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Hypoalbuminemia predicts inferior outcome in patients with AIDS-related lymphoma
Infectious Agents and Cancer volume 17, Article number: 33 (2022)
The prognostic value of serum albumin in acquired immunodeficiency syndrome (AIDS)-related lymphoma (ARL) remains covered.
We retrospectively analyzed de novo ARL patients from 2013 to 2019 across three centers. Factors correlated with progression-free survival (PFS) and overall survival (OS) were evaluated in Kaplan–Meier, univariate and multivariate Cox proportional hazard models.
A total of 86 ARL patients were enrolled with a median follow-up of 34 months. In the cohort, the OS and 2-year PFS rates were 37.5% and 35.4%, respectively. In multivariate models, older age (PFS, hazard ratios [HR] = 1.035, p = 0.037; OS, HR = 1.034, p = 0.041) and hypoalbuminemia (OS, HR = 0.910, p = 0.038) predicted inferior survival. ARL patients with hypoalbuminemia showed worse OS and 2-year PFS (p = 0.028 and p = 0.01, respectively), which was associated with poor Eastern Cooperative Oncology Group performance status (ECOG PS) and higher International Prognosis Index (IPI) score.
In conclusion, serum albumin at diagnosis is an independent prognostic factor for overall survival in AIDS-related lymphoma.
The introduction of combined antiretroviral therapy (cART) has markedly improved the outcome of people living with human immunodeficiency virus (PLWHIV) . Nevertheless, acquired immunodeficiency syndrome (AIDS) -related lymphoma (ARL) remains a leading cause of malignancies morbidity and mortality for PLWHIV, even in the immunochemotherapy era [2,3,4,5]. Approximately 70%-90% of ARL is high-grade B-cell lymphoma, such as diffuse large B cell lymphoma (DLBCL) and Burkitt’s lymphoma (BL) [6,7,8]. Great heterogeneity in survival exists for DLBCL and BL patients . The International Prognostic Index (IPI) incorporating simple clinical parameters remains widely used today. However, its prognostic significance was impaired for subgroup with long-term survival clearly < 50%, especially in PLWHIV .
Recently, several biomarkers have been suggested to be related to the prognosis of ARL, including IPI, age-adjusted IPI, CD4 + T cells count, age, Eastern Cooperative Oncology Group performance status (ECOG PS), chemotherapy, lactate dehydrogenase (LDH), Epstein- barr virus deoxyribonucleic acid (EBV DNA), hepatitis C virus, the Burkitt/Burkitt-like lymphoma subtype, history of clinical AIDS, and expression of B-cell lymphoma-2 (BCL2), cluster of differentiation 4 (CD44), Protein 53 (p53) and Immunoglobulin M (IgM) [10,11,12,13,14,15]. Alternatively, recent immunosuppression and prolonged HIV viraemia have important independent roles in the development of ARL . Otherwise, unclassifiable histology, stage III or IV, and no concomitant cART during chemotherapy were independently associated with a higher relapse rate .
Nevertheless, it is important to find the simple prognostic marker to identify ARL patients with different outcomes, especially in low-income and middle-income countries with poor infrastructure for cancer management. We therefore performed this study to evaluate the risk factors in ARL patients and would provide useful prognostic information for clinicians.
The study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Ethics Committee of Nanfang Hospital (study identifier NFEC-2021–178). The committee decided to waive the need for written informed consent from the participants in the study because the data were analyzed retrospectively and anonymously.
Patients and data collection
This retrospective multicenter study was conducted at Nanfang Hospital Affiliated with Southern Medical University, Fourth Hospital of Nanning, and Longtan Hospital of Guangxi Zhuang Autonomous Region. A total of 143 hospitalized de novo HIV-positive lymphoma patients from 2013 to 2019 were included. 86 patients with ARL, whose survival state were definite, were enrolled in the present study. The deadline for the follow-up was 2021. The pathological diagnosis of lymphoma was based on the 2008 World Health Organization (WHO) classification .
The clinical variables were evaluated, including date of enrollment, history of HIV/AIDS, histological subtype, sex, age, body mass index (BMI), baseline CD4 + T cells count, cluster of differentiation 8 (CD8 +) T cells count, CD4/CD8 ratio, erythrocyte sedimentation rate (ESR), complete blood cell count (CBC), LDH, serum albumin (ALB), red cell distribution width (RDW) ratio, Lugano classification, ECOG PS, and IPI score. All data were expressed as means ± standard deviation (SD) or median or percentage when appropriated.
Computed tomography (CT) or 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) was performed for radiological evaluation. Brain magnetic resonance imaging (MRI) was used to assess central nervous system involvement. Overall survival (OS) was defined as the time from diagnosis of ARL to the last follow-up or death from any cause. The 2-year progression-free survival (PFS) was defined as the time from diagnosis of ARL until progression, relapse, or death from any cause at 24 months.
Statistical analysis was performed by the Statistical Package for the Social Sciences (SPSS) version 17. OS and 2-year PFS were estimated by the Kaplan–Meier method and compared by the log-rank test. Distributions of clinical characteristics between the different groups were carried out by students’ test or Fisher’s exact test. Linear correlation analysis and one way analysis of variance (ANOVA) were used to analyze the relationship of ALB with other factors. The univariate and multivariate analysis was performed by Cox proportional hazard model. Hazard ratios (HR) and 95% confidence interval (CI) were used to summarize the association between variables and survival. Bivariate correlations among variables were carried out using Pearson's correlation test. All p values were two-sided, and the significance was defined as p < 0.05.
Demographic and clinical characteristics in ARL patients enrolled
A total of 86 patients with ARL were enrolled, with a median follow-up of 34 months. DLBCL is the most frequent subtype in ARL (95.3%). There were 54 (62.8%) ARL patients dead at the end of follow-up, and these patients tended to present with higher IPI score (p = 0.027) and lower CD4 + T cells (p = 0.046), as shown in Table 1. There were no significant differences in the clinical features of sex, BMI, CD8 + T cells, CD4/CD8 ratio, ESR, platelet count, LDH, serum ALB, and ECOG PS.
Prognostic factors associated with patients with ARL
Among ARL patients enrolled, the OS and 2-year PFS were 37.5% and 35.4%, respectively (Fig. 1). To further evaluate risk factors correlated with prognosis, univariable and multivariable analysis were conducted. Results from multivariate analysis demonstrated that older age (HR = 1.034, p = 0.041) and lower ALB level (HR = 0.910, p = 0.038) were independent prognostic factors associated with OS in ARL population (Table 2).
We then adopted multivariable analysis to evaluate factors correlated with 2-year PFS in ARL patients enrolled. Of note, as an unfavorable factor, age (HR = 1.035, p = 0.041) retained its statistical significance for 2-year PFS in patients with ARL (Table 3).
Hypoalbuminemia predicted worse prognosis in ARL
To further investigate ALB as a novel biomarker for prognosis in ARL, we divided patients into ALB > 35.0 g/L and ALB ≤ 35.0 g/L groups at the time of diagnosis. A Kaplan–Meier survival analysis was conducted by using data from all patients enrolled in the study. Similarly, the patients with low ALB level had remarkably worse outcomes in terms of OS (p = 0.028) and 2-year PFS (p = 0.010), when compared with those with high ALB level, as depicted in Fig. 2.
Relationship between serum album level and clinical variables
We next explored the relationship between serum album level and other clinical variables in patients with ARL by Pearson's correlation analysis. A strong correlation between serum ALB and age (r = 0.263, p = 0.016), CD4 + T cells (r = 0.250, p = 0.025), ESR (r = -0.429, p < 0.001), LDH (r = -0.305, p = 0.005), RDW-SD (red cell distribution width standard deviation, r = -0.244, p = 0.029), and BMI (r = 0.237, p = 0.039) were validated (Fig. 3).
A total of 33.3%, 45.2%, and 84.6% patients had low ALB level in ECOG PS 0, 1–2, and 3–4 groups (p = 0.002). Similarity, in patients with IPI score 0–1, 2–3, and 4–5, a total of 21.75%, 58.5% and 66.7% population, respectively, had low ALB level (p = 0.005). We therefore analyzed the ALB level in each ECOG PS group and IPI score group. The average serum ALB level was 38.47 ± 4.89, 34.98 ± 6.74, and 28.08 ± 9.17 g/L in ECOG PS 0, 1–2 and 3–4 groups respectively (P = 0.002). A similar tendency was observed in terms of IPI score groups with 38.27 ± 7.39, 33.36 ± 5.98, and 31.61 ± 8.67 g/L (p = 0.007), as shown in Fig. 4.
Patients with hypoalbuminemia (≤ 35.0 g/L) are considered to have malnutrition. Malnutrition is common in HIV infection and plays an independent and significant role in its morbidity and mortality [19, 20]. Low serum albumin at diagnosis has been identified as a simple prognostic factor in some cancers including non-Hodgkin's lymphoma (NHL) [21,22,23,24,25] which comprises more than 50% of all AIDS-defining cancers. However, its role in predicting clinical outcomes of AIDS-related lymphoma has not been evaluated.
In this study, we retrospectively confirmed that hypoalbuminemia was not uncommon at diagnosis of de novo ARL and was associated with poor survival outcome attractively. A similar trend was observed in the analyses of HIV-negative DLBCL patients [22, 24]. We also uncovered a strong relationship between hypoalbuminemia and poor ECOG PS as well as higher IPI score. As reported, IPI score and ECOG PS at diagnosis had been identified as independent risk factors for survival in ARL population and in HIV-negative lymphoma patients [9, 15, 26, 27]. These associations with adverse prognostic factors translated into shorter OS for ARL patients with hypoalbuminemia. This indicated that serum albumin level may be not only a surrogate of poor nutritional, but also driven by the aggressive tumor behavior and inflammatory status [24, 28], which was correlated with shorter survival, treatment response, treatment-related toxicity and compliance .
In the present study, we demonstrated that age was another important independent predictor of OS and 2-year PFS in patients with ARL. Our data resembles the result of a Swedish study which finds that age is the most important predictor of survival in HIV-negative DLBCL patients . In fact, a study of 100 HIV-positive lymphoma patients proved that age may be a significant prognostic factor for 2-year OS . Hence, age is generally associated with adverse prognosis in ARL. We furthermore confirmed that ALB is another important risk factor in patients with ARL.
The strengths of the study include the multicenter, population-based design, the long duration of follow-up and the relatively large number of patients with well-documented data. The main limitation of this study is its retrospective nature, which may have caused a selection bias. To overcome these problems, we applied multivariable analysis to adjust for confounding factors. Another caution is that internal and external validation is needed before applying the serum ALB to clinical practice. These factors should be clarified in future prospective studies.
In summary, we showed that hypoalbuminemia is a simple and effective prognostic factor in AIDS-related lymphoma patients. For ARL patients with hypoalbuminemia, closer follow-up and timely intervention are necessary. Further research is needed to confirm whether albumin supplementation is required for those subpopulations.
Availability of data and materials
The data are presented in the manuscript.
Acquired immunodeficiency syndrome
Analysis of variance
Acquired immunodeficiency syndrome-related lymphoma
Body mass index
Combined antiretroviral therapy
Complete blood cell count
Cluster of differentiation 4
Cluster of differentiation 8
Diffuse large B cell lymphoma
- EBV DNA:
Epstein–Barr virus deoxyribonucleic acid
- ECOG PS:
Eastern Cooperative Oncology Group performance status
Erythrocyte sedimentation rate
- FDG PET:
F-fluorodeoxyglucose positron emission tomography
Human immunodeficiency virus
International Prognosis Index
Magnetic resonance imaging
People living with human immunodeficiency virus
Red cell distribution width
Statistical Package for the Social Sciences
World Health Organization
Ehrenkranz P, Rosen S, Boulle A, Eaton JW, Ford N, Fox MP, et al. The revolving door of HIV care: revising the service delivery cascade to achieve the UNAIDS 95–95-95 goals. PLoS Med. 2021;18(5): e1003651. https://doi.org/10.1371/journal.pmed.1003651.
Noy A. Optimizing treatment of HIV-associated lymphoma. Blood. 2019;134(17):1385–94. https://doi.org/10.1182/blood-2018-01-791400.
Dolcetti R, Giagulli C, He W, Selleri M, Caccuri F, Eyzaguirre LM, et al. Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis. Proc Natl Acad Sci U S A. 2015;112(46):14331–6. https://doi.org/10.1073/pnas.1514748112.
Dal Maso L, Franceschi S. Epidemiology of non-Hodgkin lymphomas and other haemolymphopoietic neoplasms in people with AIDS. Lancet Oncol. 2003;4(2):110–9. https://doi.org/10.1016/s1470-2045(03)00983-5.
Yarchoan R, Uldrick TS. HIV-associated cancers and related diseases. N Engl J Med. 2018;378(11):1029–41. https://doi.org/10.1056/NEJMra1615896.
Carbone A, Vaccher E, Gloghini A. Hematological cancers in individuals infected by HIV. Blood. 2021. https://doi.org/10.1182/blood.2020005469 (Online ahead of print).
Kimani SM, Painschab MS, Horner MJ, Muchengeti M, Fedoriw Y, Shiels MS, et al. Epidemiology of haematological malignancies in people living with HIV. Lancet HIV. 2020;7(9):e641–51. https://doi.org/10.1016/S2352-3018(20)30118-1.
Re A, Cattaneo C, Montoto S. Treatment management of haematological malignancies in people living with HIV. Lancet Haematol. 2020;7(9):e679–89. https://doi.org/10.1016/S2352-3026(20)30115-0.
Ruppert AS, Dixon JG, Salles G, Wall A, Cunningham D, Poeschel V, et al. International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI. Blood. 2020;135(23):2041–8. https://doi.org/10.1182/blood.2019002729.
Wu D, Chen C, Zhang M, Li Z, Wang S, Shi J, et al. The clinical features and prognosis of 100 AIDS-related lymphoma cases. Sci Rep. 2019;9(1):5381. https://doi.org/10.1038/s41598-019-41869-9.
Wu J, Miao Y, Qian C, Tao P, Wang X, Dong X, et al. Clinical characteristics and outcomes in HIV-associated diffuse large B-cell lymphoma in China: a retrospective single-center study. J Cancer. 2021;12(10):2903–11. https://doi.org/10.7150/jca.51027.
Besson C, Noel N, Lancar R, Prevot S, Algarte-Genin M, Rosenthal E, et al. Hepatitis C virus or hepatitis B virus coinfection and lymphoma risk in people living with HIV. AIDS. 2020;34(4):599–608. https://doi.org/10.1097/QAD.0000000000002461.
Philippe L, Lancar R, Laurent C, Algarte-Genin M, Chassagne-Clement C, Fabiani B, et al. In situ BCL2 expression is an independent prognostic factor in HIV-associated DLBCL, a LYMPHOVIR cohort study. Br J Haematol. 2020;188(3):413–23. https://doi.org/10.1111/bjh.16176.
Chao C, Silverberg MJ, Chen LH, Xu L, Martinez-Maza O, Abrams DI, et al. Novel tumor markers provide improved prediction of survival after diagnosis of human immunodeficiency virus (HIV)-related diffuse large B-cell lymphoma. Leuk Lymphoma. 2018;59(2):321–9. https://doi.org/10.1080/10428194.2017.1334121.
Sun Y, Luo J, Qian C, Luo L, Xu M, Min H, et al. The value of nutritional status in the prognostic analysis of patients with AIDS-related lymphoma. Infect Drug Resist. 2021;14:1105–13. https://doi.org/10.2147/IDR.S295077.
Hernandez-Ramirez RU, Qin L, Lin H, Leyden W, Neugebauer RS, Althoff KN, et al. Association of immunosuppression and HIV viraemia with non-Hodgkin lymphoma risk overall and by subtype in people living with HIV in Canada and the USA: a multicentre cohort study. Lancet HIV. 2019;6(4):e240–9. https://doi.org/10.1016/S2352-3018(18)30360-6.
Schommers P, Gillor D, Hentrich M, Wyen C, Wolf T, Oette M, et al. Incidence and risk factors for relapses in HIV-associated non-Hodgkin lymphoma as observed in the German HIV-related lymphoma cohort study. Haematologica. 2018;103(5):857–64. https://doi.org/10.3324/haematol.2017.180893.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Plieri SA. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC; 2008.
Koethe JR, Heimburger DC, PrayGod G, Filteau S. From wasting to obesity: the contribution of nutritional status to immune activation in HIV infection. J Infect Dis. 2016;214(Suppl 2):S75-82. https://doi.org/10.1093/infdis/jiw286.
The LH. The syndemic threat of food insecurity and HIV. Lancet HIV. 2020;7(2): e75. https://doi.org/10.1016/S2352-3018(20)30004-7.
Semmler G, Meyer EL, Kozbial K, Schwabl P, Hametner-Schreil S, Zanetto A, et al. HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease. J Hepatol. 2021. https://doi.org/10.1016/j.jhep.2021.11.025 (Online ahead of print).
Go SI, Park MJ, Park S, Kang MH, Kim HG, Kang JH, et al. Cachexia index as a potential biomarker for cancer cachexia and a prognostic indicator in diffuse large B-cell lymphoma. J Cachexia Sarcopenia Muscle. 2021. https://doi.org/10.1002/jcsm.12837 (Online ahead of print).
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 beta2 -microglobulin. Br J Haematol. 2015;168(2):239–45. https://doi.org/10.1111/bjh.13116.
Wei X, Zheng J, Zhang Z, Liu Q, Zhan M, Huang W, et al. Consecutive hypoalbuminemia predicts inferior outcome in patients with diffuse large B-cell lymphoma. Front Oncol. 2020;10: 610681. https://doi.org/10.3389/fonc.2020.610681.
Brown JT, Liu Y, Shabto JM, Martini D, Ravindranathan D, Hitron EE, et al. Modified glasgow prognostic score associated with survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors. J Immunother Cancer. 2021;9(7):e002851. https://doi.org/10.1136/jitc-2021-002851.
Evens AM, Danilov A, Jagadeesh D, Sperling A, Kim SH, Vaca R, et al. Burkitt lymphoma in the modern era: real-world outcomes and prognostication across 30 US cancer centers. Blood. 2021;137(3):374–86. https://doi.org/10.1182/blood.2020006926.
Merli F, Luminari S, Tucci A, Arcari A, Rigacci L, Hawkes E, et al. Simplified geriatric assessment in older patients with diffuse large B-cell lymphoma: the prospective elderly project of the Fondazione Italiana Linfomi. J Clin Oncol. 2021;39(11):1214–22. https://doi.org/10.1200/JCO.20.02465.
Guner A, Kim HI. Biomarkers for evaluating the inflammation status in patients with cancer. J Gastric Cancer. 2019;19(3):254–77. https://doi.org/10.5230/jgc.2019.19.e29.
Abu Sabaa A, Morth C, Hasselblom S, Hedstrom G, Flogegard M, Stern M, et al. Age is the most important predictor of survival in diffuse large B-cell lymphoma patients achieving event-free survival at 24 months: a Swedish population-based study. Br J Haematol. 2021;193(5):906–14. https://doi.org/10.1111/bjh.17206.
The authors would like to acknowledge the patients, families, and caregivers who participated in each of these studies. This work was supported by the grants from the Major Science and Technology Special Project of China (2017ZX10302201004008), the National Natural Science Foundation of China (81971949), Natural Science Foundation of Guangdong Province (2018A030313571), the Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (LC2016PY003), and Major Science and Technology Special Project of Nanning (20193008).
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Zhang, J., Xie, Z., Cai, S. et al. Hypoalbuminemia predicts inferior outcome in patients with AIDS-related lymphoma. Infect Agents Cancer 17, 33 (2022). https://doi.org/10.1186/s13027-022-00448-w
- AIDS-related lymphoma
- Serum albumin
- Human immunodeficiency virus
- Prognostic factor
- Overall survival