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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 45  |  Issue : 2  |  Page : 68-76

Assessment of serum interleukin-15 in adult acute leukemia patients (Egyptian sample)


Department of Internal Medicine, Hematology and BMT Unit, Ain Shams University, Cairo, Egypt

Date of Submission16-Oct-2019
Date of Acceptance23-Nov-2019
Date of Web Publication29-Dec-2020

Correspondence Address:
Emad Abdel Mohsen
Department of Internal Medicine, Hematology and BMT Unit, Ain Shams University, Cairo, 1199
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejh.ejh_44_19

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  Abstract 


Background Interleukin 15 (IL-15), proinflammatory cytokine, regulates immune system functions and controls hematopoietic cell differentiation. It promotes leukemia development through enhancing survival, proliferation, and differentiation of leukemic precursors.
Aim The aim was to assess the expression of IL-15 level in adult Egyptian acute leukemia patients, its correlation with disease-free survival, overall survival and relapse rate, and its possible correlation with other prognostic parameters.
Patients and methods Serum IL-15 was measured using ELISA in 30 newly diagnosed acute lymphoblastic leukemia (ALL) patients, 30 newly diagnosed acute myeloid leukemia (AML) patients, and 30 healthy controls recruited from Ain Shams University Hospital from 2017 to 2018.
Results In ALL patients IL-15 was higher in patients compared with the control. IL-15 was higher in patients with non-high-risk cytogenetics compared with those with high-risk cytogenetics. Patients with high IL-15 who achieved first complete response (CR) were less than those with low/average IL-15. Patients with high IL-15 who achieved minimal residual disease (MRD) negativity were less than those with low/average IL-15. Patients with high IL-15 had shorter survival compared with those with low/average IL-15 level. Optimal cutoff value for IL-15 in predicting patient survival in ALL patients was 200 ng/l. In AML patients: IL-15 was higher in patients compared with the control. IL-15 was higher in patients with high-risk features compared with those without. Patients with high IL-15 achieved first CR less than those with average IL-15. Patients with high IL-15 achieved MRD negativity less than those with average IL-15. Patients with high IL-15 had shorter survival compared with those with low/average IL-15. Optimal cutoff value for IL-15 in predicting patient survival in AML patients was 190 ng/l. IL-15 has negative correlation with death date in AML patients.
Conclusion IL-15 is a useful poor prognostic marker in newly diagnosed acute leukemia patients’ also it can be used as a predictor for CR, MRD, and survival.

Keywords: acute leukemia, cytokine, minimal residual disease


How to cite this article:
Moussa MM, Sheeba M, Mohsen EA, Elshazly M, Hussein NE. Assessment of serum interleukin-15 in adult acute leukemia patients (Egyptian sample). Egypt J Haematol 2020;45:68-76

How to cite this URL:
Moussa MM, Sheeba M, Mohsen EA, Elshazly M, Hussein NE. Assessment of serum interleukin-15 in adult acute leukemia patients (Egyptian sample). Egypt J Haematol [serial online] 2020 [cited 2021 Jul 31];45:68-76. Available from: http://www.ehj.eg.net/text.asp?2020/45/2/68/305400




  Introduction Top


Leukemia is a group of complex disorders that are originated from abnormal maturation of hematopoietic precursors. Morphological, immunophenotypic, and genetic characteristics are the main criteria used by the WHO classification system to diagnose leukemia [1].

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by several genetic mutations in hematopoietic precursors. Genetic mutations in myeloid precursors usually affect the physiological process of maturation and differentiation [2]. In AML, excessive stimulation to signal transduction pathway incomprehensibly surpasses the recurrence of genetic mutations in signal transduction pathway components and receptors, suggesting that abnormal activation by extracellular factors, such as cytokines and growth factors, may play a role in leukemogenesis by providing signals to facilitate proliferation and inhibit apoptosis of leukemic cells [3].

Acute lymphoblastic leukemia (ALL) represents a group of complex hematological disorders originating from either B-cell or T-cell precursors. B-ALL comprises about 80% of cases [4]. ALL arises from genetic mutations that impair normal differentiation of lymphoid cells at the stem cell or an early progenitor stage. Abnormal release of cytokines or abnormal activation of its receptors plays a role in supplementing the genetic mutations in causing leukemogenesis, thus supporting survival and proliferation of leukemic cells [5].

IL-15 plays critical roles in hematopoietic development by controlling the differentiation of hematopoietic precursors and maintaining its survival. However, interleukin (IL)-15 can also potentiate the development of leukemia and promote tumor growth and tissue infiltration [6].


  Aim Top


The aim was to assess expression of IL-15 level in adult Egyptian acute leukemia patients, its correlation with disease-free survival, overall survival (OS) and relapse rate, and to find its possible correlation with other prognostic parameters.


  Patients and methods Top


This is a case–control study that was conducted on adult de-novo acute leukemia patients who were recruited from Clinical Hematology Department, Ain Shams University Hospital (Cairo, Egypt) over the period from April 2017 to October 2018. Thirty newly diagnosed AML patients and 30 newly diagnosed ALL patients were chosen for the study (being diagnosed using standard clinical and surface marker criteria); besides 30 age-matched and sex-matched healthy controls were included in the study.

The study was in accordance with the ethical standards of the Ethics Committee of Faculty of Medicine, Ain Shams University, and with the 1975 Helsinki Declaration as revised in 1983. Informed consent was obtained from all individual participants included in the study.

The patients were divided into two subgroups:
  1. Group 1: (AML patients) included nine patients diagnosed as AML (M1-2); eight patients diagnosed as AML (M2); four patients diagnosed as AML (M3); three patients diagnosed as AML (M4); two patients diagnosed as AML (M4-5), and one patient diagnosed as AML (M0), (M1), (M5), and (M7).
    • Twenty-one (70%) patients received (3+7) chemotherapy protocol; four (13.3%) patients received (Pethema) chemotherapy protocol; two (6.7%) patients received (2+5) chemotherapy protocol and (subcutaneous ARAC) chemotherapy protocol; and one (3.3%) patient received oral (VePesid) chemotherapy protocol.
  2. Group 2: (ALL patients) included 21 patients diagnosed as pre-B-ALL and nine patients diagnosed as T-ALL. Twenty-one (80%) patients received (hyper-CVAD) chemotherapy protocol, three (10%) patients received (CALGB 10403) chemotherapy protocol; two (6.7%) patients received (Hoelzer) chemotherapy protocol; and one (3.3%) patient received Dana Farber chemotherapy protocol.


Exclusion criteria

Acute leukemia patients who received chemotherapy before the study and relapsed acute leukemia patients.

All participants underwent full history taking and thorough physical examination, complete blood picture, blood chemistry [including liver and kidney function tests, serum electrolytes, and lactate dehydrogenase (LDH)], bone marrow aspirate (for morphological assessment and FAB classification) and immunophenotyping by flowcytometry and conventional cytogenetic analysis and fluorescence in-situ hybridization, cerebrospinal fluid sampling and computed tomography scans in indicated conditions as well as serum IL-15 measurements by enzyme-linked immunosorbent assay.

Statistical methodology

Analysis of data was done by IBM computer using SPSS (USA, IBM 2009) (the Statistical Program for Social Sciences) version 20.0 as follows:
  1. Description of quantitative variables as mean, SD, range, median, and interquartile range.
  2. Description of qualitative variables as number and percentage.
  3. χ2-Test was used to compare qualitative variables between groups.
  4. Independent t-test was used to compare the means of two independent groups in order to determine whether there is statistical evidence that the associated population means are significantly different.
  5. Mann–Whitney test was used to compare difference between two independent groups when the dependent variables are not normally distributed.
  6. Pearson’s correlation coefficient (r) test was used for correlating data.
  7. Kruskal–Wallis test was used to determine if there are statistically significant difference between two or more groups of an independent variables.


P value greater than 0.05 was considered insignificant. P less than 0.05 was considered significant. P less than 0.01 was considered highly significant.


  Results Top


Both leukemia groups were compared with the control group as regards serum IL-15 level before starting treatment. Also, serum IL-15 level was correlated to patient’s survival and to other good and poor risk clinical and laboratory characteristics of the patients. Both acute leukemia groups had higher serum IL-15 level compared with controls with statistically significant difference (P=0.015, 0.010) for ALL and AML, respectively ([Table 1]). But there was no statistically significant difference between patients with AML and ALL as regards serum IL-15 level ([Table 2]).
Table 1 Comparison between each of acute leukemia groups with controls as regards serum interleukin-15 level (ng/l)

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Table 2 Comparison between patients with acute myeloid leukemia and acute lymphoblastic leukemia as regards serum interleukin-15 level

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ALL patients with high-risk cytogenetics had lower serum IL-15 level compared with those with non-high-risk cytogenetics with statistically significant difference (P=0.047). Also, AML patients with high-risk features had higher serum IL-15 level compared with those with low or intermediate risk features with statistically significant difference (P=0.048). Otherwise, there was no statistically significant correlation between serum IL-15 level on one hand and total leukocytic count and induction chemotherapy protocols on the other hand in both patients’ groups, as well as with risk stratification among ALL patients and high-risk cytogenetics among AML patients ([Table 3]).
Table 3 Correlation between serum interleukin-15 level and other clinical and laboratory characteristics of both acute leukemia patients

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Both acute leukemia patients with a high serum IL-15 level who achieved first complete response (CR) were less than those with average serum IL-15 level with statistically significant difference (P=0.038 in ALL, P=0.015 in AML). Both acute leukemia patients with high serum IL-15 level achieved minimal residual disease (MRD) negativity less than those with low or average serum IL-15 level with statistically highly significant difference (P=0.006 in ALL, P=0.002 in AML). There was no statistically significant correlation between serum IL-15 level and relapse rate in both acute leukemia patients ([Table 4]).
Table 4 Correlation between serum interleukin-15 level and disease response in both patient groups

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Both acute leukemia groups with high serum IL-15 level had shorter survival compared with those with average serum IL-15 level with statistically highly significant difference (P=0.005 in ALL, P<0.001 in AML) ([Table 5]).
Table 5 Correlation between serum interleukin-15 level and survival in both acute leukemia groups

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The optimal cutoff value for serum IL-15 in predicting patient survival in patients with ALL and AML was 200 and 190 ng/l, respectively, which indicated that patients with serum IL-15 level greater than 200 ng/l (for ALL) or 190 ng/l (for AML) had shorter survival compared with those with lower serum IL-15 level ([Table 6], [Figure 1] and [Figure 2]).
Table 6 Receiver operating characteristic curve for serum interleukin-15 level as a predictor of survival in both acute leukemia groups

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Figure 1 Receiver operating characteristic curve for serum interleukin-15 level as a predictor of survival in the acute lymphoblastic leukemia group.

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Figure 2 Receiver operating characteristic curve for serum interleukin-15 level as a predictor of survival in the acute myeloid leukemia group.

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Serum IL-15 level had highly significant negative correlation with the date of death of AML patients (P=0.001), while there was no statistically significant correlation between serum IL-15 level and serum LDH level or percentage of blasts cell in bone marrow in both acute leukemia groups ([Table 7], [Figure 3]).
Table 7 Comparison between acute myeloid leukemia and acute lymphoblastic leukemia patients as regards correlation between serum interleukin-15 level and clinical and laboratory features

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Figure 3 Correlation between serum interleukin-15 level in patients with acute myeloid leukemia and date of death.

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  Discussion Top


Hematopoietic homeostasis is dependent on the fine-tuned interaction of a number of growth factors that regulate the balance among cell growth, proliferation, differentiation, and apoptosis. In this process, cytokines are the key regulators produced by various cell types [13]. Cytokines and chemokines have both pathogenic and therapeutic implications in leukemia. Numerous studies have documented that leukemic blasts show abnormal degrees of responsiveness to cytokine stimulation and that leukemic blasts are often the source of cytokine production, potentially initiating or sustaining paracrine or autocrine loops [3].

IL-15 is a proinflammatory cytokine that promotes proliferation of T, B, and NK cells and induction of cytolytic effector cells. It plays an important role not only in immune system but also in the growth and survival of immature hematopoietic cells, which could be the reason for its role in the pathogenesis of leukemic cells [14].

ALL is considered to arise from genetic aberrations impairing normal differentiation of lymphatic cells at either the stem cell or an early lymphocyte precursor stage. Altered expression of cytokines and/or abnormal activation of cytokine receptors have been suggested to complement genetic aberrations in leukemogenesis, thus supporting the survival and proliferation of leukemic cells [6]. In AML patients, cytokines can be produced by both leukemic blasts and cells of the immune system and the role of cytokines in the pathogenesis of acute leukemia has not been fully clarified. Thus, aberrant cytokine signaling is a feature of leukemia that may contribute to proliferation, blast survival, resistance to chemotherapy and patients’ prognosis [15].

As regards patients with acute lymphoblastic leukemia

In our study, we found that ALL patients had statistically significant higher serum IL-15 level compared with controls (P=0.015). This is in agreement with Wenjian et al. [16] who showed that serum IL-15 level was much higher in adult patients with standard risk ALL compared with healthy volunteers (P<0.001).

Kovác et al. [17] showed that IL-15 concentration was higher in bone marrow cells in pediatric ALL patients compared with those patients who achieved CR and underwent bone marrow transplantation although this difference did not achieve statistical significance. Also, Aly et al. [6] found that rs10519612 CC, rs17007695 TC, and rs17007695 CC genotypes of IL-15 gene were significantly higher in ALL patients than in controls (P<0.028, 0.001, <0.001, respectively), taking into consideration that they were measuring IL-15 gene polymorphism in genomic DNA extracted from whole blood samples using PCR.

In the study conducted by Xiong et al. [1] data has own that serum IL-15 and IL-15Rα levels are elevated in adult T-cell leukemia (ATL) patients (P=0.042). Also Chen et al. [18] and Mishra et al. [19] have shown that IL-15 was elevated in patients with human large granular lymphocyte leukemia (P<0.0009). Asadullah et al. [20] have shown that IL-15 gene expression was significantly higher in skin biopsy cells from patients with cutaneous T-cell lymphomas compared with healthy participants (P<0.05) taking into consideration that they were measuring IL-15 gene expression in skin biopsy cells using PCR.

In our study, we found that ALL patients with high-risk cytogenetics had statistically significant lower serum IL-15 level compared with those with non-high-risk cytogenetics (P=0.047); this is in agreement with the study by Wu et al. [5] which showed that Ph-positive ALL patients had a lower expression of IL-15 gene in leukemic cells compared with patients with Ph-negative ALL (P<0.05).

Our study also showed that there was no statistically significant correlation between serum IL-15 level and total leukocytic count or risk stratification in ALL patients (P=0.572, 0.411, respectively); this is in agreement with Wu et al. [5] who showed that the level of IL-15 gene expression had no correlation with total leukocytic count at the time of diagnosis (P=0.449) taking into consideration that they measured IL-15 gene expression in leukemic cells using PCR.

In contrast to our findings as regards risk stratification, Asadullah et al [20] have shown that IL-15 gene expression was higher in patients with cutaneous T-cell lymphomas with advanced lesions (P<0.05), which are characterized by a higher density of malignant cells compared with those with early-stage disease suggesting that IL-15 gene expression might increase with advanced-stage disease.

In our study, we found that ALL patients with high serum IL-15 level who achieved statistically significant first CR were less than those with average serum IL-15 level (P=0.038). This is in agreement with Wenjian et al. [16] who found that patients with low serum IL-15 level achieved early CR on day 14 more than patients with high serum IL-15 (P=0.003).

Wang et al. [21] found that patients with extranodal NK/T cell lymphoma with higher serum IL-15 level had higher possibility of failure of CR after chemotherapy (P=0.001). Also Ullrich et al. [22] showed that pretreatment of Hodgkin lymphoma cell lines with recombinant IL-15 resulted in decreased drug-induced apoptosis by etoposide and doxorubicin (P<0.05, <0.01, respectively).

In our study, we also found that ALL patients with high serum IL-15 level achieved highly statistically significant MRD negativity less than those with average serum IL-15 level (P=0.006). This is in agreement with Yang et al. [23] who showed that higher IL-15 expression in ALL children was associated with an increased risk of positive MRD after induction chemotherapy (P=0.0342 in the St Jude cohort group and P=0.003 in Children’s Oncology Group cohort group) taking into consideration that they measured IL-15 gene expression in leukemic blasts using PCR.

Our study also showed that there was no statistically significant correlation between serum IL-15 level and relapse rate in ALL patients (P=0.157). This is in contrast to the study done by Wu et al. [5] who showed that a high level of IL-15 gene expression in leukemic cells of ALL patients was associated with inferior relapse-free survival at 5 years (P=0.008). This difference may be related to the small sample size and the use of a different method for detection of IL-15.

Cario et al. [24] have found that there was no difference between IL-15 gene expression levels between patients with bone marrow relapses and the patients who remained in long-term remission (P=0.384), while a significantly higher IL-15 gene expression was detected in the diagnostic samples of patients’ leukemic bone marrow cells of ALL patients with subsequent CNS relapse (P<0.001) although initially they did not have overt CNS disease taking into consideration that they were measuring IL-15 gene expression in leukemic cells in pediatric ALL patients using PCR.

When correlating serum IL-15 level to survival, we found that ALL patients with a high serum IL-15 level had highly statistically significant shorter survival compared with those with average serum IL-15 level (P=0.005). This is in agreement with Wenjian et al. [16] who showed that patients with low serum IL-15 level had a significantly higher survival rate compared with those with high serum IL-15 level (5-year event-free survival rate: 62.2 vs 23.3%, P<0.001; 5-year OS rate: 64.1 vs 27.7%, P=0.001).

In contrast to our findings, Wu et al. [5] have Shown that that the level of IL-15 gene expression in leukemic cells of ALL patients had no impact on OS (P=0.249). Also Aly et al. [6] found that the rs10519612 CC genotype and the rs17007695 TC and rs17007695 CC genotypes of IL-15 gene had no correlation with OS in patients with ALL (P=0.980, 0.570, 0.151). This difference may be related to the small sample size and the use of a different method for detection of IL-15.

In our study, we found that the optimal cutoff value for serum IL-15 in predicting patient survival in ALL patients was 200 ng/l, which indicates that patients with serum IL-15 level greater than 200 ng/l have shorter survival compared with those with serum IL-15 level less than 200 ng/l. This is in contrast to Wenjian et al. [16] who found that the optimal cutoff value for serum IL-15 in predicting patient survival in patients with standard risk ALL was 4.82 pg/ml (4.82 ng/l) with an area under the curve value of 0.808 (P<0.001), sensitivity 79.5%, and specificity 82.1%. This difference may be related to the small sample size and the use of a different study group.

In the present study, we found that in ALL patients, there was no statistically significant correlation between serum IL-15 level and date of death, LDH level, or percentage of blasts cell in the bone marrow (P=0.221, 0.696, 0.185, respectively). Wang et al. [21] found that serum IL-15 level was higher in patients with extranodal NK/T cell lymphoma with high LDH level (LDH >245 U/l) compared with those with low LDH level (P=0.002).

As regards patients with acute myeloid leukemia

In this study, we found that serum IL-15 was much higher in AML patients than the controls (P=0.010). These results are in agreement with the study of Sanchez-Correa et al. [25] which showed that the serum IL-15 level was significantly higher in AML patients compared with healthy donors (P<0.001). Kornblau et al. [3] also found that the mean expression of serum IL-15 was significantly higher than normal in AML patients (P<0.0018).

Meazza et al. [26] also showed that human recombinant IL-15 was able to prevent apoptosis and to induce long-term proliferation of AML cell lines.

In contrast to our finding as regards serum IL-15 level in patients with AML, Szczepanski et al. [27] have found that the plasma IL-15 level was low at diagnosis and increased after induction chemotherapy in AML patients (P<0.002). This difference may be related to the small sample size.

Tefferi et al. [28] also found a significantly higher level of serum IL-15 level in patients with primary myelofibrosis compared with controls (P=0.03). Pappa et al. [29] found that the serum level of IL-15 was higher in patients with multiple myeloma compared with controls (P<0.001).

In our study, we found that there was no statistically significant correlation between serum IL-15 level and total leukocytic count in AML patients (P=0.533), which is in agreement with Kornblau et al. [3] who showed that the serum level of IL-15 had no correlation with the total leukocytic count at the time of diagnosis (P>0.05).

We also found that there was no statistically significant correlation between serum IL-15 level and high-risk cytogenetics in AML patients (P=0.146), which is in agreement with Kornblau et al. [3] who showed that the serum level of IL-15 showed no correlation with high-risk cytogenetics at the time of diagnosis in AML patients (P>0.05).

Tefferi et al. [28] also found that there is no statistically significant correlation between serum IL-15 level and unfavorable karyotyping in patients with primary myelofibrosis (P=0.6).

Our study showed that AML patients with high-risk features had a higher serum IL-15 level compared with those with low or intermediate risk features with statistically significant difference (P=0.048).

Tefferi et al. [28] found that serum IL-15 levels in patients with primary myelofibrosis correlated with the Dynamic International Prognostic Scoring System stage but without reaching statistical significance (P=0.5). Also Pappa et al. [29] found that serum IL-15 levels in multiple myeloma stage III patients were elevated in comparison with stages I and II; the difference however, did not reach statistical significance (P>0.05).

In our study, we observed that AML patients with high serum IL-15 level achieved statistically significant first CR less than those with average serum IL-15 level (P=0.015). Tinhofer et al. [30] found that autocrine IL-15 protected myeloma cell lines from death following treatment with Fas-triggering chemotherapeutic drugs (vincristine or doxorubicin) (P=0.004).

Our study also showed that AML patients with high serum IL-15 level achieved highly statistically significant MRD negativity less than those with average serum IL-15 level (P=0.002). Yang et al. [23] showed that higher IL-15 expression in ALL children was associated with an increased risk of positive MRD after induction chemotherapy (P=0.0342 in the St Jude cohort group and P=0.003 in Children’s Oncology Group cohort group) taking into consideration that they were measuring IL-15 gene expression in leukemic blasts using PCR.

We also found that there was no statistically significant correlation between serum IL-15 level and relapse rate in AML patients (P=0.505). Cario et al. [24] found that there is no difference in IL-15 gene expression levels between patients with bone marrow relapses and the patients who remained in long-term remission (P=0.384), while a significantly higher IL-15 gene expression was detected in the diagnostic samples of patients’ leukemic bone marrow cells of ALL patients with subsequent CNS relapse (P<0.001) although initially they did not have overt CNS disease taking into consideration that they measured IL-15 gene expression in leukemic cells in pediatric ALL patients using PCR.

Our study showed that AML patients with high serum IL-15 levels had highly statistically significant shorter survival compared with those with low or average serum IL-15 level (P<0.001); this is in contrast to the study by Kornblau et al. [3] which showed that there was no correlation between serum IL-15 level and survival in AML patients (P>0.05). This difference may be related to the small sample size. Tefferi et al. [28] found that in treatment-naive patients with primary myelofibrosis increased serum level of IL-15 was predictive of inferior survival (P=0.001).

In our study, we found that the optimal cutoff value for serum IL-15 in predicting patient survival in AML patients was 190 ng/l, which indicates that patients with serum IL-15 level greater than 190 ng/l have shorter survival compared with those with serum IL-15 level less than 190 ng/l. Wang et al. [21] found that the optimal cutoff value for serum IL-15 in predicting patient survival in patients with extranodal NK/T-cell lymphoma was 3.94 pg/ml (3.94 ng/l) with an area under the curve value of 0.776 (P<0.001), sensitivity of 74.4%, and specificity of 72.6%.

In this study, we reported that there was no statistically significant difference between patients with ALL and AML as regards serum IL-15 level (P=0.876).

Also in our study, we reported that the serum IL-15 level has highly statistically significant negative correlation with the date of death (P=0.001). We also found that there was no statistically significant correlation between serum IL-15 level and serum LDH level or percentage of blast cells in the bone marrow (P=0.731, 0.111, respectively). Tefferi et al. [28] found that there is no statistically significant correlation between serum IL-15 level and circulating blast percentage in the peripheral blood in patients with primary myelofibrosis (P=0.4).

Conclusion and recommendations

We concluded that serum IL-15 at diagnosis can be used as a prognostic marker in patients with acute leukemia as it positively correlated with other important prognostic markers such as cytogenetics and high-risk features. Also, serum IL-15 at diagnosis can be used as an indicator of survival and predictor of disease response in patients with acute leukemia.

So, we propose that further studies with a larger sample size are needed to confirm the significance of serum IL-15 levels in patients with acute leukemia. Moreover, interventional trials using anti-IL-15 monoclonal antibody are needed to confirm the potential therapeutic role of anti-IL-15 monoclonal antibody in acute leukemia.

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]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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