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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 42  |  Issue : 4  |  Page : 134-141

Programmed death receptor ligand-1 plasma concentration in chronic myeloid leukemia under first-line tyrosine kinase inhibitor therapy


1 Departments of Internal Medicine and Clinical Hematology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Department of Pathology, College of Medicine, Najran University, Najran, Saudi Arabia
2 Departments of Internal Medicine and Clinical Hematology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission06-Sep-2017
Date of Acceptance09-Oct-2017
Date of Web Publication9-Feb-2018

Correspondence Address:
Mohamed M Elkhawanky
7 El-Nady Street, Belbies, Sharkia, 44622, Egypt

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejh.ejh_39_17

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  Abstract 


Background Chronic myeloid leukemia (CML) cells can suppress the immune system by secreting programmed death receptor ligand-1 (PDL-1) that acts as a coinhibitory molecule for T cells leading to T-cell exhaustion and disease progression.
Aim The aim of this study was to assess the plasma level of PDL-1 in patients with chronic myelogenous leukemia and its correlation with prognostic parameters and response to first-line therapy.
Patients and methods This study was carried out on 40 patients with CML in chronic phase and 40 control healthy participants. Patients with CML were subdivided into three subgroups, including 11 newly diagnosed patients, 17 imatinib mesylate-responding patients, and 12 imatinib-resistant cases. All patients were subjected to laboratory investigations including complete blood count, peripheral blood smear examination, bone marrow aspiration (if indicated), quantitative real-time PCR for Philadelphia chromosome, and plasma PDL-1 measurement by enzyme-linked immune sorbent assay.
Results Our results showed high plasma levels of PDL-1 in patients with CML. Plasma PDL-1 levels showed a negative correlation with total lymphocyte count in imatinib-resistant subgroup. Imatinib-resistant subgroup showed a significant decreased level of PDL-1 versus newly diagnosed subgroup of patients with CML. The suggested PDL-1 cut-off value for prediction of patients with CML was 1327.5 ng/l.
Conclusion Patients with chronic-phase CML (newly diagnosed, imatinib responding, and imatinib resistant) showed a highly significant increased PDL-1 level compared with the control group. Increased plasma PDL-1 level is a predictive risk factor for CML incidence and disease progression.

Keywords: chronic myeloid leukemia, imatinib methylate, immune system, programmed death receptor-1, programmed death receptor ligand-1, tyrosine kinase inhibitor


How to cite this article:
Elkhawanky MM, El-Ghammaz AM, Hegab HM, El-Mesery MO. Programmed death receptor ligand-1 plasma concentration in chronic myeloid leukemia under first-line tyrosine kinase inhibitor therapy. Egypt J Haematol 2017;42:134-41

How to cite this URL:
Elkhawanky MM, El-Ghammaz AM, Hegab HM, El-Mesery MO. Programmed death receptor ligand-1 plasma concentration in chronic myeloid leukemia under first-line tyrosine kinase inhibitor therapy. Egypt J Haematol [serial online] 2017 [cited 2018 Apr 20];42:134-41. Available from: http://www.ehj.eg.net/text.asp?2017/42/4/134/225089




  Introduction Top


Programmed death receptor ligand-1

Tumor cells [like chronic myeloid leukemia (CML) cells] can hinder the defense ability of immune system by secreting immune-inhibitory molecules. One of these molecules is programmed death receptor ligand 1 (PDL-1) [1]. PDL-1 acts as a coinhibitory molecule for T cells by binding the programmed death receptor-1 (PD-1), which is upregulated in activated T cells [1],[2]. Binding of PDL-1 to its receptors suppresses T-cell receptor activation [3], T-cell migration, proliferation, and secretion of cytotoxic mediators and restricts tumor cell killing [4], which contribute to the progressive loss of T-cell function, termed as T-cell exhaustion [5]. In addition, PDL-1/PD-1 signaling pathway attenuates protein kinase C activation loop phosphorylation, necessary for the activation of B-cell transcription factors [6], and enhances the immunosuppressive regulatory B cells [7]. The high expression of PDL-1 in patients with cancer has been suggested to lead to disease severity [8].

Chronic myeloid leukemia

CML is a clonal myeloproliferative disorder that accounts for ∼15–20% of adult leukemias [9]. CML harbors a specific cytogenetic abnormality, termed Philadelphia chromosome (Ph) [10], that emerges from a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22) (q34;q11) [11].

CML has a triphase clinical course, including initial chronic phase (CP), secondary accelerated phase, and terminal blast crisis [12]. Approximately 90% of patients are diagnosed in the CP, with common symptoms at presentation being fatigue, abdominal fullness, anemia, leukocytosis, thrombocytosis, splenomegaly, and weight loss, but the disease eventually progresses to a blastic phase unless successfully treated [13].

Molecular monitoring for a patient with CML undergoing therapy provides important prognostic information, and international treatment recommendations incorporate specific time-dependent molecular milestones to help determine whether a patient is responding optimally ([Table 1]) [14].
Table 1 Definition of the response to tyrosine kinase inhibitors as first-line treatment, European LeukemiaNet recommendations

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The advent of tyrosine kinase inhibitor (TKI) therapy has transformed CML from a previously fatal disease into a manageable chronic disease for most patients. Before 1983, the 8-year survival rate of CML was less than 15%. The 8-year survival rate improved from 42 to 65% from 1983 to 2000 with the use of interferon-α-based therapy and allogeneic hematopoietic stem cell transplant therapy. Since the introduction of TKI therapy in 2001, the 8-year survival rate has improved significantly to 87% and continues to improve with the use of second-generation and third-generation TKI therapies [15].

Chronic myeloid leukemia and immune dysfunction

In CML, like in other malignancies, the immune system is impaired favoring immune escape of the malignant cells [16],[17]. In a mouse model of CML, high expression of PDL-1 was found in leukemic cells and that PDL-1 blockade enhanced survival of mice with CML in blast crisis [8].

High expression of PDL-1 has been implicated in resistance to cancer immunotherapy [18]. Across multiple cancer types, the inhibition of PDL-1 by using the engineered humanized antibody against PDL-1 is most effective in patients in whom preexisting immunity is suppressed by PDL-1 and is reinvigorated on antibody treatment [4], or through downregulation of PDL-1, which has the same bioequivalency when compared with anti-PDL-1 antibody treatment [19].


  Patients and methods Top


Patients

This study was carried out on 80 patients. They were classified into two groups. Group I included 40 patients diagnosed with cpCML, and their ages ranged from 26 to 67 years, with mean±SD of 49.75±9.85 years. They included 12 males and 28 females. The study was approved by the medical ethics committee, and informed consents were obtained from the patients to participate in the study.

Group I was subdivided into three subgroups: subgroup A − newly diagnosed (n=11), subgroup B − imatinib methylate responder (n=17), and subgroup C − imatinib methylate resistant (n=12).

Group II included 40 healthy controls serving as control group, and their ages ranged from 22 to 61 years, with mean±SD of 42.2±10.04 years. They included 13 males and 27 females. Both groups were age and sex matched.

This study was carried out at the Hematology Unit, Internal Medicine Department, Faculty of Medicine, Ain Shams University Hospitals.

Methods

Patients were subjected to full clinical assessment including thorough medical history and clinical examination, abdominal ultrasound imaging, and laboratory investigations including complete blood count, peripheral blood smear examination, bone marrow aspiration (if indicated), and quantitative real-time PCR for Philadelphia chromosome, which was carried out for diagnosis and assessment of response to therapy according to European Leukemia Network ([Table 1]).

Specific laboratory investigations for the measurement of plasma PDL-1, which was detected by enzyme-linked immune sorbent assay, was based on Biotin double-antibody sandwich technology by using Human Programmed Cell Death Protein Ligand-1 kit (Bioassay Technology Laboratory, Birmingham, UK).

Statistical analysis

The collected data were revised, coded, tabulated, and analyzed statistically using the SPSS statistical software (IBM SPSS Inc., version 20, Chicago, Illinois, USA). Data were presented, and suitable analyses were carried out according to the type of data obtained for each parameter. Statistical difference was considered significant if the P value was less than 0.05 and highly significant if the P value was less than 0.001.


  Results Top


Patients’ characteristics

This study was carried out on 40 patients with CML (group I) in CP. They were subdivided into three subgroups: subgroup A − newly diagnosed; subgroup B − imatinib responder; and subgroup C − imatinib resistant. Subgroup A contained 36.4% (4/11) males and 63.6% (7/11) females, and their ages ranged from 26 to 55 years with mean±SD of 45.1±10.3 years. Subgroup B comprised 11.8% (2/17) males and 88.2% (15/17) females, and their ages ranged from 36 to 67 years, with mean±SD of 51.65±10.64 years. Subgroup C included 50% (6/12) males and 50% (6/12) females, and their ages ranged from 43 to 62 years, with mean±SD of 51.3±7.3 years.

Descriptive analysis of the demographic and laboratory characteristics of the studied patients is shown in [Table 2].
Table 2 Characteristics of the studied groups

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Description of plasma programmed death receptor ligand-1 concentration in the patients studied

Patients with CML (group I) showed a highly significant (P=0.000) increased plasma PDL-1 level, which ranged between 1496 and 3997 ng/l, with mean±SD of 2506.7±649.8, in comparison with control group, as PDL-1 ranged between 901 and 1159 ng/l, with mean±SD of 1068.1±80.3 ng/l ([Figure 1]). Moreover, each patient subgroups A, B, and C exhibited a highly significant increased PDL-1 level versus the control group (P=0.000 for each), as PDL-1 in subgroup A ranged between 1496 and 3997 ng/l, with mean±SD of 2648.0±825.6; in subgroup B, ranged between 1626 and 3594 ng/l, with mean±SD of 2484.7±670.9; and in subgroup C, ranged between 2000 and 3539 ng/l, with mean±SD of 2408.3±437.5 ([Figure 2]).
Figure 1 Programmed death receptor ligand-1 levels in controls and chronic myeloid leukemia groups.

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Figure 2 Programmed death receptor ligand-1 levels in chronic myeloid leukemia subgroups.

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Patients in subgroup C (imatinib resistant) showed a significantly decreased PDL-1 levels (P=0.020) in comparison with those in subgroup A (newly diagnosed patients) ([Table 3]).
Table 3 Programmed death receptor ligand-1 levels in-between chronic myeloid leukemia subgroups

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Association between programmed death receptor ligand-1 concentration and patients’ characteristics

In subgroups A, B, and C, total lymphocyte count (TLC) ranged from 43.5–275×109/l, 3.5–6.5×109/l and 3.4–8.7×109/l, respectively; hemoglobin concentration ranged from 8.5–12.9, 9.4–11.8, and 8.8–12.7 g/dl, respectively; and platelets count ranged from 158–681×109/l, 184–285×109/l, and 156–304×109/l, respectively.

There was a significant (P=0.039) decrease in TLC in imatinib-responding subgroup B versus imatinib-resistant CML subgroup C.

In newly diagnosed patients, blast cells ratio ranged between 1 and 5%, and PCR ratio at diagnosis ranged between 2.0 and 100%. In imatinib-responder cases, blast cells ratio ranged between 1 and 4%, and PCR ratio at recruitment ranged between 0.0 and 0.04%. In imatinib-resistant patients, blast cells ratio ranged between 1 and 3%, and PCR ratio at recruitment ranged between 0.29 and 84% ([Figure 3] and [Figure 4]).
Figure 3 Blast ratio in chronic myeloid leukemia subgroups.

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Figure 4 PCR ratio in chronic myeloid leukemia subgroups.

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Subgroup B showed a significantly decreased PCR ratio versus subgroup A (P=0.010), whereas subgroup C showed a highly significant increased PCR ratio versus subgroup B (P=0.000) ([Table 4]).
Table 4 The significant difference of blast and PCR ratio in-between chronic myeloid leukemia subgroups

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PDL-1 did not show any significant correlation with complete blood count parameters, blast cells, or PCR ratios in CML subgroups except a negative (r=−0.606, P=0.037) correlation with TLC in imatinib-resistant patients (C) ([Table 5]).
Table 5 Programmed death receptor ligand-1 correlation with other parameters in patients with chronic myeloid leukemia group and subgroups

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The suggestive cut-off value for diagnosis of CML is 1327.5 ng/l, but the cut-off value between responsive and resistant CML subgroups cannot be detected, as there is no significant difference between both groups ([Figure 5]).
Figure 5 Cut-off value between imatinib-responsive and imatinib-resistant subgroups, receiver operating characteristic curve.

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  Discussion Top


Immune escape of tumor cells is a hallmark of carcinogenesis, and restoring 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 [20],[21].

The present study is concerned with the assessment of the plasma level of PDL-1 in patients being in the CP of CML, and its correlation with prognostic parameters and response to first-line therapy. In this study, high levels of plasma PDL-1 were observed in patients with cpCML with highly significant difference between patients with CML group and control group. The mean PDL-1 level in cpCML group was 2506.7±649.8 versus 1068.1±80.3 ng/l in control group. Moreover, it was significantly higher in newly diagnosed, resistant, and responded cases than in controls.

Several studies confirmed the present results and reported increased PDL-1 levels in CML, other leukemias, and solid malignant tumors [1],[4],[8],[18].

Higher PD-1 expression was demonstrated on CD8 T cells in CML compared with cells from healthy participants. Furthermore, in a mouse model of CML, higher expression of PDL-1 was found on leukemic cells [1],[8]. Furthermore, the PDL-1 expression on myeloid tumor cells was higher in patients than in healthy controls [8].

In our study, we failed to find a significant difference between PDL-1 in newly diagnosed and resistant cases in comparison with responding cases, which may be attributed to the small number of cases in our study and to the criteria used for different differentiations of progression of resistance in both diseases.

In chronic lymphocytic leukemia, PDL-1 was shown to be overexpressed on CLL cells and myeloid-derived suppressor cells from the peripheral blood of patients with CLL [22]. Chen et al. [23] measured PDL-1 expression on bone marrow samples from patients with acute myeloid leukemia and found increasing levels upon disease progression, which was an independent negative prognostic factor for M5AML.

An analysis of 196 tumor specimens from patients with renal cell carcinoma found that high tumor expression of PDL-1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death [24]. We did not study the effect of PDL-1 on survival of patients with CML because of the short duration of our study.

In the present study, all cpCML subgroups (newly diagnosed, imatinib responding, and imatinib resistant) had highly significant increased PDL-1 levels in comparison with the levels in control group. Among the CML subgroups, there was significant difference between newly diagnosed and resistant to imatinib cases despite the absence of difference between newly diagnosed and imatinib responding cases, which can be explained by the immune modulatory effects of anticancer agents.

Many anticancer agents exert immunomodulatory effects on host system in addition to their cytotoxicity. The effects of chemotherapeutic agent on expression of PDL-1 have been previously explored in breast cancer cells. Zhang et al. [25] reported that cytotoxic agents, specifically paclitaxel, etoposide, and 5-fluorouracil, could induce PDL-1 surface expression in breast cancer cells, which leads to promoted PDL-1-mediated T-cell apoptosis. On the contrary, Ghebeh et al. [26] have revealed doxorubicin-dependent down-regulation of cell surface PDL-1. The discrepancy was attributed to heterogeneity among different malignancies and agents. Another reason was cancer cells with high-level PDL-1 expression may present more aggressive potential, which confers better sensitivity to cytotoxic agents [27].

In the present study, although there is no significant difference between newly diagnosed and imatinib-responding cases or between imatinib-responding and imatinib-resistant cases regarding PDL-1 level, there is a difference in their mean levels. The newly diagnosed CML subgroup showed the highest mean PDL-1 level 2648.0±825.6 ng/l, followed by imatinib-responding subgroup 2484.7±670.9 ng/l, and the least level was the imatinib-resistant subgroup 2408.3±437.5 ng/l.

Regarding TKIs, Mumprecht et al. [1] reported that in imatinib-treated patients, the PD-1 expression in CD8+ T-cells is increased up to 60% whereas it is less than 10% in healthy controls. Interestingly, in dasatinib-treated patients, CD8+ T-cells are shown to express less than 20% of PD-1 [28].

This finding indicated that unlike imatinib, dasatinib may decrease PD-1 expression close to the levels of healthy controls, which could be of importance as the lack of PD-1 signaling pathway is associated with an improved survival and might restore the function of CML-specific CTLs [1].

In this study, a quantitative molecular detection of BCR-ABL fusion gene was done by real-time PCR from amplified RNA extract from the patient leukocytes, and the BCR-ABL/ABL ratio was determined to be used as tumor (leukemic) burden indicator.

The tumor burden was defined as the percentage of BCR-ABL rearrangement positive cells among the blood cells. An increasing BCR-ABL1/ABL1 percentage ratio over time suggests an increase in tumor burden, whereas a decreasing ratio suggests a favorable response to therapy [29].

The present study did not show any significant correlation between plasma PDL-1 concentration and TLC, blast cell number or tumor (leukemic) burden in cpCML group.

We agree with Mumprecht et al. [1] who reported that the magnitude of PD-1 expression on CD8 T cells did not correlate with the quantification level of the BCR/ABL gene product as analyzed in peripheral blood mononuclear cells. This suggests that even after an excellent molecular response is reached, by treatment with imatinib, the remaining leukemia cells in bone marrow and in lymphoid organs may escape CTL control by expressing PDL-1. Therefore, blocking the PD-1/PDL-1 interaction is a promising strategy to treat CML at different stages of the disease and may also be used in combination with TKIs.

Moreover, it was found in BCR-ABL+ acute lymphoblastic leukemia (B-ALL) that PDL-1 did not correlate with leukemic burden [30].

In CML-induced mice, the introduction of blocking PD-1 monoclonal antibody as treatment had reduced the leukemia burden as indicated by smaller spleen size and lower numbers of leukemia progenitors in the bone marrow [31].

The findings of this study suggest a role for PDL-1 in tumor immune evasion and provide support for the potential utility of PDL-1 inhibitors in the immunotherapy of patients with CML specially resistant cases, which have now entered in clinical trials for treatment of other disorders [4],[30],[32].

In this study, from the PDL-1 levels ‘measured by enzyme-linked immune sorbent assay’ in control group, a suggestive cut-off value of 1327.5 ng/l was calculated with high sensitivity and specificity, where above this value, diagnosis of CML is suspected, but more studies with more patients number are required to put a cut-off value with more sensitivity and more specificity.

Other studies conducted on other malignancies determined different cut-off values as they used other methods of detection. For example, Takada et al. [33] used 5% cut-off by using immunohistochemistry in detection of PDL-1 expression in surgically resected small cell lung cancer specimens.

Even by the use of different antibody clones, the expression rates of PDL-1 on cancer cells was variable at different cut-off values (1, 5, 10, and 50%) [34].

To determine the most appropriate cut-off value of PDL-1 necessitates further studies on more patients’ count and detection with variant methods.

We failed to determine a cut-off value for resistance to imatinib, which can be attributed to the nonsignificant difference between PDL-1 levels in responding and resistant patients to imatinib. Up to our knowledge, no other study has analyzed such issue.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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