 genes demonstrated a relatively high frequency of aberrant methylation with frequencies of 74%, 69% and 42%, respectively. WIF-1, PTEN, DKK-3 genes showed a low frequency of methylation with values of 28%, 14%, 6%, respectively. The methylation frequencies detected in MGUS were 91.6% for ECAD and FHIT, 41.6% for WIF-1, 16,6% for p16 and DKK3. The difference in methylation profile between MM and MGUS was statistically significant (X2= 37, df=5; p=0.0000). PTEN was found hypermethylated in 7/50 (14%) MM but none of MGUS or control samples were methylated. Of these 6 patients had IgG K isotype, 4 had abnormal cariotype with 13q deletion, one hyperdiploidia, one IgH rearrangements. Two patients were simultaneously hypermethylated in p16 gene promoter. No statistically significant correlation between methylation data and clinical parameters: gender, age, isotype of M component, type of light chain, haemoglobin, serum albumin level, calcium, β2 microglobulin, serum creatinine level, LDH, lytic bone lesions were found for any of examined genes. When correlation with Durie-Salmon Stage disease was tested hypermethylation of p16 and WIF-1 resulted more frequently associated with stage IIIA/B (p values 0.006 and 0.000, respectively). When gene methylation status and cytogenetics abnormalities were compared, we found that aberrant methylation of p16 and ECAD were significantly more frequent in MM patients with chromosome 13 abnormalities as sole entity or with 13q deletion associated to IgH translocations. By contrast, promoter hypermethylation of Wnt signalling antagonist genes was associated with 13q deletion co-occurring with a hyperdiploide cariotype. (X2=17; df=8 p value: 0.000). According to the number of methylated genes observed in each sample 48% MM had 3–4 hypermethylated genes. When differences between methylator phenotype and cytogenetics abnormalities were analyzed we found that 3–4 hypermethylated genes have the tendency to be associated with chromosome 13 abnormalities more often than with hyperdiploide cariotype (p value 0.05). CONCLUSION: Our results indicate that the accumulation of epigenetic events affecting genes regulating cell cycle control, cell adhesion and apoptosis is a common phenomenon in plasma cell disorders and may further contribute to the phenotype of MM cells. This is the first demonstration of PTEN inactivation as a result of promoter hypermethylation in MM patients. Since talidomide seems to have a role in the PTEN/PI3K/AKT pathway, the PTEN function is worthy to be further investigated in Multiple Myeloma.

Background: Multiple Myeloma (MM) is characterized by frequent and complex genetic abnormalities that contribute to the pathogenesis and its prognostic eterogeneity. There is evidence for two oncogenic pathways in the early development of clonal plasma cell disorder: i) non-hyperdiploid carring translocation of the immunoglobulin heavy-chain locus and various oncogenes ii) hyperdiploid tumors with infrequent IgH translocation. The MM clonogenic cell is positively selected during the development and reaction of the germinal center. The immunoglobulin gene (IG) repertoire in MM follows a pattern similar to that of the normal repertoire. However, available data from analysis of IGH and IGK/L genes according to cytogenetic aberrations are limited. In the present study we investigated the frequency and characteristics of IGK and incomplete DJH as well as complete VDJH rearrangements in parallel with chromosomal abnormalities in a series of untreated MM patients. Materials and Methods. Bone marrow aspirates were collected from 53 MM patients with a mean age of 69.6 (range 48–84) between 2003–2007. The serum monoclonal component was IgG and IgA in the 77% and 22% patients respectively; 1 patient presented with IgD k MM. Cytogenetics and FISH analysis were performed simultaneously in 37 MM. In 18 (50.5%) samples kariotype analysis was successful. Interphase FISH analysis was perfomed using a set of probes specific for RB-1 (13q14), D13S319 (13q14.3), IgH (14q32), and p53 (17p13.1) loci, t(4;14), t(14;16), t(11;14) and a multicolor probe set for detection of aneuploidy (Vysis, Downers Grove, IL, USA). Genomic DNA was isolated for clonality analysis. IGHV-J, IGHD-J, IGKV-J, IGKV-KDE, IGKJ-C-INTRON-KDE rearrangements were amplified by PCR and analyzed following the BIOMED-2 protocol. Results: Conventional cytogenetics allowed to detect 16 patients with a normal kariotype, 1 hyperdiploid kariotype with monosomy 13, 1 hyperdiploid kariotype with 3q21 deletion. FISH panel analysis resulted in 4 patients with hyperdiploid kariotype and 7 with abnormalities for RB-1 and/or D13S319. IGH rearrangements were detected in 3 patients and the t (4;14) was found in 1 case. The p53 deletion, t(11;14) and t(14;16) were not detected. The overall detection rate of clonality by amplifying VDJH and DJH rearrangements using family-specific primers was 90%. We found a high frequency (71.7%) of DJH rearrangements with DH3 segment under represented (4%). The DH7 segment was rearranged in the 15% of MM. Incomplete DJH and complete VDJH rearrangements were present at frequencies of 20% and 29.5%, respectively. IGK locus rearrangements were detected in 38 out of 53 MM and the 60% presented the non-productive IGKV-KDE and IGKJ-C-INTRON-KDE rearrangements. Parallel analysis of clonality pattern and chromosomal abnormalities showed that complete VDJH rearrangements were present in all hyperdiploid MM and in a small proportion (4/16) of the MM with normal karyotype. Conclusions: Our results confirm previous estimations about IgH repertoire usage. Despite the small numbers, our findings indicate that complete Ig rearrangements might be correlated with hyperdiploid MM. Combining cytogenetics and IgH clonality studies might help to identify distinct subgroups of MM and provide a framework for dissection of disease prognosis and clinical management. Research funded by Regione Autonoma Sardegna.

Cardiac T2* Magnetic Resonance Imaging (MRI) has been recently used to evaluate myocardial iron deposition in patients with transfusion dependent beta-thalassemia major. No comparable studies have been published for patients with myelodysplastic syndromes receiving chronic red blood cell transfusion. Therefore we measured cardiac-MRI T2* in 16 patients (10 male, 6 female) with myelodysplastic syndromes (aged 54 – 82 years, median age 67). All of them were transfusion dependent having received a median number of 60 (range 16–225) packed red blood cell transfusion equivalent to 3.2 – 45 (median 12) grams of iron. Nine have been irregularly and sporadically chelated by deferoxamine, seven were unchelated. Serum ferritin levels ranged from 1163 to 6241 mg/dl (median value 2086). None of the patients presented signs or symptoms of cardiac dysfunction at the time of the study. Cardiac-MRI T2*values obtained ranged from 5.6 to 80 (median value 46.5) milliseconds (ms). Correlation between serum ferritin and cardiac T2* value was weak ( r= 0.43, r2 =0.18). According to D. Pennel we considered as significant of myocardial iron deposition a relaxation time ≤ 20ms. Cardiac T2* was < 20ms in 3 patients who had never used iron chelators (5.6, 12.4 and 8.5 ms, respectively). They had received 39, 101 and 200 units of red blood cell transfusion, corresponding to 7.8, 20 and 40 grams of iron, respectively. Of relevance 2 of them died within few months after the end of the study and one showed early signs of left ventricular dysfunction. None of the patients with a cardiac T2* value >20 ms showed instrumental nor clinical signs of cardiac deterioration in six months follow up. No patient who had received less than 39 transfusions presented cardiac T2* value ≤20 ms. Evaluation of myocardial iron deposition by T2* cardiac MRI could be recommendable in myelodyplasia patients who had received more than 30 packed red blood cells transfusisions.

The current knowledge of potential risk factors for lymphomas is limited. There is strong evidence that altered immunological function entails an increased risk of lymphoma. CTLA-4 gene encodes for a receptor that provides a negative signal to the T-cell once an immune response is initiated and complete. It is located in the 2q33 chromosomal region that harbours several genes such as CD28, ICOS, all related to immune activation playing a pivotal role in T-lymphocyte activation. Polymorphisms in these genes have been associated to a number of autoimmune diseases, including blood disorders. We have recently reported that a functional polymorphism in the CTLA-4 gene is associated with Non-Hodgkin’s lymphoma (NHL) and may have a role in genetic susceptibility to the disease. Since CD28, CTLA-4 and ICOS are closely linked and have related functions, aim of the present study was to extend the genetic analysis to the 2q33 chromosomal region harbouring these genes. Three polymorphisms of CTLA-4 gene (at positions -308C*T, +49A*G, +642 3′UTR (AT)n), the CD28 (CAA)n, ICOS c1564T*C and D2S72 markers within a 1.3cM region were analyzed in 100 unrelated NHL patients and in 128 healthy controls both originating from the central part of Sardinia. Statistical analysis was performed to test association of each marker with NHL using Chi-squared test and Odds Ratio (OR). Haplotypes were inferred and analyzed using the PHASE 2.1 software. Exact test of Linkage Disequilibrium (LD) was calculated between all pairs of seven markers separately in cases and controls using the Arlequin program. We found a strong association of the CTLA-4 +49*A and the 3′UTR (AT)82 alleles with NHL with ORs of 2 (CI95% 1.2–3.2) and 1.6 (CI95% 1.1–2.4), respectively. The −308*C−+49*A− (AT)82 was the most represented haplotype in the studied population and resulted associated with NHL (p value = 0.0029; OR = 1.7 [CI95% 1.2–2.5]). No independent association between CD28, ICOS and D2S72 markers was observed. Genetic analysis of the entire haplotype CD28–CTLA-4-D2S72-ICOS resulted in 196 and 234 different best haplotypes in patients and controls, respectively. The most common haplotype was CD28*163-308*C-+49*A-(AT)82-D2S72*156-ICOS*T and it was found to be significantly over-represented in NHLs than in controls (p value = 0.012, OR=1.86 CI95% 1.1–3). Strong LD was observed between the three CTLA-4 gene markers and the two adjacent markers CD28 and D2S72, and less significant LD was found between ICOS and some of the CTLA-4 gene markers. We found genetic linkage between a specific haplotype in the 2q33 region and NHL, but allelic association was detected for CTLA-4 markers and for none of the adjacent functionally related gene markers. Thus, it seems possible to dissect the CTLA-4 as the true “causative” risk gene for NHL susceptibility at least in Sardinian patients.The functional characterization of disease-associated CTLA4 gene variants will be worthy of future investigation to elucidate their role in the pathogenesis of NHL.