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The lower peripheral blood lymphocyte/monocyte ratio assessed during routine follow-up after standard first-line chemotherapy is a risk factor for predicting relapse in patients with diffuse large B-cell lymphoma

Leukemia Research, 3, 38, pages 323 - 328

Abstract

A specific predictor during routine follow-up to ascertain risk for relapse after standard first-line chemotherapy in non-Hodgkin's lymphoma (NHL) has not been identified, although blood counts, lactate dehydrogenase (LDH) and imaging studies, such as computed tomography (CT) scans or positron emission tomography, have been recommended. Therefore, we studied the absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) as a marker of poststandard first-line chemotherapy for predicting relapse in patients with diffuse large B-cell lymphoma (DLBCL). 220 consecutive DLBCL patients, originally diagnosed, treated with CHOP or R-CHOP and followed up at two institutions. ALC/AMC ratio was obtained at the time of confirmed relapse or last follow-up. Patients at the time of confirmed relapse (n = 163) had a lower ALC/AMC ratio compared with those at last follow-up (n = 57) (P < 0.001). ALC/AMC ratio at the time of confirmed relapse was a strong predictor for relapse with an area under the curve = 0.813 (P < 0.001). The sensitivity and specificity for ALC/AMC ratio at the time of confirmed relapse or at last follow-up were 68.1% and 87.7%, respectively, and the relative risk of relapse with an ALC/AMC ratio < 2.8 at the time of confirmed relapse or at last follow-up was 1.845 with an odds ratio of 15.247 (95% cumulative incidence: 6.473–35.916) after CHOP or R-CHOP in DLBCL. Patients with an ALC/AMC ratio (<2.8) had a higher cumulative hazard rate of relapse compared with an ALC/AMC ratio (≥2.8) (P < 0.001). This study suggests that the lower ALC/AMC ratio can be used as a marker to assess risk of DLBCL relapse during routine follow-up after standard first-line chemotherapy.

Keywords: Absolute lymphocyte count/absolute monocyte count ratio, Relapse, Follow-up, Diffuse large B-cell lymphoma.

1. Introduction

Despite recent major advances in treating diffuse large B-cell lymphoma (DLBCL) with dose-intense regimens and the addition of the anti-CD20 monoclonal antibody rituximab, a significant proportion of patients will experience disease relapse, mainly during the first two years after completing therapy [1] . A primary aim of follow-up is to detect early relapse, with the hope of improving outcome following salvage chemotherapy. The current recommendation for long-term follow-up in patients with DLBCL, who are not participating in clinical trials, by the National Comprehensive Cancer Network is a follow-up every 3–6 months or as clinically indicated [2] . The European Society of Medical Oncology's recommendations for follow-up in NHL include follow-up every 3 months for 1 years, every 6 months for 2 years and then once a year [3] .

Risk factors used to assess clinical outcomes in DLBCL patients treated with standard therapy are identified before treatment implementation, such as the international prognostic index (IPI) [4] , gene expression profiling [5] or immunohistochemistry-based detection of prognostic biomarkers [6] and [7]. Even though these risk factors are useful to guide physicians in the identification of patients who would benefit from standard therapy, a limitation of these is that they are tested at one point in time [8] . An inexpensive factor that could be monitored during follow-up after standard therapy and predicts relapse would be needed to help to identify patients who might require further evaluation for relapse. In DLBCL, LDH has been reported to have a sensitivity of 42% and a specificity of 85% to predict relapse during follow-up [9] . Recently, absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) at diagnosis, as a simple biomarker combining an estimate of host immune homeostasis and tumor microenvironment, was recently shown to be an independent prognostic indicator in DLBCL [10] and HL [11], [12], and [13]. However, to our best knowledge, there is no data available on whether ALC/AMC ratio can help in detecting relapse. Thus, we set out to evaluate the prognostic value of peripheral ALC/AMC ratio at follow-up as a marker to assess relapse during follow-up.

2. Patients and methods

2.1. Patient

To participate in this study, consecutive 220 patients with DLBCL who were evaluated and treated with CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) or R-CHOP (rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) were followed up at the first affiliated hospital and the second hospital of Anhui Medical University between the years 2001 and 2011. Patients with primary DLBCL central nervous system lymphoma, transformed NHL, positive human immunodeficiency virus or progressed during standard first-line chemotherapy were excluded. This study was approved by the Institutional Review Board (IRB) of the first affiliated hospital and the second hospital of Anhui Medical University, and was performed in accordance with the principles expressed in the Declaration of Helsinki.

2.2. Study objective

The absolute lymphocyte count (ALC) and monocyte count (AMC) at the time of confirmed relapse or at last follow-up which were obtained from the standard complete blood cell count (CBC); the absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) was calculated by dividing the ALC by the AMC. Response criteria were based on the criteria from the International Harmonization Project [14] . Relapse was defined as any lesion or increase by ≥50% of the previously involved site from the nadir. The time to relapse was measured from the date of completed treatment to relapse. Last follow-up was measured from the date of completed treatment to the day of last follow-up or death in patients without any evidence of relapse. Follow-up procedures usually included a physical examination every month for the first 3 months and every 3 months thereafter for 2 years, then every 6 months for 3 years in our hospitals. Risk factors tested in the study included lactate dehydrogenase (LDH) at the time of confirmed relapse and at last follow-up, IPI at the time of diagnosis [age <60 vs. ≥60 years, Ann Arbor stage (III/IV vs. I/II), Eastern Cooperative Oncology Group performance status (ECOG PS) (≤1 vs. >1), LDH (>normal vs. normal) and number of extra nodal sites (ENS) involved (≤1 vs. >1)] were utilized.

2.3. Statistical analysis

The correlation between the ALC, AMC, ALC/AMC ratio and clinical parameters was assessed by the chi-square test or Fisher's exact test. We used competing risks regression to analyze the cumulative incidence of relapse in the presence of competing risks, and the cumulative hazard function was calculated using the Nelson–Aalen estimator. The choice of optimal cutoff of ALC, AMC and ALC/AMC ratio at the time of confirmed relapse or at last follow-up was based on its utility as a marker for relapse using receiver operating characteristics curves and area under the curve. The cutoff value for the ALC at diagnosis (1000/μl) was based on data from reported studies [15], [16], and [17]. The association between ALC/AMC ratio at the time of confirmed relapse or at last follow-up and risk factors with the incidence of relapse was explored using univariate and multivariate logistic regression models, and factors found to be significant (P < 0.05) in the univariate analysis were included in the multivariate analysis. To assess the predictive value of ALC/AMC ratio for relapse at the time of follow-up, a contingency table was created. P-values were not adjusted for multiple comparisons, All two-sided P-values < 0.05 were determined to be statistically significant.

3. Results

3.1. Patient characteristics

A total of 220 patients in this study, median follow-up following diagnosis was 36 months, had full information of the relapse (n = 163) or at last follow-up (n = 57). The median age for this cohort was 54 years (range: 13–84 years). The distribution of additional baseline characteristics for these patients is presented in Table 1 . At diagnosis, the median AMC was 440/μl (interquartile range: 310–600) and the median ALC was 1320/μl (interquartile range: 1100–1792); at the time of confirmed relapse (n = 163), the median AMC was 460/μl (interquartile range: 330–660) and the median ALC was 1020/μl (interquartile range: 750–1340); at last follow-up (n = 57), the median AMC was 350/μl (interquartile range: 280–440) and the median ALC was 1390/μl (interquartile range: 1100–1650). We found that higher ALC, lower AMC and ALC/AMC ratio at last follow-up compared with at the time of confirmed relapse (P < 0.001, P < 0.001, P < 0.001).

Table 1 Patient (n = 220) characteristics.

Characteristics N %
Age
 Median (range) 54 (13–84)  
 
Gender
 Male 120 55
 
Ann Arbor stage
 I 56 26
 II 60 27
 III 36 16
 IV 68 31
 
Extranodal sites of disease
 >1 54 24
 ≤1 166 76
 
ECOG PS
 >1 19 9
 ≤1 201 91
 
IPI
 0 67 31
 1 61 28
 2 47 21
 3 35 16
 4 8 3
 5 2 1
 
Treatment
 CHOP 113 56
 R-CHOP 97 44
 
At initial diagnosis (n = 220)
 Absolute monocyte count    
 Median (interquartile range) 440 (310–600)  
 Absolute lymphocyte count    
 Median (interquartile range) 1320 (1100–1790)  
 
LDH
 >Normal 58 26
 ≤Normal 162 74
 
At the time of confirmed relapse (n = 163)
 Absolute monocyte count    
 Median (interquartile range) 460 (330–660)  
 Absolute monocyte count    
 Median (interquartile range) 1020 (750–1340)  
 
LDH
 >Normal 58 36
 ≤Normal 105 64
 
At last follow-up (n = 57)
 Absolute monocyte count    
 Median (interquartile range) 350 (280–440)  
 Absolute monocyte count    
 Median (interquartile range) 1390 (1100–1650)  
 
LDH
 >Normal 3 5
 ≤Normal 54 95

Abbreviations: CHOP, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone; R-CHOP, rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone; ECOG, Eastern Cooperative Oncology Group; IPI, international prognostic index; LDH, lactate dehydrogenase; PS, performance status.

3.2. Cutoff values for the ALC, AMC and ALC/AMC ratio at the time of confirmed relapse or at last follow-up for its utility as a marker for relapse

The absolute lymphocyte count (ALC) and absolute monocyte count (AMC) at the time of relapse or at last follow-up were derived from CBC counts. The cutoff points of ALC, AMC, and ALC/AMC ratio its utility as a marker for relapse were selected by the receiver operating characteristics curves analysis. The most discriminative cutoff value of ALC was 1215/μl, with an area under the curve (AUC) value of 0.713 [95% confidence interval (CI), 0.643–0.783, P < 0.001] ( Fig. 1 a). The most discriminative cutoff value of AMC was 495/μl, with an AUC value of 0.694 (95% CI, 0.623–0.766, P < 0.001) ( Fig. 1 b). ROC curve analysis in 220 patients established 2.8 as the cutoff point of ALC/AMC ratio for relapse with an AUC of 0.813 (95% CI, 0.758–0.867, P < 0.001) ( Fig. 1 c).

gr1

Fig. 1 Receiver operating characteristic (ROC) curve analysis for ALC (a), AMC (b) and ALC/AMC ratio (c) at follow-up as a marker of relapse.

3.3. Comparison of patients with an ALC/AMC ratio ≥ 2.8 and patients with an ALC/AMC ratio < 2.8

On the basis of whether patients had an ALC/AMC ratio ≥ 2.8 vs. ALC/AMC ratio < 2.8 at the time of confirmed relapse or at last follow-up, the characteristics for patients (n = 220) are presented in Table 2 . One hundred and two patients (46.4%) had an ALC/AMC ratio ≥ 2.8 and one hundred and eighteen (53.6%) had an ALC/AMC ratio < 2.8. The only differences between the groups were ALC, AMC, ALC/AMC ratio and LDH at diagnosis, ALC, AMC and LDH at relapse or at last follow-up, IPI, Ann Arbor stage and extranodal sites of disease. A lower ALC/AMC ratio (<2.8) was significantly correlated with lower ALC (<1000/μl) (P < 0.001) at diagnosis, ALC (<1215/μl) (P < 0.001) at relapse or at last follow-up, higher AMC (≥460/μl) (P = 0.001), LDH (P < 0.001) at diagnosis, AMC (≥495/μl) (P < 0.001), LDH (P < 0.001) at relapse or at last follow-up, Ann Arbor stage (P < 0.001), the IPI (P < 0.001) and more extranodal sites of disease (P = 0.001).

Table 2 Patient's baseline characteristics based on ALC/AMC < 2.8 and ALC/AMC ≥ 2.8 at relapse or at last follow-up.

Characteristics ALC/AMC < 2.8 ALC/AMC ≥ 2.8 P
Age (years)
 <60 75 66 0.860
 ≥60 43 36  
 
Gender
 Male 70 50 0.126
 Female 48 52  
 
Ann Arbor stage
 I/II 43 29 <0.001
 III/IV 75 73  
 
LDH
 >Normal 42 16 0.001
 ≤Normal 76 86  
 
Extranodal sites of disease
 >1 40 14 0.001
 ≤1 78 88  
 
ECOG PS
 >1 14 5 0.067
 ≤1 104 97  
 
IPI
 0–1 52 76 <0.001
 2–5 66 26  
 
ALC at relapse or at last follow-up
 <1215/μl 93 30 <0.001
 ≥1215/μl 25 72  
 
AMC at relapse or at last follow-up
 ≥495/μl 72 14 <0.001
 <495/μl 46 88  
 
LDH at relapse or at last follow-up
 >Normal 47 14 <0.001
 ≤Normal 71 88  
 
ALC at diagnosis
 <1000/μl 34 8 <0.001
 ≥1000/μl 84 94  
 
R-CHOP
 No 65 58 0.791
 Yes 53 44  

3.4. Relapse rate according to prognostic factors at the time of confirmed relapse or at last follow-up

The relapse rate was significantly higher in patients with ALC < 1215/μl, AMC ≥ 495/μl, ALC/AMC ratio < 2.8 and LDH > normal compared to patients with ALC ≥ 1215/μl, AMC < 495/μl, ALC/AMC ratio ≥ 2.8 and LDH ≤ normal at the time of confirmed relapse or at follow up, respectively (80.0% vs. 65.6%, P = 0.016; 82.2% vs. 66.4%, P = 0.007; 94.1% vs. 51.0%, P < 0.001; 95.1% vs. 66.0%, P < 0.001, respectively) ( Table 3 ). Similar results were obtained when patients treated with R-CHOP (Supplementary Table 1).

Table 3 Relapse rate according to the ALC, AMC, ALC/AMC ratio and LDH at the time of confirmed relapse or at last follow-up.

Characteristic Relapse at follow-up P
  Yes No  
ALC/AMC ratio
 <2.8 111 7 <0.001
 ≥2.8 52 50  
 
Absolute monocyte count
 ≥495/μl 88 19 0.007
 <495/μl 75 38  
 
Absolute lymphocyte count
 <1215/μl 104 26 0.016
 ≥1215/μl 59 31  
 
LDH at relapse or at last follow-up
 >Normal 58 3 <0.001
 ≤Normal 105 54  

3.5. The ALC/AMC ratio in univariate and multivariate logistic regression model for predicting relapse

Logistic regression models for predicting relapse further indicate that the ALC/AMC ratio at the time of confirmed relapse or at last follow-up is significantly correlated with this clinical outcome (P < 0.001), with an odds ratio of 15.247 ( Table 4 ). Other significant factors for relapse in the univariate setting included ALC, AMC ALC/AMC, LDH at diagnosis and at the time of confirmed relapse or at last follow-up, Ann Arbor stage, extranodal sites. In a multivariate logistic regression model ( Table 4 ), ALC/AMC ratio at the time of confirmed relapse or at last follow-up remained a significant correlate for relapse (P = 0.024), and was associated with an adjusted odds ratio for relapse of 3.648 (95% CI 1.188–11.197). The ALC, AMC and LDH at the time of confirmed relapse or at last follow-up was also statistically significant (P = 0.011, P = 0.020, P = 0.038, respectively).

Table 4 Logistic regression univariate and multivariate analyses for relapse.

Variable Univariate analysis Multivariate analysis
  OR (95% CI) P OR (95% CI) P
AMC ≥ 495/μl 6.718 (2.876–15.694) <0.001 3.625 (1.226–10.717) 0.020
ALC < 1215/μl 5.498 (2.805–10.777) <0.001 3.355 (1.327–8.477) 0.011
ALC/AMC < 2.8 15.247 (6.473–35.916) <0.001 3.648 (1.188–11.197) 0.024
LDH > normal 9.943 (2.977–33.210) <0.001 4.385 (1.089–17.664) 0.038
Age ≥ 60 1.165 (0.617–2.201) 0.638  
Gender 1.220 (0.667–2.233) 0.518  
ECOG PS > 1 1.959 (0.549–6.990) 0.300  
Extranodal sites > 1 2.408 (1.059–5.476) 0.036 0.456 (0.127–1.644) 0.230
Ann Arbor stage III/IV 4.278 (2.142–8.543) <0.001 2.772 (0.985–7.802) 0.053
ALC at diagnosis < 1000/μl 3.054 (1.137–8.204) 0.027 1.042 (0.297–3.656) 0.949
LDH (at diagnosis) > normal 3.982 (1.606–9.870) 0.003 1.218 (0.376–3.945) 0.742
Containing radiation therapy 1.478 (0.683–3.198) 0.321

97 patients treated with R-CHOP had full information of the relapse (n = 78) or at last follow-up (n = 19). We also further indicate that the ALC/AMC ratio at the time of confirmed relapse or at last follow-up after R-CHOP therapy is significantly correlated with this clinical outcome (P < 0.001), with an odds ratio of 16.056. Other significant factors for relapse in the univariate setting included ALC, AMC, LDH at the time of confirmed relapse or at last follow-up and Ann Arbor stage (Supplementary Table 2). In a multivariate logistic regression model (Supplementary Table 2), ALC/AMC ratio at the time of confirmed relapse or at last follow-up and Ann Arbor stage were nearly statistically significant (P = 0.057, P = 0.050, respectively), and were associated with an adjusted odds ratio for relapse of 7.867 (95% CI 0.944–65.529) and 3.779 (95% CI 0.997–14.319).

To assess the predictive value of ALC/AMC ratio for relapse at the time of follow-up, a contingency table was created between ALC/AMC ratio < 2.8 vs. ALC/AMC ratio ≥ 2.8 at last follow-up and relapse status ( Table 5 ). The sensitivity and specificity for ALC/AMC ratio at the time of confirmed relapse or at last follow-up was 68.1 and 87.7%, respectively. The relative risk of relapse with an ALC/AMC ratio < 2.8 at the time of confirmed relapse or at last follow-up was 1.845 with an odds ratio of 15.247 (95% cumulative incidence: 6.473–35.916). In patients treated with R-CHOP (Supplementary Table 3) the sensitivity and specificity for ALC/AMC ratio at the time of confirmed relapse or at last follow-up was 65.4% and 89.5%, respectively. The relative risk of relapse with an ALC/AMC ratio < 2.8 at the time of confirmed relapse or at last follow-up was 1.568 with an odds ratio of 16.056 (95% cumulative incidence: 3.450–74.715).

Table 5 Contingency table.

Characteristic Relapse at follow-up  
  Yes No  
ALC/AMC ratio
 <2.8 111 (a) 7 (b) 118
 ≥2.8 52 (c) 50 (d) 102
 
  163 57  

Formulas: sensitivity = a/(a + c); specificity = d/(b + d); positive predictive value = a/(a + b); negative predictive value = d/(c + d); positive likelihood ratio = sensitivity/(1 − specificity); negative likelihood ratio = (1 − sensitivity)/specificity; odd ratio = ad/bc; relative risk = (a/(a + b))/(c/(c + d)).

3.6. Cumulative hazard rate for relapse based on ALC/AMC ratio and LDH at follow-up

Cumulative hazard rate for relapse based on ALC/AMC ratio post-CHOP or R-CHOP is shown in Fig. 2 . The early relapse rate was significantly higher in the low ALC/AMC ratio group (<2.8) than in the high group (≥2.8) (P < 0.001). Similar results were obtained in patients at follow-up post-CHOP (P < 0.001) (Supplementary Fig. 1).

gr2

Fig. 2 Cumulative hazard rate for relapse based on the absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) at follow-up post-CHOP or R-CHOP.

As a result of the LDH at the time of confirmed relapse or at last follow-up remained a significant correlate for relapse post-CHOP or R-CHOP in our study, we assessed the cumulative hazard rate combining both markers. We found a lower cumulative hazard rate of relapse in patients with a higher ALC/AMC ratio compared with patients with a lower ALC/AMC, regardless of whether LDH was normal or abnormal at follow-up after CHOP or R-CHOP ( Fig. 3 ) (P < 0.001) or R-CHOP only (Supplementary Fig. 2) (P < 0.001).

gr3

Fig. 3 Cumulative hazard rate for relapse based on the absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) and lactate dehydrogenase (LDH) at follow-up post-CHOP or R-CHOP.

4. Discussion

The current risk factors used to assess prognosis in DLBCL patients are identified before treatment [4], [5], [6], and [7]. An ideal risk factor is a risk factor that has the ability to predict not only future clinical outcomes but also clinical outcome at any given time point after therapy. So, recently, lymphopenia assessed during routine follow-up was found to be a risk factor for predicting early relapse in patients with DLBCL [8] and [18]. Moreover, recent work, based on gene expression profiling studies in NHL, shows that gene expression by tumor-infiltrating lymphocytes and myeloid-derived cells predict clinical outcomes [19] and [20], which implies that a prognostic system that considers features of the tumor-bearing host and the tumor microenvironment may provide prognostic information. As far as we know, there has been no study investigating whether the ALC/AMC ratio at the time of confirmed relapse or at last follow-up is a marker for relapse after standard first-line therapy in DLBCL.

Our study showed that DLBCL patients with confirmed relapse at follow-up had lower ALC, ALC/AMC ratio and higher AMC compared with these parameters at diagnosis and those without evidence of relapse at last follow-up after CHOP or R-CHOP. The ALC/AMC ratio assessed during routine follow-up after CHOP or R-CHOP was a risk factor for predicting relapse in DLBCL patients. A low ALC/AMC ratio (<2.8) at the time of confirmed relapse or at last follow-up was associated with a high odds ratio, high relative risk and high cumulative hazard rate compared with a high ALC/AMC ratio (≥2.8) at the time of confirmed relapse or at last follow-up after CHOP or R-CHOP. Moreover, a lower cumulative hazard rate of relapse in patients with a higher ALC/AMC ratio compared with patients with a lower ALC/AMC, regardless of whether LDH was normal or abnormal at follow-up after CHOP or R-CHOP.

In accordance with the literature [14] , Of the 163 cases with proven relapsed disease, further evaluation for relapse was carried out in 108 (66%) cases because of patient's symptoms and physical findings during routine physical examination and 55 (34%) cases because of CT or positron emission tomography scan findings ordered by the attending physician. Of the 55 cases in which unsuspected relapse was detected by CT or positron emission tomography scan, 28 (51%) cases had a low ALC/AMC ratio and a normal LDH. These results suggest that DLBCL patients with no symptoms or physical findings and a low ALC/AMC ratio at follow-up may require imaging to detect relapses.

Lymphopenia is considered a surrogate marker of host immunological incompetence [21] and [22]. In addition, lymphocytes (including natural killer cells) are important mediators of antibody-dependent cell-mediated cytotoxicity, and may be required for rituximab-mediated, antibody-dependent cell mediated cytotoxicity-dependent destruction of malignant B cells [23] . Not surprisingly then, lymphopenia is an adverse prognostic factor in indolent and aggressive NHL, including DLBCL. Myeloid-lineage cells, including monocytes and their progeny, promote tumorigenesis and angiogenesis [24] , and contribute to the suppression of host antitumor immunity so that not surprisingly then, development of peripheral blood neutrophilia or monocytosis are adverse prognostic factors in multiple solid tumors [25], [26], [27], and [28]. According to our calculation, the association of decreased ALC/elevated AMC and increased risk of DLBCL relapse could be the result of either (a) primary failure of immune surveillance and immune suppression yielding a permissive systemic immunological environment allowing for clinical relapse or (b) primary DLBCL relapse driven by tumor-associated events that in turn produce mediators of immune suppression manifesting as a decrease in ALC and a elevate in AMC. A mechanistic explanation for the increased risk for relapse in DLBCL patients who show low ALC and high AMC may be addressed in an appropriately designed prospective clinical trial in which relevant analyses of systemic immunity, tumor biological characteristics and tumor microenvironment. On the basis of presented data, the association between ALC/AMC ratio and relapse seems to be clinically useful in judging risk for relapse in DLBCL patients in clinical follow-up after standard first-line chemotherapy or R-CHOP.

Our study has some limitations. First, as a retrospective study, the choice of patients might have been biased, and other unrecognized bias might have influenced the results. Second, the number of patients is relatively small to confirm conclusions. Third, the relevant ALC/AMC ratio cutoff point need investigation in other independent cohort. To minimize these biases, we selected only patients with de novo DLBCL treated with standard first-line chemotherapy. In addition, receiver operating characteristics curves and area under the curve were used to determine the best ALC/AMC cutoff value in our study.

In conclusion, we have shown that the ALC/AMC ratio assessed during routine follow-up after standard first-line chemotherapy is an independent indicator of relapse in DLBCL patients. To the best of our knowledge, this study is the first to identify ALC/AMC ratio at follow-up as a marker to assess relapse after standard first-line chemotherapy in DLBCL. Thus, our study suggests that the ALC/AMC ratio at follow-up can be used as a simple, inexpensive tool to alert clinicians of relapse during follow-up after standard first-line chemotherapy in DLBCL.

Conflict of interest statement

The authors declare no conflict of interest.

Acknowledgments

This research was supported by the key technology projects of Anhui Province of China (no. 11010402168) and the project of National Natural Scientific Research Fund of China (no. 81141104).

Contributions: YLL designed the study, collected the clinical data, performed the statistical analysis, and drafted the manuscript. KSG, YYP and YJ participated in the collection of the clinical data. ZMZ conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

Appendix A. Supplementary data

The following are the supplementary data to this article:

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Footnotes

a Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, People's Republic of China

b Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, People's Republic of China

lowast Corresponding author at: Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Fuyong Road, Hefei, Anhui 230601, People's Republic of China. Tel.: +86 055163869571.