Abstract

Objective: The present study was done to evaluate the prognostic impact of the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) and serum albumin levels in the treatment outcome of Indian diffuse large B-cell lymphoma (DLBCL) patients in the rituximab era. Patients and Methods: We retrospectively analyzed the data (2013–2016) of 135 newly diagnosed DLBCL cases ≥18 years of age. All patients received Rituximab-Cyclophosphamide, Adriamycin, Vincristine, Prednisone (R-CHOP) chemotherapy. The analysis was carried out to assess the overall survival (OS) and progression-free survival (PFS) and the prognostic factors predicting the outcome. Results: Of the 135 patients in the study, 89 (65.9%) had B-symptoms, 20 (14.8%) had bulky disease, 79 (58.5%) had advanced disease (Stage III and IV), and 29 (21.5%) had primary extranodal involvement. Serum albumin ≤3.5 g% was present in 71 (52.6%) patients. About 74 (54.8%) cases were risk stratified to NCCN-IPI high-intermediate-risk group, while 18 (13.3%) patients were categorized into high-risk group. The median PFS and OS of our study cohort were 19 months (95% confidence interval [CI] = 2.59–35.4) and 38 months (95% CI = 9.02–55.68), respectively. Serum albumin ≤3.5 g/dl was significantly associated with poor OS (hazard ratio [HR] = 3.99, 95% CI = 2.25–7.07, P < 0 xss=removed xss=removed class="i" xss=removed>P < 0 xss=removed xss=removed class="i" xss=removed>P < 0 xss=removed xss=removed class="i" xss=removed>P < 0 class="b" xss=removed>Conclusion: The NCCN-IPI prognostic model and serum albumin levels have independent prognostic significance in Indian DLBCL patients. Serum albumin is a readily available, easy to standardize, and cheap investigation requiring no specialized expertise and holds promise for being incorporated in future DLBCL prognostic risk models.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma (NHL) in adults constituting around 20% of all NHL cases.[1] It is a highly heterogeneous disease with respect to tumor biology, clinical features, response to treatment, and outcome. As a result, there has always been a need for an accurate-risk stratification system that can easily differentiate the “low-risk” from the “high-risk” disease group so that the treatment can be tailored accordingly.

For around two decades, the International Prognostic Index (IPI) derived from five prognostic factors, such as age, Ann Arbor tumor stage, serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group (ECOG) performance status, and number of extranodal sites involved, holds its prognostic significance in discriminating patients with aggressive lymphomas into four discrete outcome groups with a 5-year overall survival (OS) ranging from 26% to 73% even in the postrituximab era.[2] [3] However, one potential limitation to the use of the original IPI in patients receiving rituximab is that the difference in outcomes between patients in different IPI-risk groups is relatively small. Several prognostic models have been developed since then to improvise the IPI prognostic model using the same prognostic factors in a more detailed way to provide better discrimination between risk groups.[4] One such prognostic model is the National Comprehensive Cancer Network-IPI (NCCN-IPI) that provided better discrimination between risk groups with OS ranging from 38% to 96%.[5]

Recently, several attempts have been made to more accurately segregate high risk from low-risk patients using various molecular and genetic markers (e.g., germinal center B-cell type vs. activated B-cell-like subtypes and various somatic mutations).[6] [7] [8] [9] However, their widespread use in clinical practice is still limited due to the lack of standardized protocols, sophisticated laboratories to perform these tests, and their prohibitive cost, especially in the developing world. As a result, there is an unmet need of identifying readily and universally available as well as affordable parameters that can help in predicting disease outcome.

Serum albumin may be one such parameter as several studies have shown its correlation with treatment outcome in various hematological malignancies.[10] [11] [12] [13] [14] [15] [16] [17] It is a surrogate marker of disease burden in cancers, comorbidity, and nutritional status.[18] [19] [20] [21] Notably, serum albumin was found to be statistically significant in the univariate analysis in the IPI prognostic model. However, since its values were available in an insufficient number of patients, it was excluded from the step-down regression model.[2]

Hence, the aims of the present study were to evaluate the prognostic impact of NCCN-IPI and serum albumin levels in the treatment outcome (OS and progression-free survival [PFS]) of Indian DLBCL patients in the rituximab era.

Patients and Methods

Patients

The present study is a single-institutional study carried out in a tertiary care medical university center of North India. A retrospective chart review of medical records of patients with ages >18 years with a confirmed diagnosis of DLBCL and treated with combination immunotherapy (R-CHOP) in the department of hematology from January 2013 to December 2016 was carried out. In all cases, the diagnosis of DLBCL was established by tissue biopsy and classified according to the WHO classification of tumors.[22] The following clinical and laboratory data were collected from medical files: demographic profile, clinical presentation, ECOG performance status, serum LDH level, Ann Arbor stage, number of extranodal sites involved, complete blood count, histopathological report with immunohistochemistry, Ki-67 index, and serum albumin level. The revised IPI (R-IPI) scores were calculated based on age, serum LDH, ECOG performance status, number of extranodal sites at diagnosis, and Ann Arbor stage of the disease. Low serum albumin was defined as <3>

Treatment data

All the patients in the study cohort received R-CHOP chemotherapy. The date of start and completion of R-CHOP chemotherapy cycles were recorded along with the total number of cycles that were received by each patient. Interim treatment response evaluation done by whole-body 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) between 3 and 4 cycles of R-CHOP was recorded and classified as per Lugano response assessment criteria.[23] End-of-treatment (after 6–8 cycles) PET-CT evaluation data along with 3 monthly follow-up data were systematically recorded. Other recorded data included whether the patient received the intrathecal therapy and/or radiation therapy along with its indication of use.

Statistical analysis

Descriptive statistics were obtained using mean with standard deviation or median with range and categorical variables were represented by frequencies with corresponding percentages. Differences in the distribution of individual parameters among subsets of patients were analyzed using Fisher's exact test or the Chi-square test for categorical variables and the Mann–Whitney U-test for continuous variables. OS was defined as date of diagnosis to date of death or date of last follow-up for those censored. PFS was defined as date of diagnosis to date of relapse, progression, or death. Survival curves for OS and PFS were drawn employing Kaplan–Meier method and were compared using log-rank test. Cox proportional hazards regression model was applied to consider each potential prognostic factor in univariate and multivariate analyses. Adjusted hazard ratios (HRs) were estimated with 95% confidence intervals (CIs). Bivariate associations between serum albumin and other variables were examined using Spearman's correlation coefficient. The data were analyzed using IBM SPSS statistics for windows version 21.0 (Armonk, NY). P < 0>

Results

Of the total 172 patients who were diagnosed as DLBCL at our center during the study period, 135 patients were included in the study. The reasons for excluding 37 patients from the study were as follows: five patients defaulted therapy due to the lack of finances for the treatment, eight patients received only CHOP chemotherapy, and 24 patients did not seek treatment at our center.

Baseline characteristics

The demographic and disease characteristics of these patients are shown in [Table 1]. The median age at presentation was 58 years (range: 18–82 years) with a preponderance of male (M:F = 2.5:1) patients. The mean duration of symptoms before being diagnosed as DLBCL at our center was 56.4 ± 42.3 days. Of the eligible 135 patients in the study, 89 (65.9%) had B-symptoms, 20 (14.8%) had bulky disease, 79 (58.5%) had advanced disease (Stage III and IV) at presentation, and 29 (21.5%) had primary extranodal involvement. Serum albumin <3>

| Figure 1  Progression-free survival and (b) overall survival

Prognostic factors

Univariate analysis of various potential prognostic factors showed serum albumin and NCCN-IPI to be associated with OS and PFS. Serum albumin ≤3.5 g/dl was significantly associated with poor OS (HR = 3.99, 95% CI = 2.25–7.07), P < 0 xss=removed xss=removed class="i" xss=removed>P < 0 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_96_18#FI_2" xss=removed>Figure 2]. Similarly, low NCCN-IPI (<4 xss=removed xss=removed class="i" xss=removed>P < 0 xss=removed xss=removed class="i" xss=removed>P < 0 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_96_18#TB_3" xss=removed>Table 3] and [Figure 3]. These two factors (serum albumin and NCCN-IPI) retained their prognostic significance with respect to OS and PFS in the multivariate analysis as shown in [Table 4]. Of the 74 patients in the high intermediate risk (NCCN-IPI: 4–5) and 18 patients in the high risk (NCCN-IPI: ≥6), stratification of patients based on serum albumin (≤3.5 g/dl or >3.5 g/dl) further identified the subset of patients with significantly poor OS and PFS as shown in [Table 5] and [Figure 4].

| Figure 2  Overall survival stratified according to the National Comprehensive Cancer Network-International Prognostic Index and (b) progression-free survival stratified according to the National Comprehensive Cancer Network-International Prognostic Index

| Figure 3  Progression-free survival stratified according to serum albumin and (b) overall survival stratified according to serum albumin

| Figure 4 Overall survival of high-intermediate-risk patients based on serum albumin and (b) overall survival of high-risk patients based on serum albumin

There was significant correlation found between the serum albumin and ECOG performance status (Spearman's correlation coefficient: −0.32, P = 0.001) as well as NCCN-IPI risk groups (Spearman's correlation coefficient: −0.194, P = 0.02). Similarly, a significant correlation was found between serum albumin and body mass index (BMI) (Spearman's correlation coefficient: 0.26, P = 0.03). However, no significant correlation was found between the age and serum albumin (Spearman's correlation coefficient: −0.069, P = 0.429).

1.  Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006; 107: 265-76
2.  International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 1993; 329: 987-94
3.  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: 1857-61
4.  Bari A, Marcheselli L, Sacchi S, Marcheselli R, Pozzi S, Ferri P. et al. Prognostic models for diffuse large B-cell lymphoma in the rituximab era: A never-ending story. Ann Oncol 2010; 21: 1486-91
5.  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: 837-42
6.  Visco C, Li Y, Xu-Monette ZY, Miranda RN, Green TM, Li Y. et al. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: A report from the international DLBCL Rituximab-CHOP Consortium Program Study. Leukemia 2012; 26: 2103-13
7.  Sehn LH. Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program 2012; 2012: 402-9
8.  Perry AM, Mitrovic Z, Chan WC. Biological prognostic markers in diffuse large B-cell lymphoma. Cancer Control 2012; 19: 214-26
9.  Horn H, Ziepert M, Becher C, Barth TF, Bernd HW, Feller AC. et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 2013; 121: 2253-63
10.  Chihara D, Oki Y, Ine S, Yamamoto K, Kato H, Taji H. et al. Analysis of prognostic factors in peripheral T-cell lymphoma: Prognostic value of serum albumin and mediastinal lymphadenopathy. Leuk Lymphoma 2009; 50: 1999-2004
11.  Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L. et al. Revised international staging system for multiple myeloma: A report from international myeloma working group. J Clin Oncol 2015; 33: 2863-9
12.  Watanabe T, Kinoshita T, Itoh K, Yoshimura K, Ogura M, Kagami Y. et al. Pretreatment total serum protein is a significant prognostic factor for the outcome of patients with peripheral T/natural killer-cell lymphomas. Leuk Lymphoma 2010; 51: 813-21
13.  Zhu YJ, Huang JJ, Xia Y, Zhao W, Jiang WQ, Lin TY. et al. Primary mediastinal large B-cell lymphoma (PMLBCL) in Chinese patients: Clinical characteristics and prognostic factors. Int J Hematol 2011; 94: 178-84
14.  Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International prognostic factors project on advanced Hodgkin's disease. N Engl J Med 1998; 339: 1506-14
15.  Arcaini L, Lazzarino M, Colombo N, Burcheri S, Boveri E, Paulli M. et al. Splenic marginal zone lymphoma: A prognostic model for clinical use. Blood 2006; 107: 4643-9
16.  Komrokji RS, Corrales-Yepez M, Kharfan-Dabaja MA, Al Ali NH, Padron E, Rollison DE. et al. Hypoalbuminemia is an independent prognostic factor for overall survival in myelodysplastic syndromes. Am J Hematol 2012; 87: 1006-9
17.  Kharfan-Dabaja MA, Chavez JC, Yu D, Zhu W, Fernandez-Vertiz EI, Perkins J. et al. Severe hypoalbuminemia at day 90 predicts worse nonrelapse mortality and overall survival after allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant 2011; 17: 384-93
18.  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
19.  Goldwasser P, Feldman J. Association of serum albumin and mortality risk. J Clin Epidemiol 1997; 50: 693-703
20.  Franch-Arcas G. The meaning of hypoalbuminaemia in clinical practice. Clin Nutr 2001; 20: 265-9
21.  Barchel D, Almoznino-Sarafian D, Shteinshnaider M, Tzur I, Cohen N, Gorelik O. Clinical characteristics and prognostic significance of serum albumin changes in an internal medicine ward. Eur J Intern Med 2013; 24: 772-8
22.  Swerdlow SH, Campo E, Harris NL. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency of Research on Cancer Scientific Publications; 2016
23.  Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E. et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 2014; 32: 3059-68
24.  Ochi Y, Kazuma Y, Hiramoto N, Ono Y, Yoshioka S, Yonetani N. et al. Utility of a simple prognostic stratification based on platelet counts and serum albumin levels in elderly patients with diffuse large B cell lymphoma. Ann Hematol 2017; 96: 1-8
25.  Melchardt T, Troppan K, Weiss L, Hufnagl C, Neureiter D, Tränkenschuh W. et al. A modified scoring of the NCCN-IPI is more accurate in the elderly and is improved by albumin and β2 -microglobulin. Br J Haematol 2015; 168: 239-45
26.  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: 1305-12
27.  Bairey O, Shacham-Abulafia A, Shpilberg O, Gurion R. Serum albumin level at diagnosis of diffuse large B-cell lymphoma: An important simple prognostic factor. Hematol Oncol 2016; 34: 184-92
28.  Prakash G, Sharma A, Raina V, Kumar L, Sharma MC, Mohanti BK. B cell non-Hodgkin's lymphoma: Experience from a tertiary care cancer center. Ann Hematol 2012; 91: 1603-11
29.  Khera R, Jain S, Kumar L, Thulkar S, Vijayraghwan M, Dawar R. Diffuse large B-cell lymphoma: Experience from a tertiary care center in North India. Med Oncol 2010; 27: 310-8
30.  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: 462-9
31.  Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340: 448-54
32.  McMillan DC, Watson WS, O'Gorman P, Preston T, Scott HR, McArdle CS. et al. 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: 210-3
33.  Aviles A, Yañez J, López T, García EL, Guzmán R, Díaz-Maqueo JC. Malnutrition as an adverse prognostic factor in patients with diffuse large cell lymphoma. Arch Med Res 1995; 26: 31-4
34.  Hong JY, Ryu KJ, Lee JY, Park C, Ko YH, Kim WS. et al. Serum level of CXCL10 is associated with inflammatory prognostic biomarkers in patients with diffuse large B-cell lymphoma. Hematol Oncol 2016; 12: 1-7
35.  Lv X, Feng L, Ge X, Lu K, Wang X. Interleukin-9 promotes cell survival and drug resistance in diffuse large B-cell lymphoma. J Exp Clin Cancer Res 2016; 35: 106
36.  Lech-Maranda E, Bienvenu J, Michallet AS, Houot R, Robak T, Coiffier B. et al. Elevated IL-10 plasma levels correlate with poor prognosis in diffuse large B-cell lymphoma. Eur Cytokine Netw 2006; 17: 60-6
37.  D'Angio RG. Is there a role for albumin administration in nutrition support?. Ann Pharmacother 1994; 28: 478-82
38.  Yamasaki K, Chuang VT, Maruyama T, Otagiri M. Albumin-drug interaction and its clinical implication. Biochim Biophys Acta 2013; 1830: 5435-43

| Figure 1  Progression-free survival and (b) overall survival

| Figure 2  Overall survival stratified according to the National Comprehensive Cancer Network-International Prognostic Index and (b) progression-free survival stratified according to the National Comprehensive Cancer Network-International Prognostic Index

| Figure 3  Progression-free survival stratified according to serum albumin and (b) overall survival stratified according to serum albumin

| Figure 4 Overall survival of high-intermediate-risk patients based on serum albumin and (b) overall survival of high-risk patients based on serum albumin

1.  Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006; 107: 265-76
2.  International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 1993; 329: 987-94
3.  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: 1857-61
4.  Bari A, Marcheselli L, Sacchi S, Marcheselli R, Pozzi S, Ferri P. et al. Prognostic models for diffuse large B-cell lymphoma in the rituximab era: A never-ending story. Ann Oncol 2010; 21: 1486-91
5.  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: 837-42
6.  Visco C, Li Y, Xu-Monette ZY, Miranda RN, Green TM, Li Y. et al. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: A report from the international DLBCL Rituximab-CHOP Consortium Program Study. Leukemia 2012; 26: 2103-13
7.  Sehn LH. Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program 2012; 2012: 402-9
8.  Perry AM, Mitrovic Z, Chan WC. Biological prognostic markers in diffuse large B-cell lymphoma. Cancer Control 2012; 19: 214-26
9.  Horn H, Ziepert M, Becher C, Barth TF, Bernd HW, Feller AC. et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 2013; 121: 2253-63
10.  Chihara D, Oki Y, Ine S, Yamamoto K, Kato H, Taji H. et al. Analysis of prognostic factors in peripheral T-cell lymphoma: Prognostic value of serum albumin and mediastinal lymphadenopathy. Leuk Lymphoma 2009; 50: 1999-2004
11.  Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L. et al. Revised international staging system for multiple myeloma: A report from international myeloma working group. J Clin Oncol 2015; 33: 2863-9
12.  Watanabe T, Kinoshita T, Itoh K, Yoshimura K, Ogura M, Kagami Y. et al. Pretreatment total serum protein is a significant prognostic factor for the outcome of patients with peripheral T/natural killer-cell lymphomas. Leuk Lymphoma 2010; 51: 813-21
13.  Zhu YJ, Huang JJ, Xia Y, Zhao W, Jiang WQ, Lin TY. et al. Primary mediastinal large B-cell lymphoma (PMLBCL) in Chinese patients: Clinical characteristics and prognostic factors. Int J Hematol 2011; 94: 178-84
14.  Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International prognostic factors project on advanced Hodgkin's disease. N Engl J Med 1998; 339: 1506-14
15.  Arcaini L, Lazzarino M, Colombo N, Burcheri S, Boveri E, Paulli M. et al. Splenic marginal zone lymphoma: A prognostic model for clinical use. Blood 2006; 107: 4643-9
16.  Komrokji RS, Corrales-Yepez M, Kharfan-Dabaja MA, Al Ali NH, Padron E, Rollison DE. et al. Hypoalbuminemia is an independent prognostic factor for overall survival in myelodysplastic syndromes. Am J Hematol 2012; 87: 1006-9
17.  Kharfan-Dabaja MA, Chavez JC, Yu D, Zhu W, Fernandez-Vertiz EI, Perkins J. et al. Severe hypoalbuminemia at day 90 predicts worse nonrelapse mortality and overall survival after allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant 2011; 17: 384-93
18.  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
19.  Goldwasser P, Feldman J. Association of serum albumin and mortality risk. J Clin Epidemiol 1997; 50: 693-703
20.  Franch-Arcas G. The meaning of hypoalbuminaemia in clinical practice. Clin Nutr 2001; 20: 265-9
21.  Barchel D, Almoznino-Sarafian D, Shteinshnaider M, Tzur I, Cohen N, Gorelik O. Clinical characteristics and prognostic significance of serum albumin changes in an internal medicine ward. Eur J Intern Med 2013; 24: 772-8
22.  Swerdlow SH, Campo E, Harris NL. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency of Research on Cancer Scientific Publications; 2016
23.  Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E. et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 2014; 32: 3059-68
24.  Ochi Y, Kazuma Y, Hiramoto N, Ono Y, Yoshioka S, Yonetani N. et al. Utility of a simple prognostic stratification based on platelet counts and serum albumin levels in elderly patients with diffuse large B cell lymphoma. Ann Hematol 2017; 96: 1-8
25.  Melchardt T, Troppan K, Weiss L, Hufnagl C, Neureiter D, Tränkenschuh W. et al. A modified scoring of the NCCN-IPI is more accurate in the elderly and is improved by albumin and β2 -microglobulin. Br J Haematol 2015; 168: 239-45
26.  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: 1305-12
27.  Bairey O, Shacham-Abulafia A, Shpilberg O, Gurion R. Serum albumin level at diagnosis of diffuse large B-cell lymphoma: An important simple prognostic factor. Hematol Oncol 2016; 34: 184-92
28.  Prakash G, Sharma A, Raina V, Kumar L, Sharma MC, Mohanti BK. B cell non-Hodgkin's lymphoma: Experience from a tertiary care cancer center. Ann Hematol 2012; 91: 1603-11
29.  Khera R, Jain S, Kumar L, Thulkar S, Vijayraghwan M, Dawar R. Diffuse large B-cell lymphoma: Experience from a tertiary care center in North India. Med Oncol 2010; 27: 310-8
30.  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: 462-9
31.  Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340: 448-54
32.  McMillan DC, Watson WS, O'Gorman P, Preston T, Scott HR, McArdle CS. et al. 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: 210-3
33.  Aviles A, Yañez J, López T, García EL, Guzmán R, Díaz-Maqueo JC. Malnutrition as an adverse prognostic factor in patients with diffuse large cell lymphoma. Arch Med Res 1995; 26: 31-4
34.  Hong JY, Ryu KJ, Lee JY, Park C, Ko YH, Kim WS. et al. Serum level of CXCL10 is associated with inflammatory prognostic biomarkers in patients with diffuse large B-cell lymphoma. Hematol Oncol 2016; 12: 1-7
35.  Lv X, Feng L, Ge X, Lu K, Wang X. Interleukin-9 promotes cell survival and drug resistance in diffuse large B-cell lymphoma. J Exp Clin Cancer Res 2016; 35: 106
36.  Lech-Maranda E, Bienvenu J, Michallet AS, Houot R, Robak T, Coiffier B. et al. Elevated IL-10 plasma levels correlate with poor prognosis in diffuse large B-cell lymphoma. Eur Cytokine Netw 2006; 17: 60-6
37.  D'Angio RG. Is there a role for albumin administration in nutrition support?. Ann Pharmacother 1994; 28: 478-82
38.  Yamasaki K, Chuang VT, Maruyama T, Otagiri M. Albumin-drug interaction and its clinical implication. Biochim Biophys Acta 2013; 1830: 5435-43