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Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index
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CANEP-848; No. of Pages 6 Cancer Epidemiology xxx (2015) xxx–xxx
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Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index Yi-Yang Chen a,1, Cih-En Huang a,1, Fu-Wen Liang b, Chang-Hsien Lu a,c, Pin-Tsung Chen a,c, Kuan-Der Lee a,c,d, Chih-Cheng Chen a,d,* a
Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan Department of Public Health, College of Medicine National Cheng Kung University, Tainan, Taiwan c Graduate Institute of Clinical Medical Sciences, Chang Gung University, Tao-Yuan, Taiwan d College of Medicine, Chang Gung University, Tao-Yuan, Taiwan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 26 December 2014 Received in revised form 27 March 2015 Accepted 5 April 2015 Available online xxx
Objective: Patients with hepatitis C virus (HCV) infection have been associated with development of diffuse large B-cell lymphoma (DLBCL), yet its impact on several clinical aspects, including phenotypic characteristics and treatment-related toxicities as well as survival outcome after rituximab-based immunochemotherapy, remains controversial. Methods: To elucidate the characteristics of HCV-positive DLBCL in the context of a new prognostic model, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), we retrospectively analyzed DLBCL patients diagnosed and treated with immunochemotherapy at our institute during the last decade. Results: In all, HCV infection was identified in 22 (17.7%) of 124 DLBCL patients. Except for being more likely to present with an advanced stage of disease, patients with HCV infection were phenotypically indistinguishable from HCV-negative cases. Multivariate analysis showed 3 factors independently predicted a dismal overall survival (OS) outcome: lower albumin level (<3 g/dL vs. 3 g/dL, p < 0.001; HR = 13.21, 95% CI = 2.69–64.98, p = 0.001), presence of HCV infection (vs. HCV-negative; HR = 9.75, 95% CI = 1.97–48.34, p = 0.005), and poor NCCN-IPI risk (high-intermediate or high vs. low-intermediate or low; HR = 5.56, 95% CI = 1.17–26.55, p = 0.031). Conclusions: Our study has demonstrated that HCV infection status and low serum albumin level add important prognostic values to the newly proposed NCCN-IPI model for patients with DLBCL. ß 2015 Published by Elsevier Ltd.
Keywords: Hepatitis C NCCN-IPI Diffuse large B-cell lymphoma Albumin Rituximab Prognosis
1. Introduction Ever since the first description on the relationship of hepatitis C virus (HCV) infection and non-Hodgkin’s lymphoma (NHL) [1,2], there are mounting evidence showing HCV infection increases the risk of developing B-cell lymphoproliferative disorders [3–6]. Initial reports mostly described an apparent association between HCV infection and indolent lymphoma, and the observation of a curative potential of antiviral therapy on HCV-related indolent
* Corresponding author at: No. 6, West Section, Chia-Pu Road, Pu-Tz City, Chiayi 613, Taiwan. Tel.: +886 5 3621000x2852; fax: +886 5 3623002. E-mail address: [email protected] (C.-C. Chen). 1 These two authors contributed equally to the work.
lymphoma further strengthened their strong causal relationship [7]. Subsequently, several large epidemiological studies confirmed that the theory of B-cell transformation by HCV in lymphomagenesis also applied to diffuse large B-cell lymphoma (DLBCL), as HCVinfected patients had a significantly increased risk of developing DLBCL (odds ratio 2.2–3.5) [5,8,9]. Thereafter, there is wide speculation that HCV-associated DLBCL might own specific pathogenesis and biology that is discrepant from others. HCV-positive DLBCL patients were found to be older, have elevated lactate dehydrogenase (LDH) and more frequent extranodal involvement (especially liver), and have an inferior overall survival when treated with the traditional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen [10]. The advent of rituximab (R) changes the landscape of treatment for DLBCL and significantly improves the clinical outcome [11,12], but
http://dx.doi.org/10.1016/j.canep.2015.04.004 1877-7821/ß 2015 Published by Elsevier Ltd.
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004
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controversies do exist with regard to the prognostic impacts of HCV infection on the survival outcome of DLBCL patients treated with R-CHOP. A large retrospective study from Italy showed high HCV-RNA viral load was associated with shorter survival [13], whereas a report from Japan disclosed that HCV infection was not a significant risk factor for prognosis [14]. Asides from the debatable differential outcome in HCV-positive DLBCL patients, the incorporation of older prognostic indexes (the international prognostic index [IPI] [15] or its variant revised IPI [16]) into multivariate analysis for survival outcome determination raised huge concerns on adequacy and accuracy of those studies, as IPI was created at a time when rituximab was not available and both indexes consisted of only HCV-negative or HCV-status unknown patients. Recently, collaborators from North America proposed a new prognostic model, the National Comprehensive Cancer Network (NCCN) IPI, for DLBCL patients treated with R-CHOP [17]. The enhanced NCCN-IPI clearly demonstrates superiority over the old IPI as a prognostic model for patients with DLBCL in the rituximab era, and reports from others confirmed its unparalleled predictive value [18,19]. However, like other DLBCL prognostic indexes, HCV infection status was not incorporated into the analysis for outcome prediction in the NCCN-IPI. For this reason, we carried out this retrospective study to determine the prognostic role of HCV infection in patients with DLBCL when considered in the same context with the enhanced NCCN-IPI. 2. Materials and methods 2.1. Study population Sequential patients who were 18 years of age or older with pathologically-confirmed de novo DLBCL diagnosed during the last decade at our institute were screened. Information on a variety of clinical characteristics, including patient demographics, results of baseline hemograms and biochemical tests, serological tests of hepatitis B surface antigen (HBsAg) and HCV antibody, types of therapy, treatment outcomes, and survival status, was obtained. As screening tests for the presence of HBsAg and HCV antibody were standard procedures in newly diagnosed DLBCL patients at our institute, most patients had available relevant data. Patients with human immunodeficiency virus infection were excluded from the current study. The last date of follow-up was September 30th, 2014. The study was approved by the Institutional Review Board of Chang-Gung Memorial Hospital (Taiwan) in accordance with the Declaration of Helsinki. 2.2. Risk groups, treatment, and outcome Patients were categorized as having either HCV-positive or negative DLBCL based on the presence or absence of anti-HCV antibody. The NCCN IPI, which substratified patients into low, low-intermediate (LI), high-intermediate (HI), and high risks, was used for risk stratification [17]. Lymphomatous infiltration of the bone marrow, central nervous system, liver, gastrointestinal tract, or lung was considered as high-risk extranodal involvement, as defined in the NCCN-IPI model. Histology subtypes of DLBCL, categorized as germinal center B-cell (GCB)-like and non-GCB-like, were defined as previously described and based on the results of immunohistochemical stains of tumor samples [20]. For baseline characteristics delineation, all eligible patients were included. For survival outcome comparison, only patients receiving R-CHOP-like immunochemotherapy were included for analysis. The response to treatment was assessed according to standard response criteria [21]. Overall survival (OS) was measured from the date of diagnosis until death from any cause, with observation ending at the date of last contact for patients last known to be alive. Adverse events
were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). 2.3. Statistical analysis The Mann–Whitney test was used for continuous variables versus categorical variables. For comparison of the dichotomous variables, a Pearson chi-square or a Fisher’s exact test (for expected values of >5 or 5, respectively) was applied. The variables of OS were estimated by the Kaplan–Meier method. Differences between groups were calculated using the log-rank test for univariate analysis. Cox’s proportional hazards model was used for multivariate analysis to test independent prognostic factors on survival outcome. All calculations were performed using the Statistical Package of Social Sciences software (version 17.0; SPSS, Inc., Chicago, IL, USA). The level of statistical significance was set at 0.05 for all tests. 3. Results 3.1. Clinical characteristics of the patients We screened 135 patients with pathologically confirmed de novo DLBCL diagnosed during the past decade at our institute. Based on the results of serological test of anti-HCV antibody, we identified 22 (17.7%) HCV-positive DLBCL cases out of 124 patients who had available data. Table 1 summarizes the comparison of the clinical and laboratory features between patients sub-categorized as HCV-positive and -negative DLBCL. There were no significant differences between the two subgroups of patients with respect to patient characteristics, including age, gender, and performance status (PS). The results of biochemical tests (including serum albumin, hepatic transaminases, uric acid, b2-microglobulin, and lactate dehydrogenase [LDH] levels) were not different, either. Because lymphopenia (with an absolute lymphocyte count <1.0 109/L) [22], anemia (hemoglobin <10 g/dL) [23], and thrombocytopenia (platelet count <100 109/L) [24] had all been indicated as an adverse prognostic indicators in patients with DLBCL, we used them as surrogate markers for baseline hemogram comparison but found there was no apparent discrepancy between the two groups of patients. The incidences of high-risk extranodal involvement, as defined in the NCCN-IPI model [17], were similar in both groups. Patients with HCV-positive DLBCL did not carry a significantly higher probability of lymphomatous involvement in the liver. Although HCV-positive DLBCL patients were more likely to present with an advanced stage of disease (68.2% vs. 40.2% in HCV-negative DLBCL, p = 0.017), the distributions of both groups of patients in each NCCN-IPI risk category did not differ significantly. Activated B-cell like histology was the major DLBCL subtype and accounted for about two-thirds of the patients in both groups. 3.2. Survival outcome analysis To avoid different therapies as a potential confounding factor, we excluded a minority of patients who were treated in the prerituximab era. Only patients receiving R-CHOP-like regimen as the cornerstone of treatment were included in the survival outcome analysis. Based on univariate analysis, we evaluated several factors with respect to the impacts on OS. As demonstrated in Table 2 and Fig. 1, we found that patients with more profound anemia (hemoglobin <10 g/dL vs. 10 g/dL, p = 0.034, Fig. 1A), patients with lower albumin level (<3 g/dL vs. 3 g/dL, p < 0.001, Fig. 1B), patients with HCV-positive DLBCL (vs. HCV-negative, p = 0.010, Fig. 1C), and patients with HI or high NCCN-IPI risks (vs. LI or low risks, p = 0.003, Fig. 1D) all had a far more dismal survival outcome when compared to their respective counterparts, whereas patients
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004
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CANEP-848; No. of Pages 6 Y.-Y. Chen et al. / Cancer Epidemiology xxx (2015) xxx–xxx Table 1 Clinical and laboratory features of patients with diffuse large B cell lymphoma (DLBCL) stratified by hepatitis C virus infection status. Variables Age in years; median (range) Age >60 years; n (%) Males (%) Performance status 0–1a; n (%) Extranodal involvementb; n (%) Hepatic involvement; n (%) Ann Arbor Stage III/IV; n (%) LDHc level in U/L; median (range) Elevated LDH levels; n (%) Abnormal liver function tests; n (%) Albumin level in g/dL; median (range) Albumin <3 g/dL; n (%) Elevated b2-microglobulin levels; n (%) Elevated uric acid levels; n (%) ALCd <1.0 109/L; n (%) Hemoglobin <10 g/dL; n (%) Platelet count <100 109/L; n (%) NCCN-IPI riske; n (%) Low Low-intermediate High-intermediate High Histological subtype; n (%) Non germinal center B-cell like Germinal center B-cell like a b c d e
HCV( ) DLBCL (n = 102)
HCV(+) DLBCL (n = 22) 67.0 (30.1–91.2)
0.708
66 (64.7%) 54 (52.9%) 75 (73.5%)
14 (63.6%) 13 (59.1%) 13 (59.1%)
0.990 0.600 0.176
48 (47.1%)
13 (59.1%)
0.306
7 (6.9%) 41 (40.2%) 207 (25–2467) 50 (52.1%) 15 (15.3%) 3.2 (1.9–4.7)
4 (18.2%) 15 (68.2%) 168 (47–1040)
0.105 0.017 0.310
8 (42.1%) 6 (27.3%)
0.427 0.182
3.3 (1.8–4.0)
0.848
31 (40.3%) 57 (69.5%)
4 (25.0%) 13 (76.5%)
0.395 0.771
15 (20.5%)
4 (30.8%)
0.471
21 (21.2%) 19 (19.0%) 10 (9.9%)
6 (27.3%) 5 (22.7%) 1 (4.8%)
0.537 0.768 0.687
11 37 35 13
1 7 7 4
0.753 (11.5%) (38.5%) (36.5%) (13.5%)
(5.3%) (36.8%) (36.8%) (21.1%) 0.969
45 (66.2%)
12 (66.7%)
23 (33.8%)
6 (33.3%)
Table 2 Univariate analysis of prognostic factors affecting overall survival. Variables (patients)
p-value
67.6 (18.4–91.9)
ECOG performance status. Extranodal involvement of either BM, CNS, GI/liver, or lung. Lactate dehydrogenase. Absolute lymphocyte count. National Comprehensive Cancer Network International Prognostic Index.
with non-GCB-like histological subtype also showed a trend of possibly decreased survival (vs. GCB-like subtype, p = 0.078, Fig. 1E). On the other hand, gender, lymphopenia, thrombocytopenia, presence of HBsAg, and levels of either b2-microglobulin or uric acid did not impose any significant impacts on OS duration (Table 2). To test various parameters of possible prognostic value, we performed multivariate analysis to examine the potential interaction and effects on OS. All 5 factors with potentially significant importance exhibited on univariate analysis were included in the Cox model for comparison, and 3 factors were found to independently predict an inferior OS (Table 3), including lower albumin level (<3 g/dL vs. 3 g/dL, p < 0.001; HR = 13.21, 95% CI = 2.69–64.98, p = 0.001), presence of hepatitis C infection (vs. HCV-negative; HR = 9.75, 95% CI = 1.97–48.34, p = 0.005), and poor NCCN-IPI risk (HI or high vs. LI or low; HR = 5.56, 95% CI = 1.17– 26.55, p = 0.031). 3.3. Hepatic toxicity The pretreatment transaminase levels were not significantly different between patients with or without HCV infection (Table 1). In all, 96 patients have available data for evaluation of hepatic toxicity related to immunochemotherapy. Eleven patients (11.4%) developed severe hepatic toxicity, defined as grade 3 or 4
3
5-year survival (%) Survival (95% CI)
Sex (N = 100) Male (N = 56) Female (N = 44) Absolute lymphocyte count, 109/L (N = 98) 1.0 (N = 76) <1.0 (N = 22) Hemoglobin, g/dL (N = 98) 10 (N = 77) <10 (N = 21) Platelet count, 109/L (N = 99) 100 (N = 85) <100 (N = 14) Albumin, g/dL (N = 77) 3 (N = 51) <3 (N = 26) b2-microglobulin (N = 83) Normal (N = 23) Elevated (N = 60) Uric acid (N = 71) Normal (N = 57) Elevated (N = 14) Hepatitis B surface antigen (N = 98) Negative (N = 71) Positive (N = 27) Hepatitis C infection (N = 96) Negative (N = 81) Positive (N = 15) Histological subtype (N = 70) GCB-likea (N = 24) Non-GCB-like (N = 46) NCCN-IPIb risk (N = 100) Low or low-intermediate risk (N = 86) High-intermediate or high risk (N = 14)
p value 0.704
65.3% (47.5–83.1%) 55.2% (29.6–80.8%) 0.740 66.1% (51.5–80.7%) 49.6% (14.6–84.6%) 0.034 67.4% (51.5–83.3%) 41.8% (11.6–72.0%) 0.256 67.4% (53.4–81.4%) 26.7% (0–68.3%) < 0.001 62.7% (35.5–89.9%) 33.8% (9.6–58.0%) 0.151 79.9% (58.3–100%) 55.8% (33.2–78.4%) 0.325 67.3% (49.5–85.1%) 67.5% (40.3–94.7%) 0.154 52.5% (32.7–72.3%) 78.1% (57.1–99.1%) 0.010 71.0% (57.4–84.6%) 0.0% (0.0–0.0%) 0.078 55.5% (18.5–92.5%) 45.7% (24.5–66.9%) 0.003 66.0% (49.8–82.2%) 36.5% (5.7–67.3%)
CI: confidence interval. a GCB: Germinal center B-cell; b National Comprehensive Cancer Network International Prognostic Index.
increment in transaminase or total bilirubin levels per CTCAE criteria. Among them, 3 patients were negative for both hepatitis B and C infection, and one had HBV and HCV co-infection. The remaining 7 patients were HBV carriers, and one died of fulminant hepatitis due to reactivation of HBV infection. Excluding patients with HBV infection, 19 (34.5%) and 2 (3.6%) out of 55 HCV-negative DLBCL patients developed grade 1–2 and grade 3 hepatic toxicity, respectively, whereas 5 (41.7%) out of 12 HCV-positive DLBCL patients developed grade 1–2 toxicity (p = 0.811). No HCV-positive DLBCL patients developed severe hepatic toxicity. Our results suggested that HCV-infection did not impose greater risk for hepatic toxicity in DLBCL patients receiving immunochemotherapy. 4. Discussion In the current study, we incorporated the new enhanced NCCNIPI to present important information on the clinical features and prognostic evaluation of HCV-associated DLBCL patients treated in the rituximab era. There have been persistent controversies regarding the prognostic impact of HCV infection on the survival outcome of patients with DLBCL. In the pre-rituximab era, Besson et al. reported a significantly worse 2-year OS for patients with HCVpositive DLBCL than their counterparts [10]. On the contrary, reports by Tomita et al. and Park et al. showed these patients actually had excellent clinical outcome [25,26]. A larger Italian
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004
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Fig. 1. OS curves for patients with DLBCL treated with R-CHOP-like chemotherapy. OS curves based on (A) hemoglobin level, (B) albumin level, (C) HCV infection status, (D) NCCN-IPI risk score, and (E) histologic subtypes (GCB: germinal center B-cell like). The survival curves were plotted using the Kaplan–Meier method.
series including 156 HCV-seropositive cases, with roughly onefourth treated with rituximab-containing regimen, showed these patients compared favorably in terms of survival outcome to the data reported in the literature for HCV-negative DLBCL patients [27]. Unfortunately, there was no seronegative control group, which casted doubts on the prognostic value of HCV infection status in DLBCL patients in the series. More recently, data emerge regarding the clinical outcome of HCV-positive DLBCL patients treated with R-CHOP-like chemotherapy. An Italian retrospective study described the treatment outcome of the largest HCV-positive DLBCL cohort reported in the literature thus far [13]. Among the 535 patients, roughly half of them treated with rituximab-based chemotherapy, the 71% 3-year OS rate seemed similar to those reported for HCV-seronegative population across various studies [14,28]. Nevertheless, higher
HCV-RNA viral load was found to be a powerful predictive factor for an inferior outcome in this study [13], indicating hepatitis C virus infection imposed adverse impacts on the clinical course of DLBCL. The report by Ennishi et al. showed comparable survival outcome between 131 HCV-positive and 422 HCV-negative DLBCL patients treated with R-CHOP-like chemotherapy [14]. However, the respective 3-year OS was 75% and 84%, with a marginal p value of 0.07 hovering around borderline significance, which suggested HCV-positive patients might actually fare slightly worse. Furthermore, they incorporated old IPI parameters (age, PS, LDH, extranodal sites, and stages) with HCV infection status into multivariate analysis for survival outcome prediction. As noted earlier, IPI was created at a time when rituximab was not available and its role in predicting outcome of DLBCL patients treated with R-CHOP had been seriously challenged [19]. Therefore, we used the
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004
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CANEP-848; No. of Pages 6 Y.-Y. Chen et al. / Cancer Epidemiology xxx (2015) xxx–xxx Table 3 Multivariate analysis of prognostic factors affecting overall survival (OS). Variables
Overall survival HR (95% CI)
Hemoglobin, g/dL (N = 98) 10 (N = 77) <10 (N = 21) Albumin, g/dL (N = 77) 3.0 (N = 51) <3.0 (N = 26) Histological subtype (N = 70) GCB-likea (N = 24) Non-GCB-like (N = 46) Hepatitis C infection (N = 96) Negative (N = 81) Positive (N = 15) NCCN-IPIb risk (N = 100) Low or low-intermediate (N = 86) High-intermediate or high (N = 14)
p value 0.478
1.0 1.64 (0.42–6.39) 0.001 1.0 13.21 (2.69–64.98) 0.151 1.0 0.40 (0.11–1.40) 0.005 1.0 9.75 (1.97–48.34) 0.031 1.0 5.56 (1.17–26.55)
HR: hazard ratio; CI: confidence interval. a Germinal center B-cell. b National Comprehensive Cancer Network International Prognostic Index.
enhanced NCCN-IPI parameters and risk stratification groups to better delineate the prognostic predictors in our study. We clearly demonstrated that HCV infection and low serum albumin level, in conjunction with higher NCCN-IPI risks, jointly imposed adverse impacts on the clinical outcome of patients with DLBCL. The identification of low serum albumin level as an independent poor prognostic factor in DLBCL echoed several previous reports [19,29–32]. In fact, serum albumin has been shown to retain its prognostic significance in DLBCL even in the postrituximab era [19,29–31], in spite there are some discrepancies regarding the cutoff value defining low serum level in various studies. The mechanisms by which low serum albumin level leads to inferior survival outcome have not been thoroughly studied. Tumors with aggressive phenotypes might induce intensive systemic inflammatory response with accompanying excessive release of IL-6 and TNF-b cytokines [33], both of which have been correlated with decreased albumin production [34,35]. The aggressive disease reflected by low albumin level might partly explain why these patients had particularly poor outcome, as hypoalbuminemia was associated with the highest risk of death (HR 13.2, 95% CI: 2.7–65.0, p = 0.001, Table 3) among the 3 independent adverse factors identified in our study. Similar to our report, in a recent study validating the NCCN-IPI in a middle European cohort of DLBCL patients, Melchardt et al. showed that hypoalbuminemia added indispensable information to the NCCNIPI for risk stratification in the elderly population [19], again highlighting the prognostic importance of serum albumin level as well as the NCCN-IPI in these patients in the rituximab era. Our study showed that chemoimmunotherapy in HCV-positive DLBCL patients did not lead to excessive hepatotoxicity. Whether the presence of HCV infection causes added negative impacts on the development of hepatic dysfunction in these patients is still a matter of debate as only few comparative data exist [36]. Besson et al. reported increased short-term hepatic toxicity among HCVpositive patients treated in the pre-rituximab era [10]. In spite that R-CHOP therapy was also demonstrated to be associated with more grade 3–4 liver toxicity in a Japanese cohort of HCV-positive DLBCL patients [14], another study on a patient population of the same genetic background, however, revealed that treatmentrelated hepatotoxicity was not different between HCV-positive and -negative patients [37]. With regard to rituximab-induced liver injury in HCV-positive individuals, there has been some concern that the routine use of rituximab in these patients might predispose to severe hepatic toxicity and dismal clinical outcome
5
[38]. However, this has been refuted by others showing that rituximab is not associated with excessive hepatotoxicity in those patients [13,27]. Although needs to be further confirmed in large, prospective studies, our report nevertheless provides proof of evidence demonstrating that immunochemotherapy could be safely used in patients with HCV-positive DLBCL. Although our work added valuable information regarding the clinical characteristics as well as the prognosis of HCV-positive DLBCL patients, the significant discrepancy between the findings herein and others warrants thorough epidemiologic and biological studies to determine the underlying reasons of such disparities. Dissecting the molecular characteristics of HCV-positive DLBCL to further stratify disease subtypes may partly solve this puzzle. A recent publication by Augello et al. showed that a set of 52 microRNAs defined a signature for HCV-associated DLBCL, and they identified a group of patients with specific expression pattern having a particularly poor outcome [39]. Furthermore, various host factors, HCV genotypes, and ethnic background might exert additional impacts on the outcome of these patients. To solve those controversies, future prospective and randomized clinical trials involving a large number of uniformly treated HCV-positive DLBCL patients are needed, and information on serial HCV-RNA viral loads, HCV genotypes, degree of pre-treatment liver damage/ cirrhosis, and molecular characteristics of the tumors must also be included to delineate the nature of HCV-positive DLBCL and determine whether additional factors affect the clinical outcome of these patients. In spite of the retrospective nature of our work, our results nonetheless make a strong argument that hepatitis C infection status, serum albumin levels, and parameters from the new NCCN-IPI model should be considered in the development of new prognostic models for patients with DLBCL. In conclusion, our study has demonstrated that presence of HCV infection and low serum albumin level represent significant adverse risk factors and added important prognostic values to the newly proposed NCCN-IPI model for patients with DLBCL. HCVinfected DLBCL patients, however, did not exhibit excessive hepatic toxicity following rituximab-based immunochemotherapy. Conflict of interest statement This study was supported by Chang-Gung Memorial Hospital grant to CC Chen (CORPG6B0372). All authors declare there are no competing financial interests in relation to the work. Authorship contribution Study conception and design: Chih-Cheng Chen, M.D., Ph.D.; Kuan-Der Lee, M.D., Ph.D. Acquisition of data: Pin-Tsung Chen, M.D.; Chang-Hsien Lu, M.D. Analysis and interpretation of data: Cih-En Huang, M.D.; Fu-Wen Liang, Ph.D. Drafting of manuscript: Yi-Yang Chen, M.D. Critical revision: Chih-Cheng Chen, M.D., Ph.D. Acknowledgements The authors thank Miss Hsing-Yi Tsou and Miss I-Shan Chen for assists on data collection. All data were maintained and analyzed by the principal investigators independently. No medical writers were used. References [1] Ferri C, Caracciolo F, Zignego AL, La Civita L, Monti M, Longombardo G, et al. Hepatitis C virus infection in patients with non-Hodgkin’s lymphoma. Br J Haematol 1994;88(2):392–4.
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004
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[2] Pozzato G, Mazzaro C, Crovatto M, Modolo ML, Ceselli S, Mazzi G, et al. Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia. Blood 1994;84(9):3047–53. [3] Cox MC, Aloe-Spiriti MA, Cavalieri E, Alma E, Gigante E, Begini P, et al. HCV infection, B-cell non-Hodgkin’s lymphoma and immunochemotherapy: evidence and open questions. World J Gastrointest Oncol 2012;4(3):46–53. [4] Pioltelli P, Zehender G, Monti G, Monteverde A, Galli M. HCV and non-Hodgkin lymphoma. Lancet 1996;347(9001):624–5. [5] Mele A, Pulsoni A, Bianco E, Musto P, Szklo A, Sanpaolo MG, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multicenter case-control study. Blood 2003;102(3):996–9. [6] Peveling-Oberhag J, Arcaini L, Hansmann ML, Zeuzem S. Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management. J Hepatol 2013;59(1):169–77. [7] Visco C, Finotto S. Hepatitis C virus and diffuse large B-cell lymphoma: pathogenesis, behavior and treatment. World J Gastroenterol 2014;20(32): 11054–61. [8] Nieters A, Kallinowski B, Brennan P, Ott M, Maynadie M, Benavente Y, et al. Hepatitis C and risk of lymphoma: results of the European multicenter casecontrol study EPILYMPH. Gastroenterology 2006;131(6):1879–86. [9] de Sanjose S, Benavente Y, Vajdic CM, Engels EA, Morton LM, Bracci PM, et al. Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium. Clin Gastroenterol Hepatol 2008;6(4):451–8. [10] Besson C, Canioni D, Lepage E, Pol S, Morel P, Lederlin P, et al. Characteristics and outcome of diffuse large B-cell lymphoma in hepatitis C virus-positive patients in LNH 93 and LNH 98 Groupe d’Etude des Lymphomes de l’Adulte programs. J Clin Oncol 2006;24(6):953–60. [11] Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. New Engl J Med 2002;346(4):235–42. [12] Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7(5):379–91. [13] Merli M, Visco C, Spina M, Luminari S, Ferretti VV, Gotti M, et al. Outcome prediction of diffuse large B-cell lymphomas associated with hepatitis C virus infection: a study on behalf of the Fondazione Italiana Linfomi. Haematologica 2014;99(3):489–96. [14] Ennishi D, Maeda Y, Niitsu N, Kojima M, Izutsu K, Takizawa J, et al. Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. Blood 2010;116(24):5119–25. [15] A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. New Engl J Med 1993;329(14):987–94. [16] Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007;109(5):1857–61. [17] Zhou Z, Sehn LH, Rademaker AW, Gordon LI, Lacasce AS, Crosby-Thompson A, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 2014; 123(6):837–42. [18] Mian M, Marcheselli L, Rossi A, Visco C, Chiappella A, Volpetti S, et al. A diachronic-comparative analysis for the identification of the most powerful prognostic index for localized diffuse large B-cell lymphoma. Ann Oncol 2014. [19] Melchardt T, Troppan K, Weiss L, Hufnagl C, Neureiter D, Trankenschuh W, et al. A modified scoring of the NCCN-IPI is more accurate in the elderly and is improved by albumin and beta-microglobulin. Br J Haematol 2014. [20] Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma
[21]
[22]
[23]
[24] [25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
by immunohistochemistry using a tissue microarray. Blood 2004;103(1): 275–82. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999;17(4):1244. Feng J, Wang Z, Guo X, Chen Y, Cheng Y, Tang Y. Prognostic significance of absolute lymphocyte count at diagnosis of diffuse large B-cell lymphoma: a meta-analysis. Int J Hematol 2012;95(2):143–8. Hong J, Woo HS, Kim H, Ahn HK, Sym SJ, Park J, et al. Anemia as a useful biomarker in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP immunochemotherapy. Cancer Sci 2014. Chen LP, Lin SJ, Yu MS. Prognostic value of platelet count in diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk 2012;12(1):32–7. Tomita N, Kodama F, Takabayashi M, Kawano T, Yamaji S, Fujimaki K, et al. Clinical features and outcome in HCV-positive aggressive non-Hodgkin’s lymphoma. Leuk Lymphoma 2003;44(7):1159–64. Park BB, Kim JS, Lee YY, Kang HJ, Ryoo BY, Kang JH, et al. Clinical characteristics and outcome for hepatitis C virus-positive diffuse large B-cell lymphoma. Leuk Lymphoma 2008;49(1):88–94. Visco C, Arcaini L, Brusamolino E, Burcheri S, Ambrosetti A, Merli M, et al. Distinctive natural history in hepatitis C virus positive diffuse large B-cell lymphoma: analysis of 156 patients from northern Italy. Ann Oncol 2006; 17(9):1434–40. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008;9(2):105–16. Dalia S, Chavez J, Little B, Bello C, Fisher K, Lee JH, et al. Serum albumin retains independent prognostic significance in diffuse large B-cell lymphoma in the post-rituximab era. Ann Hematol 2014;93(8):1305–12. Li X, Zhang Y, Zhao W, Liu Z, Shen Y, Li J, et al. The Glasgow Prognostic Score as a significant predictor of diffuse large B cell lymphoma treated with R-CHOP in China. Ann Hematol 2014. Park S, Han B, Cho JW, Woo SY, Kim S, Kim SJ, et al. Effect of nutritional status on survival outcome of diffuse large B-cell lymphoma patients treated with rituximab-CHOP. Nutr Cancer 2014;66(2):225–33. Ngo L, Hee SW, Lim LC, Tao M, Quek R, Yap SP, et al. Prognostic factors in patients with diffuse large B cell lymphoma: before and after the introduction of rituximab. Leuk Lymphoma 2008;49(3):462–9. McMillan DC, Watson WS, O’Gorman P, Preston T, Scott HR, McArdle CS. Albumin concentrations are primarily determined by the body cell mass and the systemic inflammatory response in cancer patients with weight loss. Nutr Cancer 2001;39(2):210–3. Gupta D, Lis CG. Pretreatment serum albumin as a predictor of cancer survival: a systematic review of the epidemiological literature. Nutr J 2010; 9:69. Brenner DA, Buck M, Feitelberg SP, Chojkier M. Tumor necrosis factor-alpha inhibits albumin gene expression in a murine model of cachexia. J Clin Invest 1990;85(1):248–55. Marignani M, Mangone M, Cox MC, Angeletti S, Veggia B, Ferrari A, et al. HCVpositive status and hepatitis flares in patients with B-cell non-Hodgkin’s lymphoma treated with rituximab-containing regimens. Digest Liver Dis 2011;43(2):139–42. Nishikawa H, Tsudo M, Osaki Y. Clinical outcome in diffuse large B-cell lymphoma with hepatitis C virus infection in the rituximab era: a single center experience. Oncol Rep 2012;28(3):835–40. Salah-Eldin MA, Ebrahim MA, El-Sadda W. Clinical outcome of HCV-positive patients with diffuse large B-cell lymphoma treated with rituximab-based chemotherapy. Ann Hematol 2014;93(11):1903–11. Augello C, Gianelli U, Savi F, Moro A, Bonoldi E, Gambacorta M, et al. MicroRNA as potential biomarker in HCV-associated diffuse large B-cell lymphoma. J Clin Pathol 2014;67(8):697–701.
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004
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Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index Yi-Yang Chen a,1, Cih-En Huang a,1, Fu-Wen Liang b, Chang-Hsien Lu a,c, Pin-Tsung Chen a,c, Kuan-Der Lee a,c,d, Chih-Cheng Chen a,d,* a
Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan Department of Public Health, College of Medicine National Cheng Kung University, Tainan, Taiwan c Graduate Institute of Clinical Medical Sciences, Chang Gung University, Tao-Yuan, Taiwan d College of Medicine, Chang Gung University, Tao-Yuan, Taiwan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 26 December 2014 Received in revised form 27 March 2015 Accepted 5 April 2015 Available online xxx
Objective: Patients with hepatitis C virus (HCV) infection have been associated with development of diffuse large B-cell lymphoma (DLBCL), yet its impact on several clinical aspects, including phenotypic characteristics and treatment-related toxicities as well as survival outcome after rituximab-based immunochemotherapy, remains controversial. Methods: To elucidate the characteristics of HCV-positive DLBCL in the context of a new prognostic model, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), we retrospectively analyzed DLBCL patients diagnosed and treated with immunochemotherapy at our institute during the last decade. Results: In all, HCV infection was identified in 22 (17.7%) of 124 DLBCL patients. Except for being more likely to present with an advanced stage of disease, patients with HCV infection were phenotypically indistinguishable from HCV-negative cases. Multivariate analysis showed 3 factors independently predicted a dismal overall survival (OS) outcome: lower albumin level (<3 g/dL vs. 3 g/dL, p < 0.001; HR = 13.21, 95% CI = 2.69–64.98, p = 0.001), presence of HCV infection (vs. HCV-negative; HR = 9.75, 95% CI = 1.97–48.34, p = 0.005), and poor NCCN-IPI risk (high-intermediate or high vs. low-intermediate or low; HR = 5.56, 95% CI = 1.17–26.55, p = 0.031). Conclusions: Our study has demonstrated that HCV infection status and low serum albumin level add important prognostic values to the newly proposed NCCN-IPI model for patients with DLBCL. ß 2015 Published by Elsevier Ltd.
Keywords: Hepatitis C NCCN-IPI Diffuse large B-cell lymphoma Albumin Rituximab Prognosis
1. Introduction Ever since the first description on the relationship of hepatitis C virus (HCV) infection and non-Hodgkin’s lymphoma (NHL) [1,2], there are mounting evidence showing HCV infection increases the risk of developing B-cell lymphoproliferative disorders [3–6]. Initial reports mostly described an apparent association between HCV infection and indolent lymphoma, and the observation of a curative potential of antiviral therapy on HCV-related indolent
* Corresponding author at: No. 6, West Section, Chia-Pu Road, Pu-Tz City, Chiayi 613, Taiwan. Tel.: +886 5 3621000x2852; fax: +886 5 3623002. E-mail address: [email protected] (C.-C. Chen). 1 These two authors contributed equally to the work.
lymphoma further strengthened their strong causal relationship [7]. Subsequently, several large epidemiological studies confirmed that the theory of B-cell transformation by HCV in lymphomagenesis also applied to diffuse large B-cell lymphoma (DLBCL), as HCVinfected patients had a significantly increased risk of developing DLBCL (odds ratio 2.2–3.5) [5,8,9]. Thereafter, there is wide speculation that HCV-associated DLBCL might own specific pathogenesis and biology that is discrepant from others. HCV-positive DLBCL patients were found to be older, have elevated lactate dehydrogenase (LDH) and more frequent extranodal involvement (especially liver), and have an inferior overall survival when treated with the traditional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen [10]. The advent of rituximab (R) changes the landscape of treatment for DLBCL and significantly improves the clinical outcome [11,12], but
http://dx.doi.org/10.1016/j.canep.2015.04.004 1877-7821/ß 2015 Published by Elsevier Ltd.
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004
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controversies do exist with regard to the prognostic impacts of HCV infection on the survival outcome of DLBCL patients treated with R-CHOP. A large retrospective study from Italy showed high HCV-RNA viral load was associated with shorter survival [13], whereas a report from Japan disclosed that HCV infection was not a significant risk factor for prognosis [14]. Asides from the debatable differential outcome in HCV-positive DLBCL patients, the incorporation of older prognostic indexes (the international prognostic index [IPI] [15] or its variant revised IPI [16]) into multivariate analysis for survival outcome determination raised huge concerns on adequacy and accuracy of those studies, as IPI was created at a time when rituximab was not available and both indexes consisted of only HCV-negative or HCV-status unknown patients. Recently, collaborators from North America proposed a new prognostic model, the National Comprehensive Cancer Network (NCCN) IPI, for DLBCL patients treated with R-CHOP [17]. The enhanced NCCN-IPI clearly demonstrates superiority over the old IPI as a prognostic model for patients with DLBCL in the rituximab era, and reports from others confirmed its unparalleled predictive value [18,19]. However, like other DLBCL prognostic indexes, HCV infection status was not incorporated into the analysis for outcome prediction in the NCCN-IPI. For this reason, we carried out this retrospective study to determine the prognostic role of HCV infection in patients with DLBCL when considered in the same context with the enhanced NCCN-IPI. 2. Materials and methods 2.1. Study population Sequential patients who were 18 years of age or older with pathologically-confirmed de novo DLBCL diagnosed during the last decade at our institute were screened. Information on a variety of clinical characteristics, including patient demographics, results of baseline hemograms and biochemical tests, serological tests of hepatitis B surface antigen (HBsAg) and HCV antibody, types of therapy, treatment outcomes, and survival status, was obtained. As screening tests for the presence of HBsAg and HCV antibody were standard procedures in newly diagnosed DLBCL patients at our institute, most patients had available relevant data. Patients with human immunodeficiency virus infection were excluded from the current study. The last date of follow-up was September 30th, 2014. The study was approved by the Institutional Review Board of Chang-Gung Memorial Hospital (Taiwan) in accordance with the Declaration of Helsinki. 2.2. Risk groups, treatment, and outcome Patients were categorized as having either HCV-positive or negative DLBCL based on the presence or absence of anti-HCV antibody. The NCCN IPI, which substratified patients into low, low-intermediate (LI), high-intermediate (HI), and high risks, was used for risk stratification [17]. Lymphomatous infiltration of the bone marrow, central nervous system, liver, gastrointestinal tract, or lung was considered as high-risk extranodal involvement, as defined in the NCCN-IPI model. Histology subtypes of DLBCL, categorized as germinal center B-cell (GCB)-like and non-GCB-like, were defined as previously described and based on the results of immunohistochemical stains of tumor samples [20]. For baseline characteristics delineation, all eligible patients were included. For survival outcome comparison, only patients receiving R-CHOP-like immunochemotherapy were included for analysis. The response to treatment was assessed according to standard response criteria [21]. Overall survival (OS) was measured from the date of diagnosis until death from any cause, with observation ending at the date of last contact for patients last known to be alive. Adverse events
were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). 2.3. Statistical analysis The Mann–Whitney test was used for continuous variables versus categorical variables. For comparison of the dichotomous variables, a Pearson chi-square or a Fisher’s exact test (for expected values of >5 or 5, respectively) was applied. The variables of OS were estimated by the Kaplan–Meier method. Differences between groups were calculated using the log-rank test for univariate analysis. Cox’s proportional hazards model was used for multivariate analysis to test independent prognostic factors on survival outcome. All calculations were performed using the Statistical Package of Social Sciences software (version 17.0; SPSS, Inc., Chicago, IL, USA). The level of statistical significance was set at 0.05 for all tests. 3. Results 3.1. Clinical characteristics of the patients We screened 135 patients with pathologically confirmed de novo DLBCL diagnosed during the past decade at our institute. Based on the results of serological test of anti-HCV antibody, we identified 22 (17.7%) HCV-positive DLBCL cases out of 124 patients who had available data. Table 1 summarizes the comparison of the clinical and laboratory features between patients sub-categorized as HCV-positive and -negative DLBCL. There were no significant differences between the two subgroups of patients with respect to patient characteristics, including age, gender, and performance status (PS). The results of biochemical tests (including serum albumin, hepatic transaminases, uric acid, b2-microglobulin, and lactate dehydrogenase [LDH] levels) were not different, either. Because lymphopenia (with an absolute lymphocyte count <1.0 109/L) [22], anemia (hemoglobin <10 g/dL) [23], and thrombocytopenia (platelet count <100 109/L) [24] had all been indicated as an adverse prognostic indicators in patients with DLBCL, we used them as surrogate markers for baseline hemogram comparison but found there was no apparent discrepancy between the two groups of patients. The incidences of high-risk extranodal involvement, as defined in the NCCN-IPI model [17], were similar in both groups. Patients with HCV-positive DLBCL did not carry a significantly higher probability of lymphomatous involvement in the liver. Although HCV-positive DLBCL patients were more likely to present with an advanced stage of disease (68.2% vs. 40.2% in HCV-negative DLBCL, p = 0.017), the distributions of both groups of patients in each NCCN-IPI risk category did not differ significantly. Activated B-cell like histology was the major DLBCL subtype and accounted for about two-thirds of the patients in both groups. 3.2. Survival outcome analysis To avoid different therapies as a potential confounding factor, we excluded a minority of patients who were treated in the prerituximab era. Only patients receiving R-CHOP-like regimen as the cornerstone of treatment were included in the survival outcome analysis. Based on univariate analysis, we evaluated several factors with respect to the impacts on OS. As demonstrated in Table 2 and Fig. 1, we found that patients with more profound anemia (hemoglobin <10 g/dL vs. 10 g/dL, p = 0.034, Fig. 1A), patients with lower albumin level (<3 g/dL vs. 3 g/dL, p < 0.001, Fig. 1B), patients with HCV-positive DLBCL (vs. HCV-negative, p = 0.010, Fig. 1C), and patients with HI or high NCCN-IPI risks (vs. LI or low risks, p = 0.003, Fig. 1D) all had a far more dismal survival outcome when compared to their respective counterparts, whereas patients
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004
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CANEP-848; No. of Pages 6 Y.-Y. Chen et al. / Cancer Epidemiology xxx (2015) xxx–xxx Table 1 Clinical and laboratory features of patients with diffuse large B cell lymphoma (DLBCL) stratified by hepatitis C virus infection status. Variables Age in years; median (range) Age >60 years; n (%) Males (%) Performance status 0–1a; n (%) Extranodal involvementb; n (%) Hepatic involvement; n (%) Ann Arbor Stage III/IV; n (%) LDHc level in U/L; median (range) Elevated LDH levels; n (%) Abnormal liver function tests; n (%) Albumin level in g/dL; median (range) Albumin <3 g/dL; n (%) Elevated b2-microglobulin levels; n (%) Elevated uric acid levels; n (%) ALCd <1.0 109/L; n (%) Hemoglobin <10 g/dL; n (%) Platelet count <100 109/L; n (%) NCCN-IPI riske; n (%) Low Low-intermediate High-intermediate High Histological subtype; n (%) Non germinal center B-cell like Germinal center B-cell like a b c d e
HCV( ) DLBCL (n = 102)
HCV(+) DLBCL (n = 22) 67.0 (30.1–91.2)
0.708
66 (64.7%) 54 (52.9%) 75 (73.5%)
14 (63.6%) 13 (59.1%) 13 (59.1%)
0.990 0.600 0.176
48 (47.1%)
13 (59.1%)
0.306
7 (6.9%) 41 (40.2%) 207 (25–2467) 50 (52.1%) 15 (15.3%) 3.2 (1.9–4.7)
4 (18.2%) 15 (68.2%) 168 (47–1040)
0.105 0.017 0.310
8 (42.1%) 6 (27.3%)
0.427 0.182
3.3 (1.8–4.0)
0.848
31 (40.3%) 57 (69.5%)
4 (25.0%) 13 (76.5%)
0.395 0.771
15 (20.5%)
4 (30.8%)
0.471
21 (21.2%) 19 (19.0%) 10 (9.9%)
6 (27.3%) 5 (22.7%) 1 (4.8%)
0.537 0.768 0.687
11 37 35 13
1 7 7 4
0.753 (11.5%) (38.5%) (36.5%) (13.5%)
(5.3%) (36.8%) (36.8%) (21.1%) 0.969
45 (66.2%)
12 (66.7%)
23 (33.8%)
6 (33.3%)
Table 2 Univariate analysis of prognostic factors affecting overall survival. Variables (patients)
p-value
67.6 (18.4–91.9)
ECOG performance status. Extranodal involvement of either BM, CNS, GI/liver, or lung. Lactate dehydrogenase. Absolute lymphocyte count. National Comprehensive Cancer Network International Prognostic Index.
with non-GCB-like histological subtype also showed a trend of possibly decreased survival (vs. GCB-like subtype, p = 0.078, Fig. 1E). On the other hand, gender, lymphopenia, thrombocytopenia, presence of HBsAg, and levels of either b2-microglobulin or uric acid did not impose any significant impacts on OS duration (Table 2). To test various parameters of possible prognostic value, we performed multivariate analysis to examine the potential interaction and effects on OS. All 5 factors with potentially significant importance exhibited on univariate analysis were included in the Cox model for comparison, and 3 factors were found to independently predict an inferior OS (Table 3), including lower albumin level (<3 g/dL vs. 3 g/dL, p < 0.001; HR = 13.21, 95% CI = 2.69–64.98, p = 0.001), presence of hepatitis C infection (vs. HCV-negative; HR = 9.75, 95% CI = 1.97–48.34, p = 0.005), and poor NCCN-IPI risk (HI or high vs. LI or low; HR = 5.56, 95% CI = 1.17– 26.55, p = 0.031). 3.3. Hepatic toxicity The pretreatment transaminase levels were not significantly different between patients with or without HCV infection (Table 1). In all, 96 patients have available data for evaluation of hepatic toxicity related to immunochemotherapy. Eleven patients (11.4%) developed severe hepatic toxicity, defined as grade 3 or 4
3
5-year survival (%) Survival (95% CI)
Sex (N = 100) Male (N = 56) Female (N = 44) Absolute lymphocyte count, 109/L (N = 98) 1.0 (N = 76) <1.0 (N = 22) Hemoglobin, g/dL (N = 98) 10 (N = 77) <10 (N = 21) Platelet count, 109/L (N = 99) 100 (N = 85) <100 (N = 14) Albumin, g/dL (N = 77) 3 (N = 51) <3 (N = 26) b2-microglobulin (N = 83) Normal (N = 23) Elevated (N = 60) Uric acid (N = 71) Normal (N = 57) Elevated (N = 14) Hepatitis B surface antigen (N = 98) Negative (N = 71) Positive (N = 27) Hepatitis C infection (N = 96) Negative (N = 81) Positive (N = 15) Histological subtype (N = 70) GCB-likea (N = 24) Non-GCB-like (N = 46) NCCN-IPIb risk (N = 100) Low or low-intermediate risk (N = 86) High-intermediate or high risk (N = 14)
p value 0.704
65.3% (47.5–83.1%) 55.2% (29.6–80.8%) 0.740 66.1% (51.5–80.7%) 49.6% (14.6–84.6%) 0.034 67.4% (51.5–83.3%) 41.8% (11.6–72.0%) 0.256 67.4% (53.4–81.4%) 26.7% (0–68.3%) < 0.001 62.7% (35.5–89.9%) 33.8% (9.6–58.0%) 0.151 79.9% (58.3–100%) 55.8% (33.2–78.4%) 0.325 67.3% (49.5–85.1%) 67.5% (40.3–94.7%) 0.154 52.5% (32.7–72.3%) 78.1% (57.1–99.1%) 0.010 71.0% (57.4–84.6%) 0.0% (0.0–0.0%) 0.078 55.5% (18.5–92.5%) 45.7% (24.5–66.9%) 0.003 66.0% (49.8–82.2%) 36.5% (5.7–67.3%)
CI: confidence interval. a GCB: Germinal center B-cell; b National Comprehensive Cancer Network International Prognostic Index.
increment in transaminase or total bilirubin levels per CTCAE criteria. Among them, 3 patients were negative for both hepatitis B and C infection, and one had HBV and HCV co-infection. The remaining 7 patients were HBV carriers, and one died of fulminant hepatitis due to reactivation of HBV infection. Excluding patients with HBV infection, 19 (34.5%) and 2 (3.6%) out of 55 HCV-negative DLBCL patients developed grade 1–2 and grade 3 hepatic toxicity, respectively, whereas 5 (41.7%) out of 12 HCV-positive DLBCL patients developed grade 1–2 toxicity (p = 0.811). No HCV-positive DLBCL patients developed severe hepatic toxicity. Our results suggested that HCV-infection did not impose greater risk for hepatic toxicity in DLBCL patients receiving immunochemotherapy. 4. Discussion In the current study, we incorporated the new enhanced NCCNIPI to present important information on the clinical features and prognostic evaluation of HCV-associated DLBCL patients treated in the rituximab era. There have been persistent controversies regarding the prognostic impact of HCV infection on the survival outcome of patients with DLBCL. In the pre-rituximab era, Besson et al. reported a significantly worse 2-year OS for patients with HCVpositive DLBCL than their counterparts [10]. On the contrary, reports by Tomita et al. and Park et al. showed these patients actually had excellent clinical outcome [25,26]. A larger Italian
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004
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Fig. 1. OS curves for patients with DLBCL treated with R-CHOP-like chemotherapy. OS curves based on (A) hemoglobin level, (B) albumin level, (C) HCV infection status, (D) NCCN-IPI risk score, and (E) histologic subtypes (GCB: germinal center B-cell like). The survival curves were plotted using the Kaplan–Meier method.
series including 156 HCV-seropositive cases, with roughly onefourth treated with rituximab-containing regimen, showed these patients compared favorably in terms of survival outcome to the data reported in the literature for HCV-negative DLBCL patients [27]. Unfortunately, there was no seronegative control group, which casted doubts on the prognostic value of HCV infection status in DLBCL patients in the series. More recently, data emerge regarding the clinical outcome of HCV-positive DLBCL patients treated with R-CHOP-like chemotherapy. An Italian retrospective study described the treatment outcome of the largest HCV-positive DLBCL cohort reported in the literature thus far [13]. Among the 535 patients, roughly half of them treated with rituximab-based chemotherapy, the 71% 3-year OS rate seemed similar to those reported for HCV-seronegative population across various studies [14,28]. Nevertheless, higher
HCV-RNA viral load was found to be a powerful predictive factor for an inferior outcome in this study [13], indicating hepatitis C virus infection imposed adverse impacts on the clinical course of DLBCL. The report by Ennishi et al. showed comparable survival outcome between 131 HCV-positive and 422 HCV-negative DLBCL patients treated with R-CHOP-like chemotherapy [14]. However, the respective 3-year OS was 75% and 84%, with a marginal p value of 0.07 hovering around borderline significance, which suggested HCV-positive patients might actually fare slightly worse. Furthermore, they incorporated old IPI parameters (age, PS, LDH, extranodal sites, and stages) with HCV infection status into multivariate analysis for survival outcome prediction. As noted earlier, IPI was created at a time when rituximab was not available and its role in predicting outcome of DLBCL patients treated with R-CHOP had been seriously challenged [19]. Therefore, we used the
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004
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CANEP-848; No. of Pages 6 Y.-Y. Chen et al. / Cancer Epidemiology xxx (2015) xxx–xxx Table 3 Multivariate analysis of prognostic factors affecting overall survival (OS). Variables
Overall survival HR (95% CI)
Hemoglobin, g/dL (N = 98) 10 (N = 77) <10 (N = 21) Albumin, g/dL (N = 77) 3.0 (N = 51) <3.0 (N = 26) Histological subtype (N = 70) GCB-likea (N = 24) Non-GCB-like (N = 46) Hepatitis C infection (N = 96) Negative (N = 81) Positive (N = 15) NCCN-IPIb risk (N = 100) Low or low-intermediate (N = 86) High-intermediate or high (N = 14)
p value 0.478
1.0 1.64 (0.42–6.39) 0.001 1.0 13.21 (2.69–64.98) 0.151 1.0 0.40 (0.11–1.40) 0.005 1.0 9.75 (1.97–48.34) 0.031 1.0 5.56 (1.17–26.55)
HR: hazard ratio; CI: confidence interval. a Germinal center B-cell. b National Comprehensive Cancer Network International Prognostic Index.
enhanced NCCN-IPI parameters and risk stratification groups to better delineate the prognostic predictors in our study. We clearly demonstrated that HCV infection and low serum albumin level, in conjunction with higher NCCN-IPI risks, jointly imposed adverse impacts on the clinical outcome of patients with DLBCL. The identification of low serum albumin level as an independent poor prognostic factor in DLBCL echoed several previous reports [19,29–32]. In fact, serum albumin has been shown to retain its prognostic significance in DLBCL even in the postrituximab era [19,29–31], in spite there are some discrepancies regarding the cutoff value defining low serum level in various studies. The mechanisms by which low serum albumin level leads to inferior survival outcome have not been thoroughly studied. Tumors with aggressive phenotypes might induce intensive systemic inflammatory response with accompanying excessive release of IL-6 and TNF-b cytokines [33], both of which have been correlated with decreased albumin production [34,35]. The aggressive disease reflected by low albumin level might partly explain why these patients had particularly poor outcome, as hypoalbuminemia was associated with the highest risk of death (HR 13.2, 95% CI: 2.7–65.0, p = 0.001, Table 3) among the 3 independent adverse factors identified in our study. Similar to our report, in a recent study validating the NCCN-IPI in a middle European cohort of DLBCL patients, Melchardt et al. showed that hypoalbuminemia added indispensable information to the NCCNIPI for risk stratification in the elderly population [19], again highlighting the prognostic importance of serum albumin level as well as the NCCN-IPI in these patients in the rituximab era. Our study showed that chemoimmunotherapy in HCV-positive DLBCL patients did not lead to excessive hepatotoxicity. Whether the presence of HCV infection causes added negative impacts on the development of hepatic dysfunction in these patients is still a matter of debate as only few comparative data exist [36]. Besson et al. reported increased short-term hepatic toxicity among HCVpositive patients treated in the pre-rituximab era [10]. In spite that R-CHOP therapy was also demonstrated to be associated with more grade 3–4 liver toxicity in a Japanese cohort of HCV-positive DLBCL patients [14], another study on a patient population of the same genetic background, however, revealed that treatmentrelated hepatotoxicity was not different between HCV-positive and -negative patients [37]. With regard to rituximab-induced liver injury in HCV-positive individuals, there has been some concern that the routine use of rituximab in these patients might predispose to severe hepatic toxicity and dismal clinical outcome
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[38]. However, this has been refuted by others showing that rituximab is not associated with excessive hepatotoxicity in those patients [13,27]. Although needs to be further confirmed in large, prospective studies, our report nevertheless provides proof of evidence demonstrating that immunochemotherapy could be safely used in patients with HCV-positive DLBCL. Although our work added valuable information regarding the clinical characteristics as well as the prognosis of HCV-positive DLBCL patients, the significant discrepancy between the findings herein and others warrants thorough epidemiologic and biological studies to determine the underlying reasons of such disparities. Dissecting the molecular characteristics of HCV-positive DLBCL to further stratify disease subtypes may partly solve this puzzle. A recent publication by Augello et al. showed that a set of 52 microRNAs defined a signature for HCV-associated DLBCL, and they identified a group of patients with specific expression pattern having a particularly poor outcome [39]. Furthermore, various host factors, HCV genotypes, and ethnic background might exert additional impacts on the outcome of these patients. To solve those controversies, future prospective and randomized clinical trials involving a large number of uniformly treated HCV-positive DLBCL patients are needed, and information on serial HCV-RNA viral loads, HCV genotypes, degree of pre-treatment liver damage/ cirrhosis, and molecular characteristics of the tumors must also be included to delineate the nature of HCV-positive DLBCL and determine whether additional factors affect the clinical outcome of these patients. In spite of the retrospective nature of our work, our results nonetheless make a strong argument that hepatitis C infection status, serum albumin levels, and parameters from the new NCCN-IPI model should be considered in the development of new prognostic models for patients with DLBCL. In conclusion, our study has demonstrated that presence of HCV infection and low serum albumin level represent significant adverse risk factors and added important prognostic values to the newly proposed NCCN-IPI model for patients with DLBCL. HCVinfected DLBCL patients, however, did not exhibit excessive hepatic toxicity following rituximab-based immunochemotherapy. Conflict of interest statement This study was supported by Chang-Gung Memorial Hospital grant to CC Chen (CORPG6B0372). All authors declare there are no competing financial interests in relation to the work. Authorship contribution Study conception and design: Chih-Cheng Chen, M.D., Ph.D.; Kuan-Der Lee, M.D., Ph.D. Acquisition of data: Pin-Tsung Chen, M.D.; Chang-Hsien Lu, M.D. Analysis and interpretation of data: Cih-En Huang, M.D.; Fu-Wen Liang, Ph.D. Drafting of manuscript: Yi-Yang Chen, M.D. Critical revision: Chih-Cheng Chen, M.D., Ph.D. Acknowledgements The authors thank Miss Hsing-Yi Tsou and Miss I-Shan Chen for assists on data collection. All data were maintained and analyzed by the principal investigators independently. No medical writers were used. References [1] Ferri C, Caracciolo F, Zignego AL, La Civita L, Monti M, Longombardo G, et al. Hepatitis C virus infection in patients with non-Hodgkin’s lymphoma. Br J Haematol 1994;88(2):392–4.
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004
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[2] Pozzato G, Mazzaro C, Crovatto M, Modolo ML, Ceselli S, Mazzi G, et al. Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia. Blood 1994;84(9):3047–53. [3] Cox MC, Aloe-Spiriti MA, Cavalieri E, Alma E, Gigante E, Begini P, et al. HCV infection, B-cell non-Hodgkin’s lymphoma and immunochemotherapy: evidence and open questions. World J Gastrointest Oncol 2012;4(3):46–53. [4] Pioltelli P, Zehender G, Monti G, Monteverde A, Galli M. HCV and non-Hodgkin lymphoma. Lancet 1996;347(9001):624–5. [5] Mele A, Pulsoni A, Bianco E, Musto P, Szklo A, Sanpaolo MG, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multicenter case-control study. Blood 2003;102(3):996–9. [6] Peveling-Oberhag J, Arcaini L, Hansmann ML, Zeuzem S. Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management. J Hepatol 2013;59(1):169–77. [7] Visco C, Finotto S. Hepatitis C virus and diffuse large B-cell lymphoma: pathogenesis, behavior and treatment. World J Gastroenterol 2014;20(32): 11054–61. [8] Nieters A, Kallinowski B, Brennan P, Ott M, Maynadie M, Benavente Y, et al. Hepatitis C and risk of lymphoma: results of the European multicenter casecontrol study EPILYMPH. Gastroenterology 2006;131(6):1879–86. [9] de Sanjose S, Benavente Y, Vajdic CM, Engels EA, Morton LM, Bracci PM, et al. Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium. Clin Gastroenterol Hepatol 2008;6(4):451–8. [10] Besson C, Canioni D, Lepage E, Pol S, Morel P, Lederlin P, et al. Characteristics and outcome of diffuse large B-cell lymphoma in hepatitis C virus-positive patients in LNH 93 and LNH 98 Groupe d’Etude des Lymphomes de l’Adulte programs. J Clin Oncol 2006;24(6):953–60. [11] Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. New Engl J Med 2002;346(4):235–42. [12] Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7(5):379–91. [13] Merli M, Visco C, Spina M, Luminari S, Ferretti VV, Gotti M, et al. Outcome prediction of diffuse large B-cell lymphomas associated with hepatitis C virus infection: a study on behalf of the Fondazione Italiana Linfomi. Haematologica 2014;99(3):489–96. [14] Ennishi D, Maeda Y, Niitsu N, Kojima M, Izutsu K, Takizawa J, et al. Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. Blood 2010;116(24):5119–25. [15] A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. New Engl J Med 1993;329(14):987–94. [16] Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007;109(5):1857–61. [17] Zhou Z, Sehn LH, Rademaker AW, Gordon LI, Lacasce AS, Crosby-Thompson A, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 2014; 123(6):837–42. [18] Mian M, Marcheselli L, Rossi A, Visco C, Chiappella A, Volpetti S, et al. A diachronic-comparative analysis for the identification of the most powerful prognostic index for localized diffuse large B-cell lymphoma. Ann Oncol 2014. [19] Melchardt T, Troppan K, Weiss L, Hufnagl C, Neureiter D, Trankenschuh W, et al. A modified scoring of the NCCN-IPI is more accurate in the elderly and is improved by albumin and beta-microglobulin. Br J Haematol 2014. [20] Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma
[21]
[22]
[23]
[24] [25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
by immunohistochemistry using a tissue microarray. Blood 2004;103(1): 275–82. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999;17(4):1244. Feng J, Wang Z, Guo X, Chen Y, Cheng Y, Tang Y. Prognostic significance of absolute lymphocyte count at diagnosis of diffuse large B-cell lymphoma: a meta-analysis. Int J Hematol 2012;95(2):143–8. Hong J, Woo HS, Kim H, Ahn HK, Sym SJ, Park J, et al. Anemia as a useful biomarker in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP immunochemotherapy. Cancer Sci 2014. Chen LP, Lin SJ, Yu MS. Prognostic value of platelet count in diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk 2012;12(1):32–7. Tomita N, Kodama F, Takabayashi M, Kawano T, Yamaji S, Fujimaki K, et al. Clinical features and outcome in HCV-positive aggressive non-Hodgkin’s lymphoma. Leuk Lymphoma 2003;44(7):1159–64. Park BB, Kim JS, Lee YY, Kang HJ, Ryoo BY, Kang JH, et al. Clinical characteristics and outcome for hepatitis C virus-positive diffuse large B-cell lymphoma. Leuk Lymphoma 2008;49(1):88–94. Visco C, Arcaini L, Brusamolino E, Burcheri S, Ambrosetti A, Merli M, et al. Distinctive natural history in hepatitis C virus positive diffuse large B-cell lymphoma: analysis of 156 patients from northern Italy. Ann Oncol 2006; 17(9):1434–40. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008;9(2):105–16. Dalia S, Chavez J, Little B, Bello C, Fisher K, Lee JH, et al. Serum albumin retains independent prognostic significance in diffuse large B-cell lymphoma in the post-rituximab era. Ann Hematol 2014;93(8):1305–12. Li X, Zhang Y, Zhao W, Liu Z, Shen Y, Li J, et al. The Glasgow Prognostic Score as a significant predictor of diffuse large B cell lymphoma treated with R-CHOP in China. Ann Hematol 2014. Park S, Han B, Cho JW, Woo SY, Kim S, Kim SJ, et al. Effect of nutritional status on survival outcome of diffuse large B-cell lymphoma patients treated with rituximab-CHOP. Nutr Cancer 2014;66(2):225–33. Ngo L, Hee SW, Lim LC, Tao M, Quek R, Yap SP, et al. Prognostic factors in patients with diffuse large B cell lymphoma: before and after the introduction of rituximab. Leuk Lymphoma 2008;49(3):462–9. McMillan DC, Watson WS, O’Gorman P, Preston T, Scott HR, McArdle CS. Albumin concentrations are primarily determined by the body cell mass and the systemic inflammatory response in cancer patients with weight loss. Nutr Cancer 2001;39(2):210–3. Gupta D, Lis CG. Pretreatment serum albumin as a predictor of cancer survival: a systematic review of the epidemiological literature. Nutr J 2010; 9:69. Brenner DA, Buck M, Feitelberg SP, Chojkier M. Tumor necrosis factor-alpha inhibits albumin gene expression in a murine model of cachexia. J Clin Invest 1990;85(1):248–55. Marignani M, Mangone M, Cox MC, Angeletti S, Veggia B, Ferrari A, et al. HCVpositive status and hepatitis flares in patients with B-cell non-Hodgkin’s lymphoma treated with rituximab-containing regimens. Digest Liver Dis 2011;43(2):139–42. Nishikawa H, Tsudo M, Osaki Y. Clinical outcome in diffuse large B-cell lymphoma with hepatitis C virus infection in the rituximab era: a single center experience. Oncol Rep 2012;28(3):835–40. Salah-Eldin MA, Ebrahim MA, El-Sadda W. Clinical outcome of HCV-positive patients with diffuse large B-cell lymphoma treated with rituximab-based chemotherapy. Ann Hematol 2014;93(11):1903–11. Augello C, Gianelli U, Savi F, Moro A, Bonoldi E, Gambacorta M, et al. MicroRNA as potential biomarker in HCV-associated diffuse large B-cell lymphoma. J Clin Pathol 2014;67(8):697–701.
Please cite this article in press as: Chen Y-Y, et al. Prognostic impact of hepatitis C virus infection in patients with diffuse large B-cell lymphoma treated with immunochemotherapy in the context of a novel prognostic index. Cancer Epidemiology (2015), http:// dx.doi.org/10.1016/j.canep.2015.04.004