Pro-Inflammatory Cytokines in Patients With Chronic Phase-Chronic Myeloid Leukaemia Treated With Imatinib: Any Role in the Monitoring of Treatment Response?

Abstract

Background:

Cancers cause changes in the levels of inflammatory cytokines by inhibiting or promoting their production thus affecting the immune system. The measurement of serum levels of cytokines may be useful in assessing these immunological changes and invariably assessing cancer status.

Objectives:

To investigate the effect of imatinib mesylate (glivec^®) on the serum levels of interleukins (IL-6 and IL-10), and C-reactive protein (CRP) in patients with chronic phase chronic myeloid leukaemia (CP-CML).

Design:

This prospective cohort study included 26 imatinib naïve CP-CML patients with no other co-morbidities and 26 age and sex-matched healthy controls.

Method:

Serum levels of interleukins (IL6 and 10) and CRP were determined using the ELISA method at recruitment for both patients and controls and repeated for the CML patients at 3 months into imatinib therapy.

Results:

The mean serum levels of IL-6 and CRP were significantly higher in CP-CML than in the controls at recruitment 439.83 ± 167.52 versus 39.62 ± 10.11 pg/ml, (t = 8.720 P ⩽ .0001), (8.45 ± 2.88 vs 2.86 ± 1.08 mg/l; t = 6.729 P ⩽ .0001) respectively. In contrast, the mean of the IL-10 in the controls (36.63 ± 12.43) was noticed to be significantly higher than the patients (22.88 ± 4.76 vs 36.63 ± 12.43 pg/ml; t = −3.851 P = .003). Interestingly, there was a significant drop in the serum levels of IL-6 (439.83 ± 167.52 vs 46.85 ± 14.48 pg/ml, (t = 8.055 P ⩽ .0001) and CRP (8.45 ± 2.88 mg/l vs 4.24 ± 1.57; t = 4.305 P = .0001) in the CML subjects 3 months into imatinib therapy. Only IL-10 had a non-significant drop in the CML subjects after 3 months of imatinib therapy. Method validation of these biomarkers was done using the Receiver operating characteristic (ROC) curve which revealed an area under the curve (AUC) of 1.000 for both IL-6 and CRP and 0.152 for IL-10.

Conclusion:

The study has concluded that treatment naïve CML is associated with a significant elevation of pro-inflammatory cytokines (IL-6 and CRP) and treatment with imatinib led to a significant decline in the serum levels of these markers suggesting that IL-6 and CRP could be useful as adjunct in the monitoring of CML treatment.

Keywords

chronic myeloid leukaemia imatinib interleukins C-reactive protein treatment response

Introduction

Many solid tumours are known to induce inflammation in their host and this is often evidenced by the elaboration of pro-inflammatory cytokines in the tumour micro-environment or the serum. Conversely, the pro-inflammatory state has been shown to play a crucial role in tumour pathogenesis and invariably adversely affects the clinical outcomes in some patients.¹ Chronic myeloid leukaemia (CML) is a clonal, acquired genetic disorder of haemopoietic stem cells accounting for 7% to 20% of all newly diagnosed leukaemia.² It is characterised by the presence of the Philadelphia chromosome (Ph+), detected in about 95% of patients. The Philadelphia chromosome is formed by a reciprocal translocation between chromosomes 9 and 22 resulting in the juxtaposition of the Abl gene from chromosome 9 and the BCR gene from chromosome 22. The resultant BCR::ABL1 fusion oncogene codes for a mutant oncoprotein with constitutive high intrinsic tyrosine kinase activity.³ The clinical features of CML may include symptoms of hyperviscosity due to high white blood cell count; headache, dizziness, blurring of vision and hearing impairment. Features of hypermetabolism such as low-grade fever, excessive sweating, malaise and weight loss which result from the elaboration of cytokines are reminiscent of many inflammatory and infectious conditions. Interestingly, these clinical manifestations often resolve completely with the use of tyrosine kinase inhibitors (TKIs) such as imatinib mesylate.^4
-6

Imatinib, a 2-phenylaminopyridine tyrosine kinase inhibitor, produces its therapeutic effects by binding to the tyrosine kinase domain of Abelson (abl) proto-oncogene, platelet derived growth factor receptor (PDGF-R) and c-kit. Once bound to these receptors, it induces conformational changes that prevent these specific intracellular kinase enzymes from phosphorylating appropriate substrates involved in signal transduction.⁷

The development of the BCR::ABL1 targeted therapy with imatinib represents a paradigm shift in the treatment of CML and has turned a once fatal disease into a chronic and manageable disorder. Since its discovery, it has been reported to induce durable remission and prolonged survival, and there has been significant improvement in the outcome when compared to the previous drugs used for its treatment such as busulphan, hydroxyurea and IFNα.^8,9

Monitoring of response of CML patients to TKIs requires a very comprehensive approach. This involves clinical evaluation, serial complete blood counts and more sensitive monitoring tools aimed at determining the cytogenetic and molecular response and to detect and quantify the measurable residual disease (MRD). This is usually accomplished using cytogenetic analysis (both conventional and fluorescent in-situ hybridisation FISH) and detection and quantification of BCR::ABL1 transcript using the polymerase chain reaction (PCR) technique.¹⁰ Polymerase chain reaction (PCR) is a very expensive but highly specialised and sensitive test which is usually done regularly (3-6 monthly) during the course of the disease to monitor cytogenetic and molecular responses.¹¹ The prevailing economic challenges and limited access to facilities for these specialised tests remain a challenge for most patients especially in resource limited settings like ours.¹² This has adversely affected their monitoring and overall treatment outcome. An alternative, cheaper, reliable and readily available monitoring marker may not be out of place. Inflammatory cytokines such as interleukins 6 and 10 and C-reactive protein (CRP) are small molecular proteins that are important in intercellular signalling and regulation of many body systems. They are crucial effectors and regulatory molecules in the immune response to leukaemia.¹³ Serum level CRP and IL-6 are elevated in most inflammatory conditions and patients with chronic myeloid leukaemia.^14
-16 Interleukin 10 (IL-10) has been described as a potent anti-inflammatory cytokine and a poor prognostic marker in patients with gastric and pancreatic cancers.¹⁷ The elevated level of IL-10 in these patients has been reported to be associated with increased tumour growth, metastatic potential and increased rate of drug resistance suggesting that IL-10 may serve as a potential therapeutic target for the treatment of these solid cancers.¹⁸ Its usefulness as a prognostic marker in CML is poorly studied and may need to be explored especially in patients with suboptimal or treatment failure. Other inflammatory cytokines identified as important biomarkers in the pathogenesis of cancers include IL-6, tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ).¹⁹ Interleukin-6 (IL-6), a pro-inflammatory cytokine has been found to play important roles in the pathogenesis of many malignancies such as in multiple myeloma where it is central to tumour survival and growth and has been identified as a prognostic marker in the disease.²⁰ It is an endogenous pyrogen that induces fever and neutrophilia in response to inflammation. It primarily stimulates granulocyte production in the bone marrow by activating common myeloid progenitor cells and drives an aberrant lymphoid progenitor towards the myeloid lineage.²¹ In CML, the production of BCR::ABL1 has been reported to elaborate the production of these inflammatory markers especially IL-6.²² This could be an alternate pathway for the leucocytosis in CML since IL-6 directly stimulates this. Hence, serial monitoring of these inflammatory cytokines may be important in patients with CML since it could be directly related to the BCR::ABL1 level and could predict the treatment outcomes. Therefore, in this prospective study, we evaluated the effect of imatinib mesylate on the host immune system of patients with BCR::ABL1 chronic phase CML using the levels of pro-inflammatory cytokines (IL-6 and CRP) and anti-inflammatory cytokine (IL-10).

Methods

This prospective cohort study included 26 consenting imatinib naïve BCR::ABL1 positive Nigerian CML patients diagnosed in chronic phase of the disease and 26 age and sex matched healthy subjects. Patients and controls with a history suggestive of recent inflammatory or infectious conditions such as respiratory tract infection, urinary tract infection, arthritis, systemic lupus erythematosus (SLE) etc. were all excluded from the study. Subjects with a history of chronic medical illnesses such as chronic kidney injury, cerebrovascular accident, heart failure and chronic liver disease were also excluded. Ethical approval was obtained from the Ethics and Research Committee of the Obafemi.

Awolowo University Teaching Hospitals Complex, Ile-Ife and the ethical approval number given is ERC/2018/02/02. Written informed consent was then obtained from each participant before each procedure. The diagnosis of CML was made by the detection of BCR::ABL1 transcript quantification performed using the Reverse Transcriptase Quantitative Polymerase Chain Reaction (RT-qPCR-TaqMan Chemistry) method and the transcript variant was performed using the Seeplex Leukaemia BCR::ABL1 transcript kit (Seegene, Seoul, Korea). Serum levels of IL-6, IL-10 and CRP were assayed for the subjects and the controls at recruitment. These were repeated for the CML patients, 3 months into imatinib therapy. Serum levels of the interleukins (IL-6 and IL-10) and CRP analysis were done by enzyme linked immunosorbent assay (ELISA) method using the QuicKey Human CRP ELISA kit (Elabscience Houston, Texas, USA). Protocols provided by the kit provider were followed strictly for the procedure. Analysis of the data for normality was carried out using the Kolmogorov-Smirnov test. The mean and standard deviation (SD) were determined for the serum CRP and IL-6 for both groups and the differences between the means ± SD were determined by paired sample T-tests. All these analyses were accomplished using the SPSS version 21.0 statistical package. (SPSS, Chicago, IL, http://www.spss.com). The alpha value was set as <.05.

Results

The mean ages ± SD in years of the 2 groups (CML patients vs Controls) were 36.75 ± 12.28 versus 35.45 ± 10.60 (t = 0.405, P = .693). There was no significant statistical difference between the mean ages of the 2 groups. Fourteen (53.8%) of the CML patients were males while 12 (46.2%) were females, giving a male-to-female ratio of 1.2 to 1.0 while the control group consisted of 13 males and 13 females each. The mean values for the IL-6, IL-10 and CRP for the CML subjects versus controls were 439.83 ± 167.52 versus 39.62 ± 10.11 pg/ml, (t = 8.720 P ⩽ .0001), 22.88 ± 4.76 versus 36.63 ± 12.43 pg/ml, (t = −3.851 P = .003), (8.45 ± 2.88 vs 2.86 ± 1.08; t = 6.729 P ⩽ .0001) respectively. The serum levels of IL6 and CRP were significantly higher in the CML patients than in the controls. Interestingly the healthy subjects had a significantly higher serum level of IL-10 than the imatinib naïve CML subjects. These are as shown in Table 1 below.

Table 1.

Baseline Serum Interleukins 6, 10 and CRP values of Patients and Controls.

Inflammatory markers	Patients (n = 26)	Controls (n = 26)	t	P-value
IL-6 (pg/ml)	439.83 ± 167.52	39.62 ± 10.11	8.720	<.0001*
IL-10 (pg/ml)	22.88 ± 4.76	36.63 ± 12.43	−3.851	.003*
CRP (mg/dl)	8.45 ± 2.88	2.86 ± 1.08	6.729	<.0001*

p-value < 0.05.

There was a significant drop in the serum levels of IL-6 (439.83 ± 167.52 pg/ml vs 46.85 ± 14.48 pg/ml, (t = 8.055 P ⩽ .0001) and CRP (8.45 ± 2.88 mg/l vs 4.24 ± 1.57; t = 4.305 P ⩽ .0001) in the CML subjects 3 months into imatinib therapy. Only IL-10 had a non-significant drop in the CML subjects after 3 months of imatinib therapy. These are shown in Table 2 and Figure 1 below.

Table 2.

Comparison of the Serum Levels of Interleukins 6, 10 and CRP for CML Patients at Baseline and 3 months on Imatinib Therapy.

Inflammatory markers	Baseline	3 mo	t	P-value
IL-6 (pg/ml)	439.83 ± 167.52	46.85 ± 14.48	8.055	<.0001*
IL-10 (pg/ml)	22.88 ± 4.76	20.92 ± 12.43	1.031	.325
CRP (mg/l)	8.45 ± 2.88	4.24 ± 1.57	4.305	.0001*

p-value < 0.05.

Figure 1.

Comparison of the serum levels of IL 6 for CML Patients at baseline and 3 months on imatinib therapy.

Further analysis was done using multivariate regression analysis, and there was statistically significant difference in the mean serum IL-6, IL-10 and CRP between the 2 groups giving a F-value of 147.326, P-value of <.0001 and Wilk’s lambda value of .098.

The validation of IL-6, IL-10 and CRP was done using the Receiver operating characteristics (ROC) curve. ROC curve gave an area under the curve of 1.000 for both IL-6 and CRP and 0.152 for IL-10. These are shown in Figure 2 below.

Figure 2.

The receiver operator characteristic curve (ROC) for IL-6, IL-10 and CRP. The area under the curve for both IL-6 and CRP was 1.000 while it was 0.152 for IL-10.

Discussion

This prospective cohort study evaluated the effect of imatinib mesylate (glivec^®) on the serum levels of inflammatory cytokines (IL-6, IL-10 and CRP) in BCR::ABL1 positive CML patients. Serum IL-6, IL-10 and CRP were done for the imatinib naïve CML patients at baseline and repeated 3 months into imatinib therapy. These were similarly assayed in age and sex-matched healthy controls at recruitment only. The results obtained from the controls were compared with the baseline values in the BCR::ABL1 positive CML. This was necessary to evaluate the effect of the disease on these pro-inflammatory and anti-inflammatory markers before the commencement of imatinib mesylate. We excluded patients and controls with clinical conditions that could significantly increase or decrease these inflammatory markers. Subjects with a history suggestive of recent inflammatory or infectious conditions such as respiratory tract infection, urinary tract infection, arthritis and systemic lupus erythematosus (SLE) were excluded from the study. Similarly, subjects with a history of chronic medical illnesses such as chronic kidney injury, cerebrovascular accident, heart failure and chronic liver disease were also excluded. This is necessary because these inflammatory conditions could significantly increase the circulating levels of the inflammatory cytokines and could interfere with our findings. The study revealed a mean age of 37.2 years for the BCR::ABL1 positive imatinib naïve CML patients at the diagnosis. This younger age at diagnosis has been consistently reported in studies on CML in Nigeria and other countries with similar sociodemographic characteristics.^23,24 Similar relatively early ages of onset have also been reported in Brazil and Pakistan.²⁵ This mean age of 37 years is significantly lower than what was reported from studies in many Western populations where their mean age at presentation was reported to be about 66 years.²⁶ Sadly, this relatively younger age of onset reported in the studied population and other similar studies in Nigeria and other African countries suggests that CML predominantly affects the young and productive population of our society. Consequently, the economic burden of CML may be more severe in our population. Recent European studies have highlighted that CML patients’ life expectancy now equates to their age and sex-matched colleagues.²⁷ This is a reality because the majority of their patients are diagnosed aged 60 years and above and TKI has improved the overall and event free survival in CML.²⁵ This is very challenging in our population since the majority of the patients are diagnosed in their thirties and will have to live with the disease for a longer duration to have a normal life span. There is also the increased tendency of disease progression and the chances of development of mutation(s) that can make them unresponsive to the available tyrosine kinase inhibitor(s) and negatively affect the life expectancy of this population of patients with CML. Patients could also develop adverse drug reactions due to long term exposure to medications. All these will adversely affect the patients and decline the overall survival. The exact reason for the early onset of chronic myeloid leukaemia among this black population is still unknown. Genetic predisposition may be responsible for the early onset of the disease in this studied population.²⁸ The significantly higher levels of IL-6 and CRP in the imatinib-naïve patients at baseline compared with the controls reported from this study may be unconnected to the high level of BCR::ABL1 oncogene in the patients at diagnosis. BCR::ABLI oncogene has been reported to directly drive IL-6 production in CML.²² The significantly elevated levels of these inflammatory cytokines in the CML patient at baseline could also be due to the significantly elevated levels of circulating CD-4 lymphocytes associated with CML.²⁹ Interestingly, imatinib treatment led to a significant decline in the serum level of IL-6 and CRP when assayed at 3 months. Incidentally, by 3 months into imatinib therapy, patients are expected to have achieved complete haematological remission (CHR) and the clinical features of hypermetabolism such as low-grade fever, excessive sweating, malaise and weight loss resulting from the elaboration of cytokines are also expected to have completely resolved. Surprisingly, the mean serum level of IL-6 and CRP obtained in the CML patients after 3 months of imatinib therapy were very close to the mean value obtained from the healthy controls at baseline suggesting that the inflammatory state of the disease in these patients has resolved completely within 3 months of treatment with TKIs. This imatinib induced significant drop in the IL-6 as reported in our study is consistent with findings from other studies.³⁰ These changes in the serum levels of IL-6 and CRP in CML confirm that CML is a pro-inflammatory state and that the role of IL-6 and CRP in the pathogenesis of the disease cannot be over-emphasised. With these findings serial IL-6 and CRP assay in patients with CML could be explored as an adjunct to the standard monitoring tool in patients with CML however, a larger cohort study will be needed to validate this claim. Thus, in addition to the standard BCR::ABL1 transcript, IL-6 and CRP may be useful as an adjunct for monitoring therapeutic response to imatinib mesylate among CML patients. Incidentally, the ROC curve gave an AUC of 1.00 for IL-6 and CRP which is highly indicative of a perfect predictive performance. Conversely, this study shows that the serum levels of IL-10 in imatinib-naïve CML patients were significantly lower than the levels in healthy controls, and there was no significant fall following 3 months of imatinib therapy. This finding suggests that the rate of fall of IL-10 is slower and lags behind that of IL-6 and CRP. Thus, IL-10 may not be useful as an early indicator of response to imatinib treatment. Interleukin 10 (IL-10) has been described as a potent anti-inflammatory cytokine and a poor prognostic marker in patients with gastric and pancreatic cancers. The elevated level of IL-10 in these patients has been reported to be associated with increased tumour growth, metastatic potential and increased rate of drug resistance suggesting that IL-10 may serve as a potential therapeutic target for the treatment of these solid cancers.¹⁸ The finding of lower IL-10 levels in our patients may be unconnected to the fact that all the patients were recruited in the chronic phase of the disease and could be assumed to be a good prognostic marker since all the patients were recruited in the early, stable and treatable stage of the disease. Thus, the baseline serum level of IL-10 could be a useful prognostic marker in CML when investigated in a larger cohort of CML patients at different phases of the disease and for longer follow up period.

Although, cytokines such as IL-6 and CRP offer a promise of providing cheaper and technically less demanding options for monitoring disease response to imatinib therapy, their lack of specificity remains a limitation to their use in routine clinical practice. However, combining the more specific BCR::ABL1 quantitation with cytokines in monitoring response to therapy during the disease course may be a more cost-effective method of disease monitoring.

Conclusion

The use of highly specific and sensitive but expensive markers such as BCR::ABL1 and Philadelphia chromosome has been the main method of monitoring the response of CML patients to tyrosine kinase inhibitors such as imatinib mesylate. However, a cheaper and technically less demanding assay of IL-6 and CRP levels by ELISA method may be a cheaper adjunct to the standard BCR::ABL1.

Footnotes

Acknowledgements

The Authors will like to appreciate the support of the staff of Departments of Haematology & Blood Transfusion and Chemical Pathology of Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, Nigeria for their support during the recruitment of patient and analyses of samples.

Abbreviations

ABL Abelson gene

AUC Area under the curve

BCR Breakpoint Cluster Region

BCR::ABL1: Recent recommendation from Human genome organisation (HUGO) Gene Nomenclature Committee to use (BCR::ABL1) in place of (BCR-ABL1)

CHR Complete Haematological Remission

CML Chronic Myeloid Leukaemia

CP Chronic phase

CRP C-reactive protein

ELISA Enzyme linked immunosorbent assay

FISH Fluorescent in-situ hybridisation

INF-α Interferon alpha

IFN-γ Interferon gamma

IL-6 Interleukin 6

IL-10 Interleukin 10

IRIS International Randomised Study of Interferon and STI571

MRD Measurable residual disease

PCR Polymerase chain reaction

PDGR Platelet Derived Growth Factor Receptor

Ph+ Philadelphia Chromosome

ROC Receiver Operating characteristic

SLE Systemic lupus erythematosus

TNF-α Tumour necrosis factor alpha

TKIs Tyrosine kinase inhibitors

ORCID iD

Ibrahim O. Ahmed

Ethical Consideration

Ethical approval was obtained from the Ethics and Research Committee of the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife and the ethical approval number given is ERC/2018/02/02. All procedures were performed in accordance with standard guidelines and regulations.

Consent to Participate

Written informed consent was obtained from each participant before each procedure.

Consent for Publication

Not applicable.

Author Contributions

TKA, BRA, OTO contributed to conception and design of the study. TKA, AIO and AMA obtained the data, TKA, AIO, AMA, OJO, OOA, OOO, OTO and BRA analysed and interpreted the data, TKA, AIO, AMA, OJO, OOA, OOO, OTO and BRA drafted the original manuscript. TKA, AIO, AMA, OJO, OOA, OOO, OTO and BRA critically revised the manuscript. All authors read and approved the final manuscript.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The datasets used and/or analysed during the current study are available from the corresponding author on request.

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