A Study of Cytokine patterns of T helper type 1 cytokine (IL-2), T helper type 2 cytokine (IL-6) and Regulatory cytokine (IL-10) in Chronic Lymphocytic Leukemia (CLL) – A Real World Data at a tertiary care center

doi:10.21203/rs.3.rs-5006565/v1

Chronic lymphocytic leukemia (CLL) remains a challenging disease to manage due to its heterogeneous nature and the lack of clarity regarding prognostic markers. This study aimed to clarify cytokine behavior in different stages (Binet and Modified Rai staging) and phases of CLL, particularly focusing on T helper cell dynamics, and investigate their potential as prognostic biomarkers.

Serum samples from 70 participants were analyzed for levels of cytokines Interleukin IL-2, IL-6, IL-10, and serum beta2 microglobulin using Sandwich ELISA and Chemiluminescence immunoassay methods. Clinical parameters, hematological profiles, and CLL disease stage were documented at baseline. Pearson chi-square, Fisher's exact tests, Mann-Whitney U tests, Kruskal-Wallis tests, and correlation analyses with p-value less than 0.05 were considered statistically significant.

In present study, 70 CLL patients were included. Median age recorded as 62 years. The proportion of the disease was 2.45 times higher in males. According to Modified Rai and Binet staging, the study participants were classified into low, moderate, or high risk as 17%, 37%, 46%, and 30%, 26%, and 44%, respectively.

The mean levels of IL-2, IL-6, IL-10, and serum beta2 microglobulin were 14.09 pg/ml, 42.92 pg/ml, 43.02 pg/ml, and 6.63 ug/L, respectively. Median levels were 7.23 pg/ml for IL-2, 44.74 pg/ml for IL-6, 31.11 pg/ml for IL-10, and 7.29 ug/L for serum beta2 microglobulin. IL-2 positively correlated with hemoglobin and platelet count but negatively correlated with lymphocyte count and serum LDH levels. Conversely, IL-6, IL-10 and Sβ2M were positively correlated with lymphocyte count and serum LDH levels but negatively correlated with hemoglobin and platelet count with p value of 0.0001.

Comparison across Modified Rai and Binet staging revealed decreasing IL-2 levels (range 35.68pg/ml to 3.55mg/ml, p value 0.00001) and increasing IL-6 (15.05pg/ml to 58.95pg/ml, p value 0.03), IL-10 (2.11pg/ml to 76.11pg/ml, p value 0.00001), and Sβ2M values (2.96ug/ml to 8.17ug/ml, p value 0.00001) with disease progression from Low to Intermediate and High risks groups. IL-6 and IL-10 has been found significant positively correlated (p value 0.00001) while IL-2 negatively correlated (p value 0.00001) with Sβ2M levels in the study patients.

These findings underscore the complex link between cytokines and CLL progression, with possible implications for prognosis and treatment. Our study found that blood levels of IL-6, IL-10, and Sβ2M rose with CLL progression, as did Interleukin-2 in the early stages of the disease. Furthermore, cytokine levels should be evaluated as a novel clinical prognostic marker for predicting early disease load and an aggressive treatment regimen to improve CLL patients' 5-year survival rates. In the coming years, cytokine levels may play an important role in treatment selection and delivering good treatment-free survival in CLL.

CLL- Chronic Lymphocytic Leukemia

IL- Interleukin

ELISA- Enzyme Linked Immunosorbent Assay

Sβ2M- Serum Beta 2 Microglobulin

Chronic lymphocytic leukemia (CLL) is leukemia characterized by slowly progressive selective clonal proliferation of B lymphocytes in blood and bone marrow with distinct phenotype, manifesting as peripheral lymphocytosis (5 x 10⁹/L) with or without nodal or extra nodal manifestation excess of mature white blood cells known as lymphocytes. CLL is the most common type of adult leukemia, affecting people over the age of 50 [1]. It is the most common leukemia in the US (30% of all leukemia) and the least common in India (5% of all leukemia). The incidence and prevalence of chronic lymphocytic leukemia (CLL) in India are not well documented due to a lack of population-based studies and systematic data collection. Although the root cause of CLL is unknown, there are a number of factors that have been identified contributing to the disease's onset [2]. CLL cells can be stimulated directly by elements of the microenvironment or through cytokines and chemokines [3]. Additionally, lymphatic tissues are the principle site of B-cell receptor (BCR) activation for both normal and malignant B-cells [4]. Thus study of cytokines in CLL opens new areas of insight into this elusive disease.

Several studies indicate the dominancy of T helper type 1(T_H1) in the early stage of CLL. T helper type 2(T_H2) immune response is documented in the late stage of the disease. Transformation of T_H1 to T_H2 is the reason for the disease progression [5]. IL-6 is an important cytokine produced by the immune cells and CLL cells which has a control T helper type 1(T_H1) to T helper type 2(T_H2) differentiation [6]. IL-10 has a role in regulatory mechanism of inhibiting T helper type 1(T_H1) thus helping in the production of more T_H2 cytokines in the later stage of the CLL disease [7, 8]

Cytokine suppression of apoptosis through altering the ratio of genes that induce and suppress apoptosis is a crucial component of the development programme [9, 10]. Cancer treatment can be enhanced by lowering the concentration of cytokines that inhibit the induction of apoptosis in malignant cells. No clarity in cytokine behavior in different stages (Binet and Rai staging) and newly diagnosed of CLL [11].

In this study we wanted to clarify the cytokine behavior in different stages (Binet and Rai staging) and newly diagnosed in CLL which may be helpful in as potential surrogate prognostic biomarkers.

The present study was an observational analytical study conducted from September 2021 to February 2023. The present study was conducted in the Department of Biochemistry in collaboration with the Department of of Hematology Medical Oncology, and Department of Pathology, AIIMS Rishikesh, India.

Inclusion criteria

Newly diagnosed treatment naïve CLL cases of all age groups and of both sex.

Exclusion criteria:

Active Second Primary Malignancy currently being treated.

Active infection at the time of screening.

Considering Gaussian distribution curve and budget availability we enrolled 70 participants in exploratory time bound manner.

Methodology

Sample collection

The study was initiated with Institutional Ethics Committee granting an approval AIIMS/IEC/700 dated 24/12/2021 for the study. After obtaining informed consent, plasma samples of newly diagnosed CLL patients were collected and preserved at -80°C. Clinical parameters such as age, gender, comorbidities, CLL disease-related symptoms, and physical findings were documented at baseline. Laboratory parameters including hemoglobin, total leukocyte count, absolute lymphocyte count, and platelet count were documented and CLL disease stage was calculated based on clinical & hematological parameters.

Five ml of whole blood collected in clot activator vials, sample centrifuged, and serum was separated. A portion was used for analysis of IL -6. Serum was stored at -80°C till processed for analysis of serum IL-2, IL-10 and Serum beta2 microglobulin.

Baseline investigations were collected including hematological parameters (such as Hemoglobin, Total Lymphocyte Count, Platelet Count measured using automated hematology analyzers). Estimation of IL-2 Levels by Sandwich ELISA using commercilaly aviablable kit Diaclone, France. Normal reference range of IL-2 was taken as 0-7pg/ml. Estimation of IL-10 Levels was done by Sandwich ELISA using commercilaly aviablable kit Diaclone, France. Normal reference range of IL-10 was taken as 0-4.9pg/ml. Estimation of Human Beta − 2 Microglobulin (β2MG) Levels by ELISA kit availble from Cal Biotech Inc, California, USA. Normal reference range of serum beta2 microglobulin was taken as 0–2µg/ml.Estimation of IL-6 Levels as doe by ADVIA Centaur® IL6 assay – Chemiluminescence Immunoassay (CLIA).Normal reference range of IL-6 was taken as 0-6.5pg/ml.

Statistical analysis:

Group-wise comparisons of distributions of clinical, laboratory and molecular data was be performed with Pearson chi-square or Fisher’s exact test. Descriptive data was be reported as mean ± standard deviation (SD. Non parametric Spearman’s rho correlation is used for correlation of cytokine levels with age. Mann-Whitney or Pearson chi-square or Fisher exact test is used for comparison of cytokine levels with gender. Serum cytokine levels and serum beta2 microglobulin (Sβ2M) are correlated with Hematological and Biochemical parameters by using Pearson or Spearman’s rho correlation. Pearson chi- square test or Kruskal –Wallis test is used for comparison of cytokine levels with disease stage. Correlation between serum cytokines and serum beta2 microglobulin level was be assessed by Pearson or Spearman’s rho correlation. P-value less than 0.05 was considered statistically significant.

In the present study, 70 CLL patients were included. Their median age recorded as 62 years. The proportion of the disease was 2.45 times higher in males. The minimum and maximum age of participants were found to be 26 years and 85 years respectively with highest number between age group 59 to 70 years (Table 01).

Table no.01 showing Age-wise frequency distribution in study group

Range (years)	No. of patients having CLL
	Males	Females
0–15	0	0
16–30	0	1
31–45	5	3
46–60	15	8
61–75	23	6
76–90	7	2
Total	50	20

All of the patients included in the study were asymptomatic. CLL disease stage of patients in the present study at diagnosis was found to be Low, Intermediate and High grade according to Modified Rai staging as 17%, 37%, 46% respectively (Fig. 1A). Low, Intermediate and High grade according to Binet staging was found to be 30%, 26%, and 44% respectively (Fig. 1B). Also 43% patients in this study has been presented along with other comorbidities like Diabetes mellitus, Hypertension, Hyperthyroidism, Carcinoma bladder, Chronic liver disease with portal hypertension etc.

Correlation of serum Interleukins (IL-2, 6, 10) and serum beta 2 microglobulin with Hematological parameters

In our study population, mean ± standard deviation of hematological parameters including Hemoglobin (g/dl) was found to be 10.473 ± 2.4561, Lymphocyte (%age) 78.483 ± 19.6906, Platelet (10³cells/uL) 143.39 ± 97.040. Serum mean levels of LDH (U/L) were also recorded as 318.78 ± 140.866. The correlation of cytokines with hematological parameters was attempted (Table 02). IL-2 is positively correlated with Hemoglobin concentration and platelet count but negatively correlated with Lymphocyte count and serum LDH levels, using spearman’s rho (p < 0.05) (Fig. 2).

IL-6 is negatively correlated with Hemoglobin concentration and platelet count and positively correlated with Lymphocyte count and serum LDH levels, using spearman’s rho (p < 0.05) (Fig. 3).

IL-10 is negatively correlated with Hemoglobin concentration and platelet count and positively correlated with Lymphocyte count and serum LDH levels, using spearman’s rho (p < 0.05) (Fig. 4).

Serum beta2 microglobulin is positively correlated with Lymphocyte count and serum LDH levels but negatively correlated with Hemoglobin concentration and Platelet count, using Spearman’s rho (p < 0.05) (Fig. 5).

Correlation of serum Interleukins and serum beta 2 microglobulin with Staging

Serum Interleukins (IL-2, 6, 10), Serum Beta2 microglobulin levels and Modified Rai & Binet staging of Low (0 stage), Intermediate (1 &2 stages) and High risk (3&4 stages) were compared using Kruskal-Wallis test (p value < 0.05). The Chi-square statistic is significant at the 0.05 level. (Table 02). As CLL advances from the early to the late and highly advanced stages, mean IL-2 levels drop from 35.68 ± 11.60 pg/ml, 17.10 ± 12.12 pg/ml, and 3.55 ± 3.72 pg/ml in low, Intermediate and high-risk group respectively. This was statistically significant difference among groups. In present study, 12 out of 12 patients enrolled in low- risk group, 20 out of 26 in Intermediate risk group, and only 4 out of 32 patients in High-risk group by Modified Rai staging had values of IL-2 more than upper limit (> 7 pg/ml). So high values were more commonly found in low, intermediate group as compared to High-risk group.

IL-6 levels are raised in all stages of diasese with levels ranging from 4.68pg/ml to 91.80pg/ml. Serum IL-6 mean levels increased as CLL advances from the early to the late and highly advanced stages, mean IL-6 levels were 15.05 ± 5.93 pg/ml, 36.04 ± 20.89 pg/ml and 58.95 ± 18.10 pg/ml, in low, Intermediate and high-risk group respectively. This was also statistically significant difference among groups. In high risk group 32 out of 32 patients had values above upper limit (> 6.5 pg/ml), 25 out of 26 in intermediate and 11 out of 12 in low risk group had IL-6 vlaues above upper limit.

IL-10 levels are raised in most in high risk stages of diasese. Serum IL- 10 mean levels increased as CLL advances from the early to the late and highly advanced stages, mean IL-6 levels were 2.11 ± 1.3 pg/ml, 21.17 ± 23.45 pg/ml, and 76.11 ± 30.07 pg/ml, in low, Intermediate and high-risk group respectively. This was also statistically significant difference among groups. In low risk group none among 12 had values above upper limit (> 4.9 pg/ml), 18 out of 26 in intermediate and 31 out of 32 in high risk group had IL-10 vlaues above upper limit. Thus, IL-10 levels increased dramatically in the late and severe phases. As illness progresses, serum beta 2 microglobulin (Sβ2M) levels rise from 1.36µg/ml to 10.00µg/ml, indicating an increase in B-cell lymphocytes.

Correlation between serum Interleukins (IL-2, IL-6, IL-10) and serum beta 2 microglobulin (Sβ2M)

Interleukins IL-2, 6, 10 are correlated with serum beta2 microglobulin using non parametric spearman’s rho correlation with p = 0.00001(p < 0.05) (Table 02). There found a significant correlation between interleukins and Sβ2M values. IL-2 is negatively correlated with Sβ2M and IL-6 and IL-10 are positively correlated with Sβ2M.

Table 2: Sample characteristics: Serum levels of Interleukin -2, Interleukin-6, Interleukin- 10, Serum beta2 microglobulin and correlation with various hematological parameters, and CLL risk category.

	N= 70	Interleukin-2 (IL-2) pg/ml	Interleukin-6 (IL-6) pg/ml	Interleukin-10 (IL-10) pg/ml	Serum beta2 microglobulin (Sβ2M) mg/ml
Mean± SD (range)		14.09±14.72 (52.70 -0.01)	42.92±24.14 (4.68-91.80)	43.02±39.80 (0.16- 128.38)	6.63±2.71 (1.36mg/ml to 10.00mg/ml
Correlation with Hemoglobin (g/dl)		0.603^** ^(0.00001)	-0.468^** ^(0.00001)	-0.536^** ^(0.00001)	-0.458^** ^(0.00001)
Correlation with Lymphocyte (% age)		-0.159 ^(0.188)	0.145 ^(0.232)	0.081 ^(0.503)	0.057 ^(0.637)
Correlation with Platelet (10³cells/µl)		0.481^** ^(0.00001)	-0.330^** ^(0.005)	-0.483^** ^(0.00001)	-0.387^** ^(0.001)
Correlation with Lactate Dehydrogenase (LDH) (U/L)		-0.187 ^(0.120)	0.154 ^(0.202)	0.123 ^(0.309)	0.266^* ^(0.026)
Risk(N) Using Modified Rai Staging	Mean ± SD
Low (n=12)		35.68 ± 11.60	15.05 ± 5.93	2.11 ± 1.3	2.96 ± 0.69
Intermediate (n=26)		17.10 ± 12.12	36.04 ± 20.89	21.17 ± 23.45	6.42 ± 2.72
High (n=32)		3.55 ± 3.72	58.95 ± 18.10	76.11 ± 30.07	8.17 ± 1.59
Chi-Square (p-value)		45.824 ^(0.00001)	31.180 ^(0.00001)	45.314 ^(0.00001)	26.308 ^(0.00001)
	Staging Type	IL-2	IL-6	IL-10	Sβ2M
Correlation with Chi Square p-value	Modified Rai Staging P value	0.00001	0.0312	0.00001	0.00001
Correlation with Chi Square p-value	Binet Staging P value	0.00001	0.009	0.00001	0.00001
Serum beta2 microglobulin (Sβ2M)	Correlation coefficient	-0.610^**	0.614^**	0.621^**	-
	Sig. (p-value)	0.0000	0.00001	0.00001	-

p– value <0.05 is considered significant

**. Correlation is significant at the 0.01 level (2-tailed).

*. Correlation is significant at the 0.05 level (2-tailed).

In our study, proportion of CLL was found to be 2.45 times higher in males than in females. This is consistent with demography provided by SEER Data Analysis in National Cancer Institute (NCI) and National Institute of Health (NIH) and National Comprehensive Cancer Network (NCCN) guidelines [12, 13]. The median age in present study was found to be 62 years with more incidence between 59–70 years which was in accordance with several Indian studies [5–7]. In Western countries, 25–30% of CLL patients had a median age of less than 55 years. About 90% of people diagnosed with CLL are more than 50 years of age with the average incidence at 71 years [14].

Serum Interleukin levels in study patients

In present study elevated levels of IL-2 (> 7 pg/ml) with median levels of 7.23 pg/ml was recorded. These higher levels of serum cytokines estimated in CLL patients were compared against the clinical staging and we found that high values were more commonly found in low, intermediate group as compared to High-risk group. G. Semenzato et al study documented that the patients with CLL displayed higher levels of serum IL-2 in low risk patients. Semenzato G et al. study also found serum lL-2 levels of 1781 U/mL, which were higher than normal age-matched controls [15]. Proliferative response of IL 2 has been shown on normal or neoplastic progenitor B cells, hence considered to be pro-tumoral [16]. It is known to reduce apoptosis, is relapsed by CD4 + T cells after an antigenic stimulus and acts via the IL-2 receptor (IL-2R). Musolino et al. found that serum IL-2R was higher in CLL patients and it was also linked to Rai staging and aggressiveness of the leukemia [17].

In the study by L. Fayad et al., serum IL-6 levels were higher in CLL patients than in healthy volunteers (median, 1.45 pg/mL; range, undetectable to 110 pg/mL) as were serum IL-10 levels (5.04 pg/mL; undetectable to 74 pg/mL). They assessed individually or in combination, elevated serum IL-6 and IL-10 levels were independent prognostic factors correlating with the advanced disease features and short survival [18].

In present study also elevated levels of IL-6 (> 6.5 pg/ml) were common in all risk categories of CLL patients, with highest mean value of 58.95 ± 18.10 pg/ml recorded in high risk group. These results mirror previous findings in various other studies where raised levels were found to increase in disease stage-dependent manner [19, 20]

Another recent study by Wang et al found that increased autocrine IL-6 production was associated with a worse clinical course of CLL. Wang et al found that along with the increase in concentration of IL-6, patients had a shorter lymphocyte doubling time. They were more likely to receive therapy and it also linked with 17p/11q deletion and overall progression-free survival. Their results mention multiple mechanisms for suppression of apoptosis of B cells by IL-6 namely by activating both STAT3 and NF-κB pathway (Bcl‐xL and Mcl‐1 protein expression are upregulated) and mitochondrial translocation of STAT3 being affected by IL-6 [21].

Growth of B cell lymphocytes is promoted by serum L-6 via autocrine pathway [22, 23]. Zhu et al.'s study discovered higher levels of IL-6 in the plasma of chemotherapy-treated CLL patients than in the plasma of untreated controls [24].

Also, in the present study serum IL-10 most of the patients had value > 2.03 pg/ml and highest value was 128.38 pg/ml. IL-10 levels are raised in most in high risk stages of disease, with serum IL- 10 mean levels increasing as CLL advances from the early to the late and highly advanced stages. In the study by Khodashenas et al., the serum concentrations of IL-6 and IL-10 were measured to look into their correlation with treatment response and CLL prognosis. However, according to them no significant difference were found in serum levels of IL-6 and IL-10 between patients with advanced stage of CLL when compared to those with early stages before initiation of treatment [25].

Similarly a study by Antosz et al revealed lower mRNA expression of IL-10 in CLL B cells. However, post treatment an increase in IL-10 mRNA expression was seen in leukemic cells [26]. While other authors reported that serum IL-10 levels were increased in B-CLL patients, which may operate as an element to extend the lifespan B-CLL lymphocytes in vivo [27].

In fact, in Rai stage 2 and beyond, IL-10 blocks the programmed cell death of B-CLL lymphocytes [28]. IL-10 increased expression has been linked to frequently overexpressed CD5 molecule in CLL [29]. This increased expression induction of of IL-10 by CD5 was also shown to increase B cell [30] via STAT3 and NFAT2 Activation [31]. IL-10 also known to influence high-affinity IL-2 receptors by augmenting them and further promoting B-CLL cells growth [32].

Hematological parameters play a part in CLL diagnosis, monitoring, prognosis assessment, and treatment decision-making. Marziye Bagheri et al. study found platelet/lymphocyte ratio to be a prognostic marker in CLL, with a correlation to an advanced clinical course [33].

In our study, a significant correlation was found between IL-2 and hemoglobin concentration and platelet count. We also found a significant correlation between serum levels of IL-6 and IL-10 and lymphocyte count. Elevated serum LDH levels have a prognostic significance in patients with treatment-naive CLL [27, 34]. In our study, positive correlation of serum LDH levels with IL-6, IL-10 and Sβ2M levels was found, indicating the high disease load with lymphocytosis in untreated CLL patients.

In our study, we found elevated levels of serum B2M in high risk CLL patients and 70% patients had Sβ2M value > 10.0 µg/ml. This was in accordance with many previous studies that reported noticeably elevated levels of Sβ2M in their population group [35–37].

Beta2-microglobulin has been recognized as a reliable prognostic marker in CLL patients. In the International prognostic index for Chronic Lymphocytic leukemia (CLL-IPI), 2 points are added to final score if Sβ2M value > 3.5 mg/L, with higher scores pointing at advanced stage of CLL.

In this study we attempted to clarify the cytokine behavior in different stages in newly diagnosed in CLL. However, the absence of wider cytokine panel and small number of study participants are two major limitation of our study.

The present study explores the role of inflammatory and regulatory cytokine levels in newly diagnosed patients in different stages of CLL disease in Indian population. In CLL, cytokines are important in the pathogenesis and disease progression. Our study revealed that serum IL-6, IL-10 and Sβ2M levels increased in accordance with CLL progression while raised Interleukin-2 were found in the early stage of the disease with subsequent decline. Though encouraging, our study result just indicate at potential use of cytokine levels as novel marker for disease stage. In forthcoming years with further research, cytokine levels may play a role in better understanding CLL. To obtain results that can be applied in a clinical setting, larger studies with a larger panel of cytokines can be tried.

Patents

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Supplementary Materials: No supplementary materials available for this submission.

Author Contributions: “Conceptualization, MN and UKN.; methodology, MN; software, ST and RB; validation, MN, UKN, YB, and ST.; formal analysis, ST and MN.; investigation, ST, MN, HC, and UKN.; resources, MN and UKN.; data curation, YB and UKN.; writing—original draft preparation, ST and RB.; writing—review and editing, ST, RB and MN.; visualization, MN and UKN.; supervision, AAM, KM, YB, HC, MN and UKN.; project administration, MN.; funding acquisition, ST and MN. All authors have read and agreed to the published version of the manuscript.”

Funding: This research received no external funding

Institutional Review Board Statement: “The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of ALL INDIA INSTITUTE OF MEDICAL SCIENCES, RISHIKESH and given AIIMS/IEC/21/700 dated 24/12/2021.

Informed Consent Statement: “Informed consent was obtained from all subjects involved in the study.” And “Written informed consent has been obtained from the patient(s) to publish this paper”, there were no ethical issues in this study.

Data Availability Statement: The data that support the findings of this study are available within the article.

Competing Interests – None

Acknowledgements - None

Conflicts of Interest: “The authors declare no conflicts of interest.”

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No competing interests reported.

A Study of Cytokine patterns of T helper type 1 cytokine (IL-2), T helper type 2 cytokine (IL-6) and Regulatory cytokine (IL-10) in Chronic Lymphocytic Leukemia (CLL) – A Real World Data at a tertiary care center

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Version 1

Abstract

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1. Introduction

2. Materials and Methods 400 words

3. Results

4. Discussion

5. Conclusions

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Version 1