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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 18  |  Issue : 4  |  Page : 398-403

Plasma level of programmed death receptor ligand-1 and CD25 in chronic myeloid leukemia patients and their correlations with response to first-line therapy


1 Al-Emam Al-Sadek Hospital, Babylon, Iraq
2 Child Protection Hospital, Baghdad, Iraq

Date of Submission08-Sep-2021
Date of Acceptance05-Oct-2021
Date of Web Publication18-Dec-2021

Correspondence Address:
Noor Abdul Razaq Jaleil
Al-Emam Al-Sadek Hospital, Babylon.
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/MJBL.MJBL_66_21

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  Abstract 

Background: Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm that is characterized by the presence of the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between the breakpoint cluster region (BCR) of chromosome 22 and the Abelson homolog 1 (ABL1) region of chromosome 9. Programmed death-ligand 1 (PD-L1; also known as B7 homolog 1 and CD274) is an immune checkpoint protein, and its engagement with programmed cell death protein-1 (PD-1) receptor on T cells activates co-inhibitory signaling to suppress the function of cytotoxic T lymphocytes (CTLs). Interleukin-2 receptor (IL-2R, CD25) expression is a soluble form of the a-chain of IL-2R (sIL-2R). The IL-2/IL-2 receptor α (IL-2RA) signaling pathway is essential for the regulation of immune responses. Objective: To assess the plasma level of PDL-1 and CD25 in patients with CML and their correlations with response to the first line of therapy, tyrosine kinase inhibitor (imatinib). Materials and Methods: This case-control study was conducted on 66 patients with CML in the chronic phase (CP) from May 2019 to October 2019. The patients were sequentially selected and subdivided into three subgroups: 20 new diagnoses before starting treatment, 30 imatinib therapy responders, and 16 imatinib resistant for each group. Plasma samples were tested for the levels of PD-L1 and CD25 by the enzyme-linked immunosorbent assay technique. Results: Programmed cell death ligands were significantly increased in the plasma of patients with CML compared with the control group, and there was a significant increase in the plasma PD-L1 of patients with a new diagnosis compared with imatinib responders and patients who were resistant. There was no significant difference in PD-L1 level between the responder and resistant groups. Soluble CD25 was significantly increased in the plasma of patients with CML compared with the control group, and there was a significant increase in the plasma CD25 of patients with a new diagnosis compared with imatinib responders and patients who were resistant. There was no significant difference in CD25 level between responder and resistant groups. Conclusion: Plasma PD-L1 and CD25 levels were significantly higher in adult patients with CML compared with healthy subjects, and these levels were significantly higher in patients with CML who are newly diagnosed compared with imatinib therapy responders and resistant counterparts. There is no significant difference between responders and resistant groups in regard to PD-L1 and CD25.

Keywords: D25, ML, PD-L1


How to cite this article:
Jaleil NA, Abed WM. Plasma level of programmed death receptor ligand-1 and CD25 in chronic myeloid leukemia patients and their correlations with response to first-line therapy. Med J Babylon 2021;18:398-403

How to cite this URL:
Jaleil NA, Abed WM. Plasma level of programmed death receptor ligand-1 and CD25 in chronic myeloid leukemia patients and their correlations with response to first-line therapy. Med J Babylon [serial online] 2021 [cited 2022 Jan 26];18:398-403. Available from: https://www.medjbabylon.org/text.asp?2021/18/4/398/332761




  Introduction Top


CML is a clonal myeloproliferative neoplasm that results from the neoplastic transformation of hematopoietic stem cells.[1] It is characterized by the rearrangement of the long arms of chromosomes 9 and 22, resulting in the Ph chromosome, creating the fusion oncogene BCR–ABL1. This genetic event that encodes for a constitutively active tyrosine kinase occurs in a hematopoietic progenitor and confers proliferative and antiapoptotic effects.[2]

CML is a triphasic disease. Usually, it starts with a relatively indolent phase, a CP that may last for years. If left untreated, it inevitably progresses to either both or an accelerated phase (AP) and a blast or acute phase (BP); the blastic crisis is associated with a poor prognosis and a median survival time measured in months.[3]

CML represents about 14% of all leukemias and 20% of adult leukemias worldwide. The annual incidence is approximately 1.6 cases per 100,000 adults, with a slight male preponderance.[4]

CML is rare below 20 years old, but the frequency increases with each decade of life; the median age of onset is 50–60 years.[2]

The diagnostic hallmark of CML is the presence of the Ph chromosome, which is present in the majority of patients with CML,[2] and it is generated by a reciprocal translocation of chromosomes 9 and 22. This genetic aberration results in the formation of the BCR–ABL1 fusion gene, which codes for a constitutively active form of the ABL1 kinase.[5]

Tyrosine kinase inhibitors (TKIs) are orally administered agents that compete with adenosine triphosphate for its binding site on ABL, leading to abolishing tyrosine phosphorylation of the proteins involved in BCR–ABL signal transduction and finally resulting in apoptosis of the cancer cell. The first TKI that was considered as the first-line treatment of CML was imatinib mesylate.[6]

TKIs such as imatinib and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR) BCR–ABL1 ≤ 0.01% in patients with CML. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to a successful treatment-free remission (TFR), which occurs in approximately half of all patients with CML who discontinue the TKI therapy.[7]

In some cases of CML, quiescent, self-renewing leukemia stem cells (LSCs) are resistant against chemotherapy and specific TKIs. T-cell-based immunotherapy has been shown to be efficacious in solid tumors and leukemia, and allogeneic stem cell transplantation and donor lymphocyte infusions (DLIs) are the only curative treatments in CML.[8]

Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors are widely used in many types of solid tumors and are often considered to be in the same immunotherapy subclass.[9]

PD-1, a cell surface protein belonging to the CD28 family, is encoded by the PDCD1 gene located in chromosome 2q37.132. PD-1 is a key immune checkpoint receptor, which is mainly expressed on activated T, B, dendritic cells, and natural killer cells.[9]

On the surface of activated T cells, PD-1 expression is upregulated after the recognition of peripheral antigens by T cells; subsequently, the elevated binding of PD-1 to PD-L1 and PD-L2 becomes a key step for downstream inhibitory signaling.[9] PD-L1, also known as B7 homolog 1 and CD274, is an immune checkpoint protein, and its engagement with PD-1 receptor on T cells activates coinhibitory signaling to suppress the function of cytotoxic T lymphocytes (CTLs).[10] PD-L1/CD274 is encoded by PD-L1/CD274 (encoded by PDCD1LG1 in chromosome 9).[11]

Interleukin-2 (IL-2) is one of the most studied cytokines driving T-cell proliferation, activation, and survival. It binds to the IL-2 receptor and consists of three chains: the α (CD25), β, and common γ (γc). A high level of soluble CD25 (sCD25) has been associated with a poor prognosis in patients with non-Hodgkin’s lymphoma.[12]

One novel marker of CML LSCs is the IL-2 receptor alpha chain CD25. Here, we provide an overview of markers and targets displayed by CML LSCs, with a special focus on the expression and function of CD25.[13]

Aim of study

To assess the plasma level of PDL-1 and CD25 in patients with CML and their correlations with response to the first line of therapy (TKI imatinib).


  Materials and Methods Top


A case-control study was conducted on 66 patients with CML in the CP from May 2019 to October 2019. The patients were collected from the Hematology Department of Baghdad Teaching Hospital in Medical City and the Hematology Department of Marjan Teaching Hospital in Babil.

Selected patients with CML were subdivided into three subgroups: 20 newly diagnosed CML untreated patients in CP, 30 imatinib responder patients (response to TKI is BCR–ABL ≤ 0.10 after 12 months), and 16 imatinib-resistant patients (BCR–ABL ≥ 0.10 after 12 months).

Inclusion criteria

  1. Adults.


  2. Newly diagnosed untreated CML in patients with CP.


  3. Imatinib mesylate responder patients with CML, after one year from starting treatment.


  4. Imatinib mesylate-resistant CML patients, after one year from starting treatment.


Exclusion criteria

  1. Any patient in AP or blastic crises.


  2. Any patient with chronic illness.


  3. Other types of hematological malignancies.


  4. Solid cancers.


  5. Active inflammatory disease.


Control group

A total of 20 healthy individuals were included in this study as a control group. The age of these subjects ranged between 22 and 60 years and they were 10 males and 10 females; the C-reactive protein test was done for all controls, and their results were negative.

Therapy

The treated patients were on imatinib 400 mg/once daily at least for one year and not more than five years.

From each patient included in this study, a venous blood sample of 2 mL was withdrawn; the samples were collected in (K3-EDTA) tubes.

After complete blood count by a hematology auto analyzer and a blood smear was done, the remaining anticoagulated blood was centrifuged at room temperature for 15 min at 1000×g within 30 min of collection to obtain plasma. Then, 250 μL of plasma was collected from each sample by a calibrated pipette from the upper part of the separated plasma, kept in Eppendorf tubes of 0.5 mL capacity, and frozen at ≤ 40°C at the National Blood Transfusion Center until the performance of PD-L1 and CD 25 assay.

The peripheral blood smear and bone marrow aspirate smears were examined for establishing the diagnosis of newly diagnosed patients, and the remaining were stored at –40°C until (PD-L1 and human cluster of differentiation 25) an enzyme-linked immunosorbent assay was conducted using the (ELISA) Kit Mybiosource (USA) following the manufacturer’s instructions.

Statistical analysis

Statistical analysis was performed with the SPSS 23 statistical software program. Univariate data were summarized using standard descriptive statistics, tabulation of categorical variables, and histograms of numerical variables. Kruskal–Wallis test (a rank-based nonparametric test equivalent to analysis of variance) was used to determine whether there are statistically significant differences between two or more groups of an independent variable on a continuous or ordinal dependent variable. Exact tests were used to calculate the P value. In all statistical analyses, a P < 0.05 was considered significant.


  Results Top


The mean age of the patients’ group was 44.12 ± 12.47 years and that of the control group was 40.1±8.3 years. The range for patients and controls age was 18–70 and 22–60 years, respectively.

CMLs were observed more in males, 59.1% (39/66) than in females, 40.9% (27/66) with an M: F ratio of 1.5:1.

In this study, most patients presented with signs and symptoms of splenomegaly: They were 18 out of 66 (29%), 13 patients presented with anemia (18%), 5 patients presented with bleeding at the time of diagnosis (8%), 9 out of 66 patients with CML presented with fever and weight loss (14%), and the remaining patients, 20 out of 66 (31%), had nonspecific symptoms.

The white blood cell (WBC) count range for newly diagnosed patients was 35–310 × 109/L, for imatinib responders 4.2–9.4 × 109/L, and for imatinib-resistant patients 3.5–220 × 109/L; the mean WBC count of the patients during the new diagnosis was 107.86 ± 87.397 × 109/L, for responders 6.309 ± 1.709 × 109/L, and for resistant patients 46.143 ± 60.065 × 109/L).

The Hb mean for newly diagnosed patients was 9.86 ± 3.134 g/dL, for responders 12.46 ± 1.623 g/dL, and for resistant patients 10.6 ± 2.359 g/dL. The range for newly diagnosed patients was 5.7–15.8 g/dL, for responders 7.9–15.2 g/dL, and for resistant patients 4.1–13.9 g/dL.

The platelet count range for newly diagnosed patients was 16–1056 × 109/L, for imatinib responders 149–399 × 109/L, and for imatinib-resistant patients 58–1000 × 109/L. The mean platelet count for newly diagnosed patients was 336.85 ± 273.68 × 109/L, for responders 228.7 ± 63.315 × 109/L, and for resistant patients 445.062 ± 347.056 × 109/L.

By using Kruskal–Wallis test, the median (interquartile range [IQR]) and range values of PD-L1 for newly diagnosed patients were 9.851 (9.851) ng/mL and 4.437–14.791 ng/mL; for imatinib responders, they were 6.095 (6.095) ng/mL and 1.551–14.619 ng/mL; and for imatinib-resistant patients, they were 6.023 (6.023) ng/mL and 2.705–14.161 ng/mL. However, the median (IQR) and range values for controls were 0.9255 (0.925) ng/mL and 0.782–1.204 ng/mL. There was a statistically significant difference in the mean of PD-L1 level between patients and controls with a P-value of <0.001 [Table 1].
Table 1: Comparison between PD-L1 levels in group of patients with CML and control group

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There is a statistically significant difference in the mean PD-L1 level of the newly diagnosed patients and responder and resistant patients (P < 0.001, 0.002), respectively. However, there is a statistically insignificant difference in the median PD-L1 level of the responder patients and resistant patients [Table 2].
Table 2: Comparison between PD-L1 levels between CML patient groups

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The median (IQR) and range values of CD25 for newly diagnosed patients were 12.882 (12.882) ng/mL and 7.629–62.208 ng/mL, for imatinib responders 11.576 (11.576) ng/mL and 0.082–15.983 ng/m, and for imatinib resistant patients 10.904 (10.576) ng/mL and 1.23–19.522 ng/mL; however, the mean and range values for controls were 0.829 (0.829) ng/mL and 0.588–1.102 ng/mL. There is a statistically significant difference in the mean of PD-L1 level between patients and controls with a P value of <0.001 [Table 3].
Table 3: Comparison of CD25 levels between CML patient group and control group

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There is a statistically significant difference in the median CD25 level of the newly diagnosed patients and responder and resistant patients (P < 0.003, 0.013), respectively. However, there is a statistically insignificant difference in the median PD-L1 level of the responder patients and resistant patients [Table 4].
Table 4: Comparison of CD25 levels between CML patient groups

Click here to view



  Discussion Top


Immune escape of tumor cells is a hallmark of carcinogenesis, and the restoration of antitumor immunity is emerging as a novel treatment approach. Relevant target molecules are immune checkpoints, which under physiological conditions regulate the activation of immune effector cells to maintain self-tolerance and prevent autoimmunity. PD-1 and its ligands PDL-1 constitute one of the most prominent immune checkpoint ligand/receptor axes that are involved in providing and maintaining an immunosuppressive tumor microenvironment.[14],[15]

Originally, an elevated level of sCD25 was associated with lymphocyte activation.[16] However, in hematological malignancies, sCD25 is thought to be released from tumor cells and it has been correlated to tumor burden in the patients.[17]

In this study, the mean age of patients with CML who were included was 44.12 ± 12.47 and with a range of 18–70 years. These results are comparable with two Iraqi studies in 2018,[18],[19] an Iranian study in 2018,[20] and an Indian study in 2016.[21]

The CML cases were observed more in males (59.1% of cases) than in females, These results are comparable with other Iraqi studies in 2016, 2009, 2008,[22],[23] and an Iranian study in 2018.[20]

Regarding the clinical presentation: At the time of diagnosis, most patients presented with signs and symptoms of splenomegaly and nonspecific symptoms followed by anemia whereas a few patients presented with fever and weight loss. In comparison with an Iraqi study in Erbil, splenomegaly was the most common presentation,[18] whereas in another Iraqi study in Duhok weakness/fatigue and fever were the most common presentation.[24] In another study conducted by Usman et al. in Pakistan, abdominal fullness or distension and fever were the most frequent clinical presentations.[25]

The probable causes for these various presentations are the difference in sample sizes and the time of data collection, as most patients stated different complaints every time and the lack of specific archives for patients’ presentations.

In this study, the hematological parameters at the beginning of the study were in accord with those of the study done by Elkhawanky et al.,[26] except in patients resistant to imatinib because in this study some patients were not only molecular resistant but also hematological resistant.

The plasma level of PD-L1 was checked in all patients with CML included in this study (the new diagnosis, responder, and the resistant) and showed a highly statistically significant difference from the control group (P < 0.001). This finding totally agrees with studies conducted by Elkhawanky et al., who exhibited a highly significant increased PDL-1 level versus the control group (P = 0.000 for each).[26] In their study, Mumprecht et al. found an upregulation of PD-L1 in CP CML and even at higher levels in BP CML.[27] Also, in their study, Christiansson et al.,[28] showed that patients with CML expressed higher levels of PD-L1 on myeloid cells compared with control subject cells.

Also in this study, the plasma level of PD-L1 of patients newly diagnosed with CML showed a highly statistically significant difference from the responder group (P < 0. 001), which is inconsistent with that seen in the study conducted by Elhawanky et al.[26] This may be due to more patients in our study (30 patients imatinib responders/20 newly diagnosed) compared with those (17/11) in the study by Elhawanky et al.

There was a significant difference (P < 0.002) in plasma level of PD-L1 between patients newly diagnosed with CML and imatinib-resistant patients. This finding again totally agrees with the studies conducted by Elkhawanky et al.,[26] which explains this finding by the immune-modulatory effects of anticancer agents.

There is no significant difference between imatinib responder patients and resistant patients (P = 1.0), and this totally agrees with the study conducted by Elkhawanky et al. Many anticancer agents exert immunomodulatory effects on the host system in addition to their cytotoxicity.

The plasma level of soluble CD25 was checked in all patients with CML included in this study (the newly diagnosed, the responder, and the resistant), and it showed a highly statistically significant difference from the control group (P < 0.002). This finding totally agrees with the study conducted by Christiansson L. et al.; in their study, the level of sCD25 in blood plasma from patients with CML (n = 14) and control subjects (n = 18) was studied using ELISA. The level in patients was significantly higher compared with the level in control subjects (P < 0,0001). It is also suggested that plasma sCD25 can act in an immunosuppressive manner by binding free IL-2, thereby inhibiting it to bind to and support T cell activation. As others have shown that patients with hematological malignancies, such as B cell malignancies and CML, have increased the level of sCD25 in plasma,[28] and also these results are totally agreed with Kawatani et al.,[29] Sulaiman et al.,[24] Nakase et al.,[30] and Christiansson et al.[31]

Also in this study, the plasma level of sCD25 of patients newly diagnosed with CML showed a highly statistically significant difference from the responder and resistant group (P < 0.003 and 0.013, respectively); however, unfortunately, no similar study for comparison was found for the time being. However, a study was conducted on patients with CML to compare between CP, AP, and blastic crisis.[32] Patients with CML with blastic crisis showed much higher sIL-2R levels (range: 2,580–172,000 U/mL). Further, sera were collected from patients with CML blastic crisis after effective therapy (range: 2,580–7,200 U/mL).[32] Also, in another study on patients with lymphoma, the level of serum sIL-2R was significantly elevated in patients with active disease compared with those in remission and correlated with the clinical stage of the lymphoma.[33] Another study was conducted on patients with AL (AML and ALL); this study showed that the plasma sCD25 level was high in patients with acute leukemia, and plasma sCD25 levels were significantly lower after chemotherapy in the patients with ALL but were not significantly lower in the patients with AML.[34]


  Conclusions Top


  1. Plasma PD-L1 and CD25 levels were significantly higher in adult patients with CML compared with healthy subjects.


  2. Plasma PD-L1 and CD25 levels were significantly higher in newly diagnosed adult patients with CML compared with imatinib therapy responders and resistant counterparts.


  3. There is no significant difference between responders and resistant groups compared with PD-L1 and CD25.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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