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Abstract

BACKGROUND:

Peripheral blood absolute monocyte count (AMC) and lymphocyte to monocyte ratio (LMR) have strong prognostic value in various forms of lymphomas. It was found that higher AMC and lower LMR were associated with poor prognosis in B cell lymphoma. However, their prognostic significance in systemic anaplastic large cell lymphoma (sALCL) remained to be determined.

OBJECTIVE:

This study was aimed at investigating the prognostic significance of AMC and LMR in sALCL.

METHODS:

A total of 29 newly diagnosed patients with sALCL were retrospectively included in study, prognostic significance of AMC, LMR, performance status (PS), international prognostic index (IPI), prognostic index for T-cell lymphomas (PIT) and other indicators were analyzed.

RESULTS:

Univariate analysis showed high AMC, LMR $<$ 2.5, PS $\geqslant$ 2, extranodal involvement, no response to treatment and B symptoms predicted inferior PFS; LMR $<$ 2.5, no response to treatment, elevated LDH, IPI $\geqslant$ 3, PIT $\geqslant$ 2 and PS $\geqslant$ 2 predicted inferior OS. High AMC, PS $\geqslant$ 2 were independent prognostic factors for PFS; PS $\geqslant$ 2, no response to treatment and elevated LDH were independent prognostic factors for OS.

CONCLUSIONS:

AMC was an independent prognostic factor for PFS in sALCL, and LMR $<$ 2.5 also indicated poor prognosis.

Keywords

Anaplastic large cell lymphoma absolute monocyte count absolute lymphocyte count lymphocyte to monocyte ratio prognosis

1. Introduction

Anaplastic large cell lymphoma (ALCL) is a relatively rare type of non-Hodgkin lymphoma (NHL), a Chinese report showed that ALCL was the third most common type of mature T cell lymphoma [1]. Clinically, ALCL can be classified into systemic type and skin type according to the location and manifestation of the disease. Anaplastic lymphoma kinase (ALK) protein was derived from t(2;5) chromosomal abnormality. According to the expression of ALK, ALCL was divided into ALK-positive group and ALK-negative group [2]. 2008 WHO classification established ALK-positive ALCL as an independent type. It is generally believed that the prognosis of ALK-positive ALCL is better than that of ALK-negative ones. Because of the low incidence, there are few reports on ALCL. The disease is highly invasive, with frequent extranodal invasion and poor prognosis. Until now, there is no recognized clinical prognosis criterion.

The prognostic significance of peripheral blood absolute lymphocyte count (ALC) reduction in Hodgkin’s lymphoma (HL) has been well established, and was incorporated into the International Prognostic Score (IPS) scoring system [3]. In recent years, a series of studies have shown that peripheral blood monocyte had prognostic significance in patients with lymphoma. It was found that high absolute monocyte count (AMC) and low lymphocyte to monocyte ratio (LMR) were associated with decreased progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed diffuse large B cell lymphoma(DLBCL) and HL, suggesting that AMC might be of prognostic value [4, 5, 6]. These results further confirmed the earlier study that the monocytes involved in the tumor microenvironment and host immunity [5]. However, the prognostic significance of peripheral blood AMC, LMR and ALC in patients with sALCL remained to be determined. The aim of this study was to analyze the prognostic impact of AMC, LMR, ALC on PFS and OS in patients with sALCL.

2. Material and methods

2.1 Study population

Totally 29 patients with newly diagnosed sALCL from February 2008 to November 2015 at the First Affiliated Hospital of Nanjing Medical University consisting of 19 males and 10 females were retrospectively included in this study; the median age was 40 years, with 28% of cases older than 60 years. All the diagnoses were based on the criteria of WHO 2016 Classifications of Tumors of Hematopoietic and Lymphoid Tissues [7]. All the cases received dose-adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)/CHOP-like regimen as the first-line treatment, and median cycles were 6 (range, 1–12). Responded to the therapy including complete remission (CR) or complete remission unconfirmed (CRu) and partial remission (PR), no response to treatment including stable disease (SD) and progressive disease (PD). Clinical data including gender, age, Ann-Arbor stage, B symptoms, ALK expression, Eastern Cooperative Oncology Group performance status (ECOG PS), the international prognostic index (IPI) score, the prognostic index for T-cell lymphomas (PIT) score, bone marrow involvement and extranodal lesions, ALC, AMC, LMR and serum lactate dehydrogenase (LDH), beta 2 microglobulin ( $\beta$ 2-MG) were collected.

2.2 Statistical methods

PFS was defined as the period from the date of diagnosis to the date of disease progression or the last follow-up date; OS was defined as the period from the date of diagnosis to death due to any reason or last follow-up time. The continuous variables were compared by Mann-Whitney U test. The survival curves were plotted by Kaplan-Meier method and log-rank test was used for comparison. Multivariate survival analysis was performed by Cox regression analysis. All statistical analyses were performed using SPSS (version 19.0) software (IBM Corporation, Armonk, NY, USA). The optimal value of cutoff was obtained using X-tile software. $P<$ 0.05 was considered as statistically significant.

Table 1
Comparison of AMC among groups

Variables	Median AMC (range, $\times$ 10 ${}^{9}$ /L)	$P$ -value	Median ALC (range, $\times$ 10 ${}^{9}$ /L)	$P$ -value
Sex		0.251		0.183
Male ( $n=$ 19)	0.59 (0.23–9.20)		1.51 (0.51–17.10)
Female ( $n=$ 10)	0.45 (0.03–0.78)		1.29 (0.20–1.78)
Age		0.092		0.354
$>$ 60 years ( $n=$ 8)	0.37 (0.03–0.59)		1.26 (0.20–1.78)
$\leqslant$ 60 years ( $n=$ 21)	0.60 (0.23–9.20)		1.44 (0.51–17.10)
ECOG PS		0.056		0.312
$\geqslant$ 2 ( $n=$ 11)	0.60 (0.42–0.96)		1.22 (0.61–2.36)
$<$ 2 ( $n=$ 18)	0.39 (0.03–9.20)		1.49 (0.20–17.10)
ESI		0.001		0.444
$>$ 1 ( $n=$ 7)	0.75 (0.60–9.20)		1.44 (0.90–17.10)
$\leqslant$ 1 ( $n=$ 22)	0.46 (0.03–1.44)		1.30 (0.20–5.43)
BMI		0.340		0.563
Positive ( $n=$ 5)	0.60 (0.36–9.20)		1.47 (0.61–17.10)
Negative ( $n=$ 24)	0.53 (0.03–1.44)		1.30 (0.20–5.43)
LDH		0.647		0.125
$>$ ULN ( $n=$ 6)	0.55 (0.03–0.96)		1.44 (0.20–2.63)
$\leqslant$ ULN ( $n=$ 23)	0.55 (0.23–9.20)		0.85 (0.51–17.10)
$\beta$ 2-MG		0.004		1.000
$>$ ULN ( $n=$ 7)	0.70 (0.42–0.96)		1.22 (0.90–2.36)
$\leqslant$ ULN ( $n=$ 16)	0.50 (0.23–0.71)		1.39 (0.51–2.01)
IPI		0.372		0.161
$\geqslant$ 3 ( $n=$ 7)	0.60 (0.03–0.96)		1.10 (0.20–2.36)
$<$ 3 ( $n=$ 22)	0.51 (0.23–0.71)		1.46 (0.51–17.10)
Response assessment		0.038		0.759
No response to treatment (SD or PD) ( $n=$ 9)	0.71 (0.23–9.20)		1.44 (0.51–17.10)
Response to treatment (CR/CRu or PR) ( $n=$ 20)	0.50 (0.03–1.44)		1.30 (0.20–5.43)
Ann-Arbor stage		0.510		0.357
I/II ( $n=$ 13)	0.51 (0.26–9.20)		1.51 (0.80–17.10)
III/IV ( $n=$ 16)	0.60 (0.03–1.44)		1.30 (0.20–5.43)
ALK expression		0.430		0.629
Positive ( $n=$ 16)	0.56 (0.03–9.20)		1.37 (0.20–17.10)
Negative ( $n=$ 13)	0.55 (0.26–0.78)		1.30 (0.61–1.95)
PIT		0.341		0.449
$\geqslant$ 2 ( $n=$ 8)	0.60 (0.03–0.96)		1.26 (0.20–2.36)
$<$ 2 ( $n=$ 21)	0.50 (0.23–9.20)		1.44 (0.51–17.10)

Notes: ALC, absolute lymphocyte count; ALK, Anaplastic lymphoma kinase; AMC, absolute monocyte count; $\beta$ 2-MG, beta-2 microglobulin level; BMI, bone marrow involvement; CR, complete remission; CRu, complete remission unconfirmed; ECOG PS, Eastern Cooperative Oncology Group performance status; ESI, extranodal sites involvement; IPI, international prognostic index; LDH, lactate dehydrogenase level; PD, progressive disease; PIT, prognostic index for T-cell lymphomas; PR, partial remission; SD, stable disease; ULN, upper limit of normal.

3. Results

3.1 Clinical characteristics of patients

In 29 patients with sALCL, 40% of patients had a PS $\geqslant$ 2 and 55% of patients were in stage III/IV. Forty percent of patients presented with B symptoms. The incidence of bone marrow involvement (BMI) and more than 1 extranodal sites involvement (ESI) were 17% and 24%, respectively. Fifty-five percent of patients were ALK positive. Twenty-one percent and 30% of patients had elevated serum LDH and $\beta$ 2-MG, respectively. Twenty-four percent of patients had an IPI score $\geqslant$ 3, and 28% of patients had a PIT score $\geqslant$ 2. The median AMC and ALC of the patients was 0.6 $\times$ 10 ${}^{9}$ /L (range: 0.03–9.2) and 1.3 $\times$ 10 ${}^{9}$ /L (range: 0.2–1.9), respectively.

3.2 The relationship between AMC, ALC and other clinical indicators

AMC in cases with ESI $>$ 1 was significantly higher than that in cases without ESI $>$ 1 (median 0.75 vs 0.46, $P=$ 0.001). AMC were significantly higher in cases with elevated $\beta$ 2-MG than other cases (median 0.75 vs 0.5, $P=$ 0.004). Patients who did not respond to treatment (SD or PD) had a higher AMC (median 0.71 vs 0.5, $P=$ 0.038) compared with those with response to treatment (CR/CRu or PR). There was no significant difference in ALC among groups (see Table 1).

Figure 1.

The progression-free survival (PFS) and overall survival (OS) curves of 29 patients with systemic anaplastic large cell lymphoma (sALCL).

Figure 2.

The progression-free survival (PFS) curves of the two groups after absolute monocyte count (AMC) grouping with the cutoff value of 0.6 $\times$ 10 ${}^{9}$ /L.

Figure 3.

The progression-free survival (PFS) and overall survival (OS) curves of the two groups after lymphocyte to monocyte ratio (LMR) grouping with the cutoff value of 2.5.

3.3 Clinical outcomes and prognostic analysis

The median follow-up was 20 months (6–61 months), the median PFS was 11 months (1–58 months), and the median OS was 49 months (10–88 months) (Fig. 1). Univariate and multivariate survival analyses were performed for each clinical index with PFS and OS. First, using X-tile analysis software, we selected 0.6 $\times$ 10 ${}^{9}$ /L as the best cutoff of AMC ( $P=$ 0.003) to predict its prognostic significance. The patients were divided into two groups according to the cutoff. Survival analysis showed that cases with AMC $>$ 0.6 $\times$ 10 ${}^{9}$ /L ( $n=$ 9) had significantly shorter PFS ( $P=$ 0.001) (Fig. 2). While OS in the two groups showed no significant difference. By the same way, we selected 2.5 as the best cutoff of LMR ( $P=$ 0.010) and survival analysis showed that patients with LMR $<$ 2.5 ( $n=$ 13) had significantly worse PFS ( $P=$ 0.008) and OS ( $P=$ 0.020) (Fig. 3). ALC $<$ 1.0 $\times$ 10 ${}^{9}$ /L had been widely recognized as a prognostic indicator of poor prognosis in the IPS system of HL, and it was also found that ALC $<$ 1.0 $\times$ 10 ${}^{9}$ /L was a prognostic factor of peripheral T cell lymphoma – not otherwise specified [8]. Therefore, we chose 1.0 $\times$ 10 ${}^{9}$ /L as the best cutoff value of ALC, but survival analysis showed no significant difference in PFS and OS between two groups.

Clinical features such as gender, age $>$ 60 years, B symptoms, ALK, LDH $>$ ULN, ECOG PS $\geqslant$ 2, Ann-Arbor stage $\geqslant$ III, ESI $\geqslant$ 2 stage, IPI $\geqslant$ 3, PIT $\geqslant$ 2, LMR $<$ 2.5, BMI and no response to treatment were included into univariate analysis, and we found that AMC $>$ 0.6 $\times$ 10 ${}^{9}$ /L ( $P=$ 0.001), B symptoms ( $P=$ 0.003), ECOG PS $\geqslant$ 2 ( $P=$ 0.003), ESI $\geqslant$ 2 ( $P=$ 0.036), LMR $<$ 2.5 ( $P=$ 0.008) as well as no response to treatment ( $P=$ 0.006) indicated poor PFS and ECOG PS $\geqslant$ 2 ( $P=$ 0.007), no response to treatment ( $P=$ 0.008), LDH $>$ ULN ( $P=$ 0.026), PIT $\geqslant$ 2 ( $P=$ 0.001), LMR $<$ 2.5 ( $P=$ 0.020) and IPI $\geqslant$ 3 ( $P=$ 0.045) indicated poor OS. Because the reason of collinearity of AMC and LMR, we did two separate multivariates analyses for the PFS, respectively. One only including the AMC but not LMR and the other including LMR but not AMC. We found that only AMC $>$ 0.6 $\times$ 10 ${}^{9}$ /L ( $P=$ 0.017, HR: 6.217, 95% CI: 1.386–27.892) and ECOG PS $\geqslant$ 2 ( $P=$ 0.003, HR: 4.748, 95% CI: 1.684–13.383 or $P=$ 0.033, HR: 3.891, 95% CI: 1.120–13.524) were independent prognostic factors for PFS. It was also found that ECOG PS $\geqslant$ 2 ( $P=$ 0.037, HR: 34.489, 95% CI: 1.232–965.578), no response to treatment ( $P=$ 0.012, HR: 25.802, 95% CI: 2.059–323.273), elevated LDH level ( $P=$ 0.019, HR: 13.254, 95% CI: 1.521–115.473) independently predicted worse OS (see Tables 2 and 3).

Table 2
Results of univariate and multivariate survival analyses of PFS in patients with sALCL

	Univariate analysis		Multivariate analysis
Variables	HR (95% CI)	$P$ -value	HR (95% CI)	$P$ -value	HR (95% CI)	$P$ -value
AMC $>$ 0.6 $\times$ 10 ${}^{9}$ /L	7.260 (2.208–23.870)	0.001	6.217 (1.386–27.892)	0.017		#
B symptoms	5.058 (1.706–15.000)	0.003	2.120 (0.466–9.656)	0.331	1.558 (0.372–6.521)	0.544
ECOG PS $\geqslant$ 2	5.336 (1.772–16.060)	0.003	4.748 (1.684–13.383)	0.003	3.891 (1.120–13.524)	0.033
ESI $\geqslant$ 2	3.559 (1.089–11.630)	0.036	0.435 (0.116–1.631)	0.217	1.336 (0.425–4.206)	0.620
No response to treatment	5.295 (1.600–17.520)	0.006	1.322 (0.292–5.985)	0.718	2.564 (0.580–11.342)	0.214
LMR $<$ 2.5	3.391 (1.371–8.386)	0.008		#	1.004 (0.235–4.291)	0.995

Notes: AMC, absolute monocyte count; ECOG PS, Eastern Cooperative Oncology Group performance status; ESI, extranodal sites involvement; LMR, lymphocyte to monocyte ratio; sALCL, systemic Anaplastic large cell lymphoma. ${}^{\#}$ Because the reason of colinearity of AMC and LMR, we did two separate multivariates analyses for the PFS. One only including the AMC but not LMR and the other LMR but not AMC.

Table 3

Results of univariate and multivariate survival analyses of OS in patients with sALCL

	Univariate analysis		Multivariate analysis
Variables	HR (95% CI)	$P$ -value	HR (95% CI)	$P$ -value
ECOG PS $\geqslant$ 2	6.503 (1.666–25.390)	0.007	34.489 (1.232–965.578)	0.037
No response to treatment	7.257 (1.691–31.140)	0.008	25.802 (2.059–323.273)	0.012
LDH $>$ ULN	5.699 (1.232–26.370)	0.026	13.254 (1.521–115.473)	0.019
IPI $\geqslant$ 3	4.538 (1.033–19.950)	0.045	0.181 (0.019–1.748)	0.140
PIT $\geqslant$ 2	27.930 (5.003–156.000)	0.001	1.769 (0.144–21.686)	0.655
LMR $<$ 2.5	3.998 (1.239–12.900)	0.020	3.090 (0.221–43.299)	0.402

Notes: ECOG PS, Eastern Cooperative Oncology Group performance status; IPI, international prognostic index; LDH, lactate dehydrogenase level; LMR, lymphocyte to monocyte ratio; PIT, prognostic index for T-cell lymphomas; sALCL, systemic Anaplastic large cell lymphoma; ULN, upper limit of normal.

4. Discussion

In recent years, some studies have shown that the abnormal levels of AMC and ALC in peripheral blood have prognostic values for lymphoma, and the increase of AMC and the decrease of ALC are often associated with poor prognosis. However, the prognostic significance of ALC and AMC in sALCL has not been explored. Our study found that AMC levels were significantly elevated in sALCL patients with ESI $>$ 1, elevated $\beta$ 2-MG and no response to treatment, suggesting that elevated AMC may be associated with poor outcome. In order to further study the influence of ALC and AMC on the prognosis of sALCL, we first defined the best cutoff value of AMC. In this study, X-tile software was used to determine the optimal cutoff value of AMC is 0.6 $\times$ 10 ${}^{9}$ /L and LMR is 2.5. We chose 0.6 $\times$ 10 ${}^{9}$ /L as the cutoff value of AMC, and which is close to the reference value of routine blood test. Univariate and multivariate survival analysis showed that patients with AMC $>$ 0.6 $\times$ 10 ${}^{9}$ /L had significantly worse PFS, and LMR $<$ 2.5 had significantly worse PFS and OS. This finding is consistent with that of a study of 94 cases of newly diagnosed PTCL patients, in which patients with AMC $>$ 0.8 $\times$ 10 ${}^{9}$ /L had significantly poorer prognosis [9]. In a study of follicular lymphoma in Italy, the patients with elevated AMC and decreased ALC had a significantly poorer prognosis, and the optimal cutoff values were 0.63 $\times$ 10 ${}^{9}$ /L and 1 $\times$ 10 ${}^{9}$ /L, respectively [10]. There are different cutoff values of AMC in different studies [11]. The differences in cutoff values among studies may be related to the differences in lymphoma types and races. In the study, we found that ALC had no significant effect on PFS or OS and AMC had no significant effect on OS, which might be related to the small number of patients included in our study and relatively short follow-up.

Studies on monocytes and prognosis of lymphoma found that the monocytes are closely related to the tumor microenvironment. Increased monocytes in tumor microenvironment were involved in the pathogenesis of lymphoma, and further lead to inferior clinical outcomes. Studies have shown that malignant T cells remained viable when cultured with autologous monocytes, but cell death increased after monocytes depletion. Monocytes are recruited to the tumor microenvironment by CCL5, and help malignant T cells survive [12]. Further studies found that tumor derived interleukin (IL)-10 blocks the differentiation of monocytes to mature dendritic cells (DC), and immature DCs stimulate lymphoma growth by contact-dependent manner [13]. In addition to DC, monocytes are involved in the pathogenesis of lymphoma by tumor-associated macrophages (TAM). TAM produce matrix metalloproteinase 9 to cleave IL-2 receptor alpha, further activating regulatory T cells which lead to suppression of anti-lymphoma response [14]. TAM can also induce anti-apoptotic gene transcription by releasing B-cell activating factor (BAFF), which thereby reduce the apoptosis of lymphoma cells and cause drug resistance [15, 16]. Studies found that in lymphoma tissues from cases with poor prognosis, CD163 positive macrophages, vascular endothelial growth factor (VEGF) and microvessel density (MVD) were increased [17]. Further functional studies found that TAM secrete angiogenic factors to promote angiogenesis [18], indicating that TAM is involved in angiogenesis of lymphoma. These results suggest that monocytes and their derived cells play an important role in the pathogenesis of lymphoma.

By multivariate analysis, we also found that ECOG PS $\geqslant$ 2 is an independent prognostic parameter for both PFS and OS, suggesting that the PS of patients at diagnosis can affect the prognosis, as patients with good PS can tolerate high-dose chemotherapy and have fewer complications. While the IPI is not an independent prognostic factor for PFS and OS and PITis an prognostic parameter for OS but not for PFS, indicating that IPI may not quite suitable apply to T cell lymphoma although it has been widely used in B cell lymphoma [19], as a result, we may need to continue to look for better comprehensive prognosis evaluation system for T cell lymphoma. No response to treatment is an independent prognostic parameter for OS, and it suggests that efficient first-line treatment to achieve remission is important for the long-term survival of patients.

5. Conclusion

We found AMC, which is simple and easy to get, had its prognostic significance for sALCL patients. The higher AMC ( $>$ 0.6 $\times$ 10 ${}^{9}$ /L) was associated with poorer PFS and LMR $<$ 2.5 associated with worse PFS and OS; multivariate Cox analysis showed that increase of AMC was a prognostic factor independent of IPI. However, a large cohort is needed to further clarify the best cutoff value of AMC, LMR, ALC and its impact on prognosis of sALCL, more in-depth basic research is necessary to investigate the novel role of monocyte and lymphocyte in the pathogenesis of sALCL and other lymphomas.

Footnotes

Acknowledgments

This study was supported by National Natural Science Foundation of China (81470328, 81600130, 8177 0166, 81720108002), Jiangsu Province’s Medical Elite Programme (ZDRCA2016022), Project of National Key Clinical Specialty, National Science and Technology Pillar Program (2014BAI09B12), Jiangsu Provincial Special Program of Medical Science (BL2014086 and BE2017751) and National Science and Technology Major Project (2017ZX09304032).

Conflict of interest

The authors declare no conflict of interest.

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Prognostic significance of peripheral blood absolute monocyte count and lymphocyte to monocyte ratio in anaplastic large cell lymphoma

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Material and methods

2.1 Study population

2.2 Statistical methods

Table 1 Comparison of AMC among groups

3.1 Clinical characteristics of patients

3.2 The relationship between AMC, ALC and other clinical indicators

Table 2 Results of univariate and multivariate survival analyses of PFS in patients with sALCL

5. Conclusion

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Comparison of AMC among groups

Table 2
Results of univariate and multivariate survival analyses of PFS in patients with sALCL