ABSTRACT
Objective
To investigate the prognostic value of lactate dehydrogenase (LDH), serum albumin (ALB) and the lactate dehydrogenase/albumin ratio (LAR) in diffuse large B-cell lymphoma (DLBCL) before primary treatment.
Methods
The clinical data of 212 primary adult DLBCL patients admitted to the First People's Hospital of Lianyungang from January 2017 to December 2022 were analyzed retrospectively. The optimal cutoff values of LDH, ALB, and LAR were determined using ROC curves. Survival curves of LDH, ALB, and LAR were plotted and analyzed using the Cox regression model and Kaplan–Meier method with the log-rank test.
Results
Among the 212 patients admitted, the study derived the optimal cutoff values for ALB, LDH, and LAR as 38, 301, and 6, respectively. The Kaplan–Meier method and log-rank test analysis indicated a significant association between lower ALB levels, elevated LDH levels, elevated LAR levels, and shorter overall survival (OS) and progression-free survival (PFS) (P < 0.05). Additionally, the critical values of ALB and LDH were grouped into three categories. The differences in OS and PFS among these three groups were statistically significant (P < 0.05). Cox multifactorial analysis revealed that the LAR was an independent factor influencing the prognosis of OS and PFS, with a higher prognostic value than LDH and ALB alone.
Conclusion
Decreased ALB levels and elevated LDH and LAR levels at the time of initial diagnosis are indicative of a poor prognosis in DLBCL patients. Furthermore, the study highlighted that the LAR has a higher prognostic value than LDH and ALB alone.
Introduction
DLBCL, a common adult non-Hodgkin's lymphoma, exhibits highly aggressive and heterogeneous features [Citation1]. Patient response to chemotherapy varies significantly, with approximately one-third of patients experiencing drug-resistant relapse or an inferior survival outcome [Citation2]. The International Prognostic Index (IPI) is currently used as a prognostic criterion for DLBCL [Citation3], relying on conventional clinical and pathological parameters. However, it fails to reflect any potential prognostic impact of DLBCL biological heterogeneity [Citation4] (such as genotyping) and the tumor microenvironment, including the body's immune and inflammatory responses.
Four genetic subtypes of DLBCL patients, known as MCD, BN2, the N1, and EZB, have been identified based on specific genetic mutations. These subtypes are distinguished by differences in gene expression and response to immunochemotherapy, which can guide precise treatment for DLBCL patients [Citation5]. However, genetic testing is complex and expensive, and bone marrow aspiration biopsy, an invasive procedure, can be challenging to perform in elderly or severely ill patients. Therefore, there is a need for a simple and noninvasive test that can effectively assess the survival prognosis of DLBCL patients.
Serum albumin (ALB) is the most abundant protein in plasma and can be easily measured. It is widely used in clinical practice and plays a crucial role in the prognostic assessment of many diseases [Citation6]. For instance, serum albumin levels have been found to predict 30-day mortality in infected patients and serve as a prognostic biomarker for septic patients in the intensive care unit [Citation7]. Furthermore, these levels have been shown to provide additional prognostic information for patients treated with R-CHOP, identifying subgroups of patients with low/low-moderate DLBCL with worse outcomes. This information can be valuable in guiding treatment decisions for individual patients [Citation8, Citation9]. Tumor cells are known to be metabolically promoted by high glucose uptake and enhanced lactate production. Lactate dehydrogenase (LDH), which can be easily and routinely measured in many clinical laboratories, is an important marker in this regard. Elevated LDH levels, a negative prognostic biomarker, allow tumor cells to suppress and evade the immune system by altering the tumor microenvironment [Citation10]. Elevated LDH levels are also a prognostic marker for various tumors included in the IPI prognostic criteria. Recent studies have shown a close relationship between LDH and ALB levels and the prognosis of DLBCL [Citation11–14].
LDH and albumin levels provide valuable information about the patient's immune status, inflammatory response, and tumor load and have been identified as important prognostic indicators for various types of cancer. Previous studies have demonstrated the prognostic significance of LAR in colon cancer [Citation15], gastric cancer [Citation16], and breast cancer [Citation17]. However, the prognostic value of the LAR in DLBCL has received less attention.
In recent years, genotyping and the tumor microenvironment have emerged as important factors influencing the prognosis of DLBCL. Given that genetic testing is complex and costly and bone marrow aspiration biopsy is an invasive procedure, there is a need for a simple and user-friendly test that can effectively assess the survival prognosis of DLBCL patients. Research has found that ALB, LDH and LAR in DLBCL patients, all of which have important value for prognosis, can be used as aids in determining patient prognosis during clinical treatment. In this study, we analyzed the expression levels of LDH, ALB and LAR in 212 adult DLBCL patients and evaluated the prognostic value of DLBCL patients through a simple and convenient examination procedure.
Materials and methods
Subjects
From 2017/01–2022/12, the clinical data of 212 primary adult DLBCL patients at the First People’s Hospital of Lianyungang all received standard chemotherapy regimens.
Inclusion and exclusion criteria
The inclusion criteria for this study were as follows: adult patients with pathologically confirmed primary lymphoma, complete clinical data, no other malignancies detected during follow-up, and expected survival of more than 3 months.
The exclusion criteria included the following: 1) a prior history of malignancy; 2) individuals who had received antitumor therapy prior to enrollment; 3) patients with more serious acute and chronic diseases prior to enrollment (such as acute cardiac infarction, heart failure, uremia, cirrhosis, and other diseases that severely affect other organs); 4) lymphoma patients with other lymphatic system diseases (including central nervous system involvement) as comorbidities, and 5) patients with incomplete clinical data.
Research methodology
Clinical data collection
Clinical data of 212 patients with DLBCL treated for the first time at our hospital were collected, including the albumin value (ALB), lactate dehydrogenase (LDH), germinal center B-cell (GCB), age, sex, B symptoms, body mass index (BMI, Normal BMI is 18.5-23.9), bone marrow invasion (BMI*), Eastern Cooperative Oncology Group score (ECOG), number of extranodal sites, hepatitis B positive (HBV), Ann Arbor stage, white blood cell count (WBC), mononuclear cells (MONO), hemoglobin count (HGB), and International Prognostic Index (IPI).
| (2) | Treatment method | ||||
First-line treatment regimens for patients were R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimens, second-line regimens were R-DA-EPOCH (rituximab, etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone) regimens, and treatment was chemotherapy-based.
| (3) | Follow-up visits | ||||
Follow-up visits were conducted by telephone and by reviewing inpatient or outpatient medical records. The follow-up cutoff time was December 2022. In this study, patient survival was assessed by disease-free survival (PFS) and overall survival (OS), with PFS time referring to the time from diagnosis of DLBCL to the onset of disease progression, death, or last follow-up, and OS time referring to the time from diagnosis of DLBCL to death (from any cause), loss to follow-up, or last follow-up. Pathology or long-term follow-up results were used as the gold standard for evaluation.
| (4) | Statistical analysis methods | ||||
SPSS 26.0 software was used to process the data, and subject operating characteristic curves (ROC curves) were used to determine the optimal threshold values for ALB, LDH, and LAR. The Kaplan–Meier method was applied to plot survival curves, and the Spearman test was used to analyze the correlation of factors. Cox proportional risk regression models were performed for univariate and multifactorial survival analysis to evaluate the value of ALB, LDH and LAR and other related indicators in assessing the efficacy and prognosis of patients with lymphoma, and ROC curves were used to further evaluate the predictive value of ALB, LDH and LAR regarding the prognosis of patients with DLBCL. P < 0.05 was considered a statistically significant difference.
Results
Patient clinical data
The median age of the 212 DLBCL patients was 62 years (18-92 years), 104 (49.1%) were male and 108 (50.9%) were female. The distribution of data could be summarized as follows: sixty years or older accounted for 124 (58.5%), 104 patients (49.1%) had abnormal BMI, 115 (54.2%) had Ann Arbor stage III/IV, GCB 30 (14.2%), 66 patients (31.1%) with ECOG score ≥ 2, 52 patients (24.5%) with MONO>6.0 × 109/L, 21 patients (9.9%) with B-type symptoms (fever, night sweats, and weight loss) at diagnosis, 46 patients (21.7%) with number of extranodal sites ≥ 2, 118 patients (55.7%) with IPI ≥ 2, and BMI*, HBV, WBC ≥ 14 × 109/L, HGB ≤ 100 g/L in less than 20% of all patients. The general clinical data of the patients are shown in .
Table 1. General clinical data of 212 patients with DLBCL.
Albumin value (ALB), lactate dehydrogenase (LDH), germinal center B-cell (GCB), body mass index (BMI, normal BMI is 18.5-23.9), bone marrow invasion (BMI*), Eastern Cooperative Oncology Group score (ECOG), hepatitis B positive (HBV), white blood cell count (WBC), mononuclear cells (MONO), hemoglobin count (HGB), International Prognostic Index (IPI).
Treatment of patients at follow-up
As of December 2022, the median OS follow-up for the 212 DLBCL patients was 35.5 (3.0-175.5) months. The median PFS follow-up was 24.5 (2.5-157.1) months. All patients completed follow-up through outpatient follow-up records and telephone contact.
Calculate the optimal cutoff values for LDH and ALB
Data were processed using SPSS 26.0 statistical software, and the area under the curve (AUC) of pretreatment LDH was calculated from the ROC curve as 0.642 (95% CI: 0.564-0.720). The critical value was determined according to the ROC curve: LDH was 301. The ROC curve is shown in a.
Figure 1. a. ROC curve of lactate dehydrogenase (LDH). b. ROC curve of albumin value (ALB).
The area under the curve (AUC) of pretreatment ALB was 0.599 (95% CI: 0.522-0.677). The critical value was determined from the ROC curve: ALB, 38. The ROC curve is shown in b.
The cutoff values of LDH and ALB calculated from the ROC curves were used to categorize patients into high and low groups – the LDH ≥ 301 group and the LDH < 301 group, the ALB ≥ 38 group and the ALB < 38 group. Among the patients, 61 (28.8%) patients in the LDH ≥ 301 group had significantly shorter OS and PFS (P < 0.001) than 151 (71.2%) patients in the LDH < 301 group (a, b), and 102 (48.1%) patients in the ALB < 38 group had a shorter OS and PFS time (P < 0.001) than 110 (51.9%) patients in the ALB ≥ 38 group, and all differences were statistically significant (a, b).
Figure 2. Kaplan–Meier survival analysis of LDH. Overall survival (a) and progression-free survival (b) according to LDH in DLBCL patients.
Figure 3. Kaplan–Meier survival analysis of ALB. Overall survival (a) and progression-free survival (b) according to ALB in DLBCL patients.
The area under the curve (AUC) of the pretreatment LAR was 0.653 (95% CI: 0.577-0.729). The critical value was determined from the ROC curve: the LAR was 6. The ROC curve is shown in .
Figure 4. ROC curve of the LAR.
LAR was used to categorize patients into high and low groups based on the critical value calculated by the ROC curve. The LAR ≥ 6 group and LAR < 6 group were identified. Among them, patients in the LAR ≥ 6 group had significantly shorter OS and PFS than those in the LAR < 6 group. This difference was statistically significant (a, b).
Figure 5. Kaplan–Meier survival analysis of LAR. Overall survival (a) and progression-free survival (b) according to the LAR in DLBCL patients.
Relationship between LDH and ALB levels and clinical characteristics
Analysis of the clinical indicators in both groups revealed that ALB was significantly correlated with age (P = 0.009), sex (P = 0.029), B symptoms (P = 0.001), Ann Arbor stage (P < 0.001), number of extranodal sites ≥ 2 (P = 0.001), HGB ≤ 100 g/L (P < 0.001), BMI* (P = 0.015), IPI ≥ 2 (P < 0.001), LAR (P < 0.001); LDH was significantly correlated with B symptoms (P < 0.001), Ann Arbor stage (P < 0.001), number of extranodal sites ≥ 2 (P = 0.013), MONO ≥ 6.0 × 109/L (P < 0.001), HGB ≤100 g/L (P = 0.001), BMI* (P = 0.005), IPI ≥ 2 (P < 0.001), and LAR (P < 0.001). ()
Table 2. Comparison of LDH and ALB in different clinicopathological features of DLBCL patients.
Univariate and multifactorial cox regression analyses
Factors that may affect patient prognosis were included in the statistical analysis. The Cox regression model was used for unifactorial and multifactorial survival analysis of patients to analyze the prognostic value of the collected clinical data for patients with diffuse large B-cell lymphoma.
The results of the univariate analysis were as follows: prognostic factors affecting OS in patients with DLBCL, including number of extranodal sites ≥ 2, HGB ≤ 100 g/L, IPI ≥ 2, ALB < 38 g/L, and LDH ≥ 301 with LDH/ALB ≥ 6, were statistically significant (P < 0.05). Prognostic factors affecting PFS in patients with DLBCL included Ann Arbor stage III/IV, number of extranodal sites ≥ 2, HGB ≤ 100 g/L, BMI*, IPI ≥ 2, ALB < 38 g/L, and LDH ≥ 301 with LDH/ALB ≥ 6 (P < 0.05) ().
Table 3. Univariate analysis of prognosis.
Based on the results of the Cox univariate analysis, the factors with a P value of P < 0.05 were selected for the Cox multifactor analysis, and the results are shown in .
Table 4. Multivariate analysis of prognosis.
Since LAR is the result of the combination of LDH and ALB, LDH and ALB were excluded to reduce interference. A separate COX multifactor analysis was performed for LAR and other factors, and the results are shown below ().
Table 5. Multivariate analysis of prognosis.
Multifactorial analysis showed that the prognostic effect of the LAR might be higher than that of LDH and ALB.
As shown above, a multifactorial analysis revealed that ALB < 38 g/L, LDH ≥ 301 and LAR ≥ 6 were independent factors affecting the prognosis of OS and PFS; however, the results of the multifactorial analysis showed that the prognostic effect of the LAR might have higher prognostic value for prognostic assessment than LDH and ALB alone, and further research is needed in the follow-up.
Comparison of ALB combined with LDH for Kaplan–Meier analysis
Patients with ALB (≥38) and LDH (<301) were defined as Group A (94 patients), those with ALB (<38) and LDH (≥301) were defined as Group C (45 patients), and the rest were defined as Group B (73 patients) ().
Table 6. Clinical data analysis of ALB and LDH.
The Kaplan–Meier method was used to plot the survival curves, and the results showed that the differences between the 3 groups were statistically significant (P < 0.001) as shown in a, b.
Figure 6. Kaplan–Meier survival analysis of LDH + ALB. Overall survival (a) and progression-free survival (b) according to LDH + ALB in DLBCL patients.
Discussion
Research has found that ALB and LDH in DLBCL patients have significant value for prognosis and can be used as an aid in determining patient prognosis during clinical treatment [Citation18–22]. Additionally, the LAR has also been found to be used as a prognostic assessment of the disease, although there is limited information about the relationship between the LAR and DLBCL. Studies have shown that a decrease in ALB concentration affects body metabolism, nutritional status, and substrate transport [Citation23]. Moreover, nutritional status and inflammation can inversely lead to diminished ALB synthesis, making ALB a reflection of systemic nutritional status and a simplistic indicator of the inflammatory response [Citation24]. It is important to note that ALB also increases the drug half-life and reduces toxicity [Citation25]. Continuous hypoproteinemia is a simple and effective poor prognostic factor in DLBCL patients, and follow-up should focus on patients with hypoalbuminemia after treatment termination [Citation26]. According to the literature, DLBCL patients aged 80 years or older with hypoalbuminemia may not be suitable for standard chemotherapy, and alternative or palliative care options should be considered in such cases [Citation27]. The combination of early albumin changes with established biomarkers has been shown to improve the prognostic outcome of immune checkpoint inhibitor monotherapy in patients with non-small cell lung cancer [Citation28]. Metabolic changes in rapidly dividing cancer cells are closely associated with increased glucose uptake and abnormal activity of lactate dehydrogenase (LDH). LDH regulates the conversion of glucose to lactate [Citation26]. Elevated serum LDH levels are an independent prognostic factor for hematologic tumors, indicating high tumor load and higher aggressiveness. LDH, which is present in tissues and fluctuates in value with a slight loss, plays an important role in early clinical tumor diagnosis as a tumor biomarker Garcia et al [Citation29]. Serum LDH levels >320 U/L (above the upper limit of normal), age and clinical stage had a significant prognostic impact on achieving complete remission (CR) in patients with lymphoma. LDH is also recognized as one of the diagnostic criteria for the DLBCL prognostic assessment IPI, NCCN-IPI.
The results of previous phase I trials on patients with relapsed or refractory lymphoma have shown that histological type (i.e. tumor aggressiveness), elevated serum LDH levels, and low serum albumin levels are the main prognostic factors for poor overall survival [Citation30]. Therefore, the use of LAR may help in comprehensively assessing the inflammatory response of the organism, nutritional status, and tumor load. Several studies have reported a significant association between the LAR and various types of tumors [Citation31–34], making it an independent poor prognostic factor. However, the prognostic value of LAR in lymphoma is not frequently reported.
In this study, we retrospectively analyzed the clinical data of 212 adult patients with primary DLBCL. The optimal cutoff values for serum albumin and LDH were calculated by ROC curves as 38 and 301, respectively (P < 0.001). There were no specific criteria regarding the optimal cutoff values for ALB and LDH. The results of univariate analyses showed that low ALB values (<38) and high LDH values (≥301), as well as high LAR values (≥6), were independent poor prognostic factors for overall survival (OS) and progression-free survival (PFS) (P < 0.001), with statistically significant differences. To exclude the interference of LAR with LDH and ALB, we performed multifactorial analyses separately. These analyses revealed that HGB ≤ 100 g/L and ALB < 38 g/L were independent factors affecting the prognosis of OS. Furthermore, HGB ≤ 100 g/L, number of extranodal sites ≥ 2, and IPI ≥ 2 were independent factors affecting the prognosis of PFS. Additionally, the multifactorial analysis for LAR showed that HGB ≤ 100 g/L, LAR ≥ 6, and number of extranodal sites ≥ 2 were independent factors affecting OS prognosis. Similarly, HGB ≤ 100 g/L, LAR ≥ 6, number of extranodal sites ≥ 2, and IPI ≥ 2 were independent factors affecting PFS. Multifactorial analyses of LDH and ALB did not yield significant results, possibly due to the influence of different physiological processes on their presence or activity in the blood. Additionally, the prognostic factors of PFS and OS may be influenced by other clinical variables, such as patient age, sex, and type of tumor pathology. These variables may obscure the prognostic importance of LDH and ALB. However, when the LAR was analyzed in conjunction with other factors, both PFS and OS showed statistical significance. This is because the combination of LDH and ALB reflects the balance of cellular metabolism, protein synthesis, and immunity, providing more comprehensive physiological information about the patient. Furthermore, IPI ≥ 2 was identified as an independent prognostic factor for PFS (P < 0.001), offering more meaningful information compared to analyzing LDH and ALB separately.
The optimal cutoff value for the LAR was determined to be 6 (P < 0.001) in combination with LDH and albumin. Both univariate and multifactorial analyses demonstrated that high LAR values (≥6) were independent prognostic factors for overall survival (OS) and progression-free survival (PFS) (P < 0.001) with statistically significant differences. The combination of LAR provides more comprehensive predictions compared to LDH or ALB alone, as LDH reflects metabolic activity and ALB reflects the nutritional status of the malignancy. This combination allows for a more comprehensive assessment of disease severity and patient survival while reducing the influence of nonspecific factors and improving prediction specificity. Furthermore, hemoglobin (Hb) was found to be an independent prognostic factor in both univariate and multifactorial analyses. Low Hb levels are a common clinical indicator in tumor patients, with various factors contributing to anemia, such as the tumor itself, complications, and chemotherapy [Citation35–37]. Pretreatment Hb < 10.0 g/dL is an overall prognostic factor associated with a poor outcome in patients with DLBCL [Citation38]. Hb analysis is easily performed in the clinical setting, cost-effective, and widely available, making it a highly useful indicator in clinical practice.
The study analyzed ALB combined with LDH, and the patients were classified into three groups: the ALB < 38 and LDH ≥ 301 group, the ALB ≥ 38 and LDH < 301 group, and the other group. The results showed statistically significant differences in overall survival (OS) and progression-free survival (PFS) among the three groups (P < 0.001). By comparing the three indices of ALB, LDH, and LAR, ALB and LDH were found to be better biological markers. However, the LAR provided more prognostic value than ALB and LDH applied separately. Therefore, the LAR can be useful in assisting the prognostic diagnosis of DLBCL patients.
Conclusion
In this retrospective analysis of 212 adult patients with primary DLBCL, it was found that high LDH levels and low ALB were independent prognostic markers of poor outcomes. Additionally, the LAR was identified as a comprehensive representation of the systemic status of patients and an independent poor prognostic factor for overall survival (OS) and progression-free survival (PFS). These findings were statistically significant. However, it is important to acknowledge the limitations of this study. First, as a retrospective analysis, the study may be affected by selection bias. Second, the small sample size and short follow-up period may not fully represent the DLBCL patient population. Furthermore, the lack of a suitable control group for comparative assessment is another limitation. Therefore, more standardized studies are needed to further analyze and improve the prognosis of DLBCL patients.
Author contributions
Conceptualization, methodology, formal analysis, and investigation were performed by Wenke Wu and Lei Miao. Lidong Zhao contributed to the methodology. Software development was done by Yuanxin Zhu and Wenke Wu. Jianping Mao conducted the formal analysis. Zhimei Cai was responsible for the investigation. Yajun Ji and Lei Wang provided the necessary resources. Data curation was carried out by Wenke Wu. The original draft of the manuscript was written by Wenke Wu and Lei Miao. The manuscript was reviewed and edited by Ying Wang and Tao Jia. All authors have read and agreed to the published version of the manuscript.
Ethical approval
From January 2017 to December 2022, 212 patients with DLBCL were eligible for the study and were approved by the Institutional Review Board of the First People's Hospital of Lianyungang, Jiangsu Province. (Institutional Review Board [IRB] no. KY-20220620002-01).
Informed consent statement
The requirement for written informed consent was waived by the IRB because of study subjects’anonymity and minimal risk to patients.
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