|Year : 2017 | Volume
| Issue : 2 | Page : 120-123
Chronic myeloid leukemia and ferritin levels
Kumar Saurabh, Veena Singh Ghalaut, Jyoti Bala
Department of Biochemistry, Pt. B.D. Sharma PGIMS, Rohtak, Haryana, India
|Date of Web Publication||23-Nov-2017|
D-2, New Bharat Nagar, Bhiwani, Haryana
Source of Support: None, Conflict of Interest: None
Background: Ferritin is a positive acute-phase reactant, exhibiting increased levels in blood during the acute-phase response. High plasma ferritin levels have been reported for various types of cancers, irrespective of the amount of total body iron. Hence, this study was designed to assess the status of ferritin levels in chronic myeloid leukemia (CML) patients both before and after chemotherapy and to compare them with age- and sex-matched healthy controls. Methods: Thirty patients of CML after confirmed diagnosis were taken up for the study. CML patients were treated by imatinib therapy. Serum ferritin was estimated by enzyme-linked immunosorbent assay in thirty newly diagnosed CML patients and in thirty age- and sex-matched healthy controls. The test was repeated at first complete remission or at 3 months (whichever is earlier) in CML patients. Patients and controls were categorized into three groups as follows: (1) Group I: Control group –age- and sex-matched healthy volunteers (2) Group II: CML patients at the time of diagnosis (before imatinib therapy) (3) Group III: CML patients at first complete remission or at 3 months of imatinib therapy (whichever is earlier). Results: The ferritin levels were significantly increased in Group II and Group III (387.68 ± 221.61 ng/mL and 295.43 ± 169.17 ng/mL, respectively) as compared to controls (73.27 ± 60.82 ng/mL) (P = 0.000 and P = 0.000, respectively). The ferritin levels were decreased in Group III as compared to Group II, although the difference was not statistically significant (P = 0.075). Conclusion: Our study revealed that serum ferritin could be a useful marker in determining disease progression or monitor the effectiveness of treatment in leukemic patients.
Keywords: Chronic myeloid leukemia, ferritin, imatinib, remission
|How to cite this article:|
Saurabh K, Ghalaut VS, Bala J. Chronic myeloid leukemia and ferritin levels. Biomed Biotechnol Res J 2017;1:120-3
| Introduction|| |
Chronic myeloid leukemia (CML) is the most common adult leukemia in India, and the annual incidence ranges from 0.8 to 2.2/100,000 population in males and 0.6 to 1.6/100,000 population in females. Though CML is predominantly a disease affecting adults, a minority of patients are children and young adults. The median age of diagnosis is 38–40 years in India which is a decade earlier than the median incidence in the Western world. CML is a pluripotent stem cell disease characterized by anemia, extreme blood granulocytosis and granulocytic immaturity, basophilia, often thrombocytosis, and splenomegaly. In CML, a single cell produces clone in which there is an enormous expansion of progenitors for granulocytic and often megakaryocytic cells. The hematopoietic cells contain a reciprocal translocation between chromosomes 9 and 22 in >95% of patients referred to as the Philadelphia chromosome. The fusion gene encodes a constitutively active tyrosine kinase (TK) (BCR-ABL) responsible for initiation and maintenance of the chronic phase of CML.,
Treatment includes Imatinib mesylate (Gleevec®) which functions through competitive inhibition at the adenosine triphosphate (ATP)-binding site of ABL kinase in the inactive conformation, which leads to inhibition of tyrosine phosphorylation of proteins involved in BCR-ABL signal transduction. It shows specificity for BCR-ABL, the receptor for platelet-derived growth factor (PDGF) and TK. The efficacy of imatinib is judged by measuring the three benchmarks: hematological response, cytogenetic response, and molecular response.
Ferritin is a positive acute-phase reactant, exhibiting increased levels in blood during the acute-phase response. It protects the cell from iron-mediated redox reactions by causing intracellular iron sequestration and its storage in nontoxic soluble form. Ferritin has been found in most human tissues and its principal locations are liver, spleen, and bone marrow, with the lesser quantities found in heart, small intestine, placenta, kidney, skeletal muscle, and cancer cells. Ferritin and iron homeostasis have role in the pathogenesis of many diseases including disease involved in iron absorption, transport, and storage, atherosclerosis, cancer, liver disease, renal disease, neuropsychiatric disorders, and diabetes. Ferritin can modulate many immune functions, plays a role in pro- and anti-apoptotic pathways, and implicated in the pathology of cancer. Many factors have been suggested to contribute to the hyperferritinemia associated with cancer including inflammation, hepatic necrosis due to metastasis and chemotherapy, blood transfusions, and a decrease in hepatic clearance of ferritin.
Aulbert and Schmidt investigated different types of leukemias and found that serum ferritin can be used as a tumor marker in myeloid leukemia. Extremely high serum ferritin levels were seen in acute myeloid leukemia (AML) patients before treatment and in blast crisis of CML (i.e., 21-fold increased serum ferritin concentrations). In patients with CML during the chronic-phase, normal serum ferritin concentrations were observed, whereas blast crisis was associated with highly raised serum ferritin levels. They concluded that serum ferritin concentration must be valued as a clinically useful tumor marker in these types of leukemias, exhibiting a helpful and simple parameter in monitoring the activity of the disease. In contrast to our results, Akanni et al. in their study reported significantly decreased mean serum ferritin levels in CML patients as compared to healthy age- and sex-matched controls.
Conflicting data are available regarding ferritin status in CML patients, and chemotherapy response on ferritin levels is not clear in these patients. With such a background, this study was designed to assess the status of ferritin levels in CML patients both before and after chemotherapy and to compare them with age- and sex-matched healthy controls.
| Methods|| |
The present study was conducted in the Department of Biochemistry, in collaboration with the Department of Medicine (Clinical Hematology Unit), Pt. B. D. Sharma, Post Graduate Institute of Medical Sciences, Rohtak. Thirty patients of CML were taken up for the study. The diagnosis was made by history taking, clinical examination, total and differential leukocyte count, bone marrow examination, and cytogenetic studies. CML patients were treated by imatinib therapy.
Serum ferritin levels were estimated in newly diagnosed thirty CML patients and in thirty age- and sex-matched healthy controls. The tests were repeated at first complete remission or at 3 months (whichever is earlier) in CML patients. Complete history taking and physical examination with anthropometry were done in controls and cases (before and after treatment). Serum ferritin was estimated by enzyme-linked immunosorbent assay.
Patients and controls were categorized into three groups:
- Group I: Control group – age- and sex-matched healthy volunteers
- Group II: CML patients at the time of diagnosis (before imatinib therapy)
- Group III: CML patients at first complete remission or at 3 months of imatinib therapy (whichever is earlier).
| Results|| |
- The ferritin levels were significantly increased in Group II and Group III (387.68 ± 221.61 ng/mL and 295.43 ± 169.17 ng/mL, respectively) as compared to controls (73.27 ± 60.82 ng/mL) (P = 0.000 and P = 0.000, respectively). The ferritin levels were decreased in Group III as compared to Group II, although the difference was not statistically significant (P=0.075, [Table 1] and [Figure 1])
- Seventeen male patients (80.95%) and 6 female patients (66.67%) achieved remission at 3 months of induction of chemotherapy while 4 male patients (19.0%) and 3 female patients (33.33%) failed to achieve remission [Table 2] and [Figure 2].
|Table 1: Mean ferritin levels in controls and chronic myeloid leukemic patients|
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|Figure 1: Ferritin levels in controls and chronic myeloid leukemic patients|
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| Discussion|| |
In the present study, ferritin levels were significantly increased in CML patients both before and after chemotherapy as compared with controls.
Studies have reported significantly higher serum ferritin concentration in patients with newly diagnosed hematologic malignancies as compared to control group. Serum ferritin levels in untreated patient group and remission group were significantly higher than that of control group. The level of serum ferritin in patients who achieved complete remission after chemotherapy decreased significantly, but was slightly higher than that of normal controls. The reason may be attributed to the fact that few residual cancerous cells exist even when complete remission was achieved, indicating a positive correlation between serum ferritin and tumor burden. An experiment by Chen et al. suggested that iron overload may boost the growth of leukemia cell by inhibiting apoptosis.
Raised serum ferritin levels in leukemia patients occur mainly because of increased capacity of ferritin synthesis by myelogenous cells, resulting in increased circulating ferritin concentration. During remission phase, ferritin concentration decreased but was still higher than controls. It has been observed that increased circulating ferritin concentration during chemotherapy is because of ferritin released from damaged cells. Although raised ferritin concentrations have been reported in newly diagnosed as well as relapse patients with AML, data on CML patients are very scarce. Many factors have been suggested to contribute to the hyperferritinemia associated with cancer, including inflammation, hepatic necrosis due to metastasis or chemotherapy, blood transfusions, and a decrease in hepatic clearance of ferritin.
Asian men had a 69 ng/mL (155 pmol/L) higher adjusted mean serum ferritin level (P < 0.001) and Asian women had 23 ng/mL (52 pmol/L) higher adjusted mean ferritin level (P < 0.001).
Proteolytic cleavage of high molecular weight kininogen (HK) produces two molecules: bradykinin, a potent peptide hormone that mediates nitric oxide release, vasodilation, and pain and 2-chain high-molecular-weight kininogen, Kallikrein cleaved HK (HKa). This locally produced HKa may recruit ferritin from the circulation or adjacent cellular sources to the endothelial cell surface, making ferritin an effective inhibitor of this reaction even at low serum ferritin concentrations. Thus, ferritin, which is elevated during inflammation and malignancy by antagonizing the antiangiogenic effects of HKa, may allow the pro-angiogenic effects of bradykinin and other biologically active pro-angiogenic molecules to predominate, thus shifting the balance toward angiogenesis.
Ferritin is also modulated by cytokines, such as tumor necrosis factor-alpha (TNF-α) and interferon-1, during inflammation. CXCR4-mediated ferritin nuclear translocation may play a role in the receptor-mediated tumor growth. The inhibitory role of ferritin heavy chain (FHC) in chemokine-initiated ERK1/2 activation is underway. Stimulation of chemokine receptors predominantly activates the ERK1/2 pathway which plays an important role in cell survival, whereas stimulation by TNF-α or several other cytokines predominantly activates the c-Jun N-terminal kinase pathway which is involved in cell apoptosis. This suggests that ferritin plays a critical role in controlling the balance between cell survival and cell death.
In contrast to our results, Akanni et al. in their study reported significantly decreased mean serum ferritin levels in CML patients as compared to healthy age- and sex-matched controls. The results of their study were agreed by other researchers also, where a significant difference was seen in advanced carcinoma of breast, ovaries, lungs, and esophagus.
Aulbert and Schmidt assessed ferritin levels in different types of leukemias and found that serum ferritin can be used as a tumor marker in myeloid leukemia. Serum ferritin levels in patients with hematologic malignancies at early and recurrent stages are significantly increased. The detection and surveillance of changes of serum ferritin could be helpful for assessing conditions and prognosis of these patients.
Extremely high serum ferritin levels were seen in blast crisis of CML (i.e., 21-fold increased serum ferritin concentrations) by Zhang et al. In patients with CML during the chronic phase, normal serum ferritin concentrations were observed, whereas blast crisis was associated with highly raised serum ferritin levels. They concluded that serum ferritin concentration must be valued as a clinically useful tumor marker in these types of leukemia, exhibiting a helpful and simple parameter in monitoring the activity of the disease.
| Conclusion|| |
Findings of the present study revealed that serum ferritin could be a useful marker in determining disease progression or monitor the effectiveness of treatment in leukemic patients as increased levels are seen in CML cases both before and after chemotherapy as compared with their age-matched healthy controls.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]