|Year : 2015 | Volume
| Issue : 1 | Page : 30-36
Basophil progenitor marker histamine and its relation to the treatment response in Egyptian chronic myeloid leukemia patients
Amro M El-Ghammaz MD 1, Gehan M Hamed2, Mona F Abdel Fattah2, Mohamed H Attia1
1 Hematology and Bone Marrow Transplantation Unit, Internal Medicine Department, Ain Shams University, Cairo, Egypt
2 Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||01-Dec-2014|
|Date of Acceptance||03-Dec-2014|
|Date of Web Publication||24-Apr-2015|
Amro M El-Ghammaz
37 Mohamed Korayem Street, Nasr City, Cairo
Source of Support: None, Conflict of Interest: None
Introduction Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL fusion gene with constitutive tyrosine kinase activity that activates many signaling pathways contributing to the abnormal growth and survival of leukemic cells. Basophilia is a strong independent prognostic variable that correlates with the phase of CML. In CML, basophils are difficult to be identified by their morphology due to their immaturity or low frequency by tyrosine kinase inhibitors (TKIs) therapy. It is important to predict responses to therapy and to monitor levels of minimal residual disease in CML patients by cytogenetics and PCR. However, these parameters are expensive and require special technologies. Thus, the aim of the current study was to clarify whether the serum level of the basophil-marker histamine correlates with hematologic, cytogenetic, and molecular responses in CML patients and with the achievement of the optimal response to TKI therapy.
Patients and methods The histamine level was measured by enzyme-linked immunosorbent assay in 48 CML patients, together with cytogenetic analysis at diagnosis and after 6 months from the start of imatinib treatment. Molecular study of BCR-ABL was also performed at 6 months.
Results Histamine levels were upregulated in CML patients at diagnosis compared with the healthy control group and correlated with the total leukocytic count, the absolute peripheral blood basophil count, and the percent of bone marrow basophils. After 6 months of imatinib treatment, histamine levels were significantly reduced in CML patients compared with the levels at diagnosis and were still significantly higher than in controls. Histamine levels at 6 months correlated significantly with PCR measurements for BCR-ABL. A significant difference in histamine levels was found between patients according to their hematological, cytogenetic, and molecular responses. Also, it differed significantly among TKI response groups (optimal, warning, failure).
Conclusion We found that the serum histamine level may serve as a cheap early predictor of cytogenetic and molecular remission as well as the response to imatinib. However, we could not encourage measuring serum histamine as an alternative to PCR for BCR-ABL for the monitoring of minimal residual disease.
Keywords: chronic myeloid leukemia, histamine, imatinib
|How to cite this article:|
El-Ghammaz AM, Hamed GM, Abdel Fattah MF, Attia MH. Basophil progenitor marker histamine and its relation to the treatment response in Egyptian chronic myeloid leukemia patients. Egypt J Haematol 2015;40:30-6
|How to cite this URL:|
El-Ghammaz AM, Hamed GM, Abdel Fattah MF, Attia MH. Basophil progenitor marker histamine and its relation to the treatment response in Egyptian chronic myeloid leukemia patients. Egypt J Haematol [serial online] 2015 [cited 2020 Feb 20];40:30-6. Available from: http://www.ehj.eg.net/text.asp?2015/40/1/30/155793
| Introduction|| |
The major BCR-ABL fusion gene is recognized as the hallmark of chronic myeloid leukemia (CML) and presumably as the cause of its development. The oncogenic protein tyrosine kinase, in turn, is responsible for the leukemia phenotype through the constitutive activation of multiple signaling pathways involved in the cell cycle and in adhesion and apoptosis , .
A number of prognostic factors correlate with the phase of CML and are indicative of a poor survival. Among them are the blast count, basophilia, cytopenia, and additional chromosomal defects indicating clonal evolution ,,,,,, . Basophilia is invariably found in all patients. In fact, a number of clinical studies have shown that basophilia is an independent adverse prognostic variable in patients with CML ,,,, . However, depending on the disease phase, basophils may be quite immature and thus difficult to identify by morphology  . In addition, it is often impossible to quantify basophils during imatinib treatment because of their low frequency. The application of basophil markers may be helpful in this regard. Of particular interest are markers expressed at all stages of basophilopoiesis such as histamine  . Histamine is an essential mediator and marker of basophils and their progenitors, and it is highly upregulated in CML ,, . Studies performed on basophil progenitors in healthy individuals and in patients with CML suggest that the production of histamine is an early event in basophil development. Thus, even the most immature basophil progenitor cells express histamine , . Therefore, histamine has been considered as a useful marker to determine basophil lineage involvement , . Other studies have shown that histamine is a potential regulator of growth and differentiation of myeloid progenitor cells , .
In order to best determine an individual's response to tyrosine kinase inhibitors (TKIs), an operational set of goals, defined within specific time periods, have been established for all patients , . An initial requirement is the achievement of a complete hematological response (CHR). Further response to treatment is subsequently monitored by sequential cytogenetic assessments of the bone marrow (BM) with the aim to achieve a complete cytogenetic response (CCgR). Subsequent evaluation of the therapeutic response is recommended by means of a molecular analysis, with reverse transcriptase PCR (RT-PCR). Patients that achieve a major molecular response (MMolR) are predicted to have a remarkably low risk of disease progression  . A number of patients still do not succeed in obtaining a CHR, 20-25% do not achieve a CCgR  , and fewer than 10% of the patients achieve MMolR  . Definitions of optimal, warning, and failure of response needed to be determined and are now well recognized  .
Currently, RT-PCR is the most sensitive method for detecting low numbers of BCR-ABL transcripts in a patient, but it still has some drawbacks  . For example, loss of CHR or a cytogenetic response have clear implications; however, loss of MMolR within the context of a sustained CCgR allows for less precise interpretation, in part because of a lack of standardization of RT-PCR assays, and that any increment in transcript number should be confirmed by serial analysis  . Also, interpretation of RT-PCR results might theoretically be confounded by the fact that BCR-ABL transcripts can be detected at a very low level in the blood of many normal persons, the majority of whom will never have CML ,, . It remains important to rationalize these data in order to improve the monitoring of minimal residual disease (MRD) by developing more precise techniques and research for more specific markers of cure.
The aim of the current study was to investigate whether the serum level of the basophil marker histamine in CML patients may serve as an independent early predictor of cytogenetic and molecular remissions and to clarify whether it correlates with the achievement of an optimal response to TKI therapy.
| Patients and methods|| |
The study group
A total of 48 Egyptian CML patients were included in this study. They were diagnosed, treated, and followed up at the Hematology and Bone Marrow Transplantation Unit of Ain Shams University Hospitals. All patients signed an informed consent at the time of study entry. They were subjected at diagnosis to detailed history taking, a thorough physical examination, complete blood count, blood film emphasizing on percents and absolute counts of peripheral blood (PB) basophils and blasts, BM aspiration and examination for the disease phase, and the percentage of BM basophils and blasts. WHO criteria (2008) were used to define the phase of the disease: chronic phase (CP), accelerated phase (AP), and blast phase (BP)  . Patients also underwent BM karyotyping and BM fluorescent in-situ hybridization to determine the percentage of Philadelphia-positive cells at diagnosis.
Measurement of histamine levels at diagnosis and at the sixth month
The histamine level was measured in all enrolled patients at diagnosis and at the sixth month. These were compared with histamine serum levels in 24 age-matched and sex-matched controls. Histamine was quantitatively measured in plasma using the Histamine ELISA kit LDN (Labor Diagnostika Nord GmbH & Co. KG, Nordhorn, Germany).
First, histamine was quantitatively acylated, followed by the subsequent use of a competitive enzyme-linked immunosorbent assay kit using the microtiter plate format to which the antigen is bound. Acylated standards, controls, and samples and the solid phase-bound analyte competed for a fixed number of antiserum-binding sites. After the system is in equilibrium, free antigen and free antigen-antiserum complexes were removed by washing. The antibody bound to the solid phase was detected by an anti-rabbit IgG-peroxidase conjugate using tetramethyl benzidine as a substrate. The reaction was monitored at 450 nm. Quantification of unknown samples was achieved by comparing their absorbance with a reference curve prepared with known standard concentrations. The expected reference range in the plasma was less than 1 ng/ml; the analytical sensitivity of the test was 0.12 ng/ml. The intra-assay reproducibility of the test showed a coefficient of variation of 5.6% and the interassay reproducibility showed a coefficient of variation of 6.3%.
The treatment strategy
All patients received initial cytoreduction with hydroxyurea. Patients were shifted to imatinib mesylate 400 mg/day after the appearance of cytogenetic results. During follow-up, the imatinib dose was reduced to 300 mg/day because of cytopenia in selected cases (n = 2, 4.2%).
Evaluation of response at the sixth month
Complete blood count and blood film performed at the sixth month were used to assess the achievement of a hematological response. Double-fusion fluorescent in-situ hybridization was applied on BM samples with the determination of the percent of residual Philadelphia-positive cells to detect the cytogenetic response. The molecular response was detected by measuring the percentage of BCR-ABL transcript relative to c-ABL as an internal reference-gene. BCR-ABL was quantified by real time-PCR with Light Cycler-technology (Roche, Berlin, Germany)  . European Leukemia Net recommendations were used to define hematological, cytogenetic, and molecular responses  , as well as optimal, warning, and failure of response at 6 months ([Table 1])  .
|Table 1 Response definitions for first-line imatinib at baseline and at 6 months|
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Descriptive statistical analysis of the main characteristics of the patients and controls was performed (mean, SD, range, number, and percentage). The unpaired t-test and the one-way analysis of variance test were used for the comparison of continuous variables in different groups. The paired t-test was used to compare quantitative variables in the same group. Correlations between the histamine level and various measured parameters were calculated by the Spearman correlation. All P values were two-sided and were considered to be significant when less than 0.05. Statistical analyses were carried out in SPSS 13.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
Consent was obtained from all subjects. The study was approved by the Ethical Committee of Faculty of Medicine of Ain Shams University.
| Results|| |
Baseline characteristics of the 48 studied patients are summarized in [Table 2]. Twenty-eight (58.3%) patients were younger than 45 years and 20 (41.7%) were older. The male-to-female ratio was 21/27 (males = 43.8%). About 42 (87.5%) patients were in CP, whereas six (12.5%) patients were in AP/BP. Four (8.3%) patients had abnormal Philadelphia clone ([Table 3]).
The histamine level in patients and controls at diagnosis
The mean histamine level at diagnosis was significantly higher in CML patients (5.5 ± 2.7 ng/ml, range = 2-13) compared with the normal control group (1.3 ± 0.9 ng/ml, range = 0.28-4) (P < 0.001) as shown in [Figure 1]a.
|Figure 1 A comparison of histamine levels (a) between chronic myeloid leukemia (CML) patients and controls at diagnosis (P < 0.001), (b) between CML patients at diagnosis and at the sixth month (P < 0.001), and (c) between CML patients and controls at the sixth month (P < 0.001).|
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Comparison of the histamine level at diagnosis among patient groups
There was no significant difference in the initial histamine levels among CML patients with regard to their age, sex, phase of disease, or the presence of clonal cytogenetic abnormalities as shown in [Table 4].
|Table 4 Comparison of histamine levels at baseline and at the sixth month among the patient groups|
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Correlation of the histamine level at diagnosis with other disease parameters
The histamine level at diagnosis correlated significantly with the initial total leukocytic count (TLC) (r = 0.473; P = 0.001), the absolute PB basophil count (r = 0.505; P < 0.001), and the percent of BM basophils (r = 0.381; P = 0.008). There was no correlation between histamine levels at diagnosis and initial hemoglobin (P = 0.946), initial platelets (P = 0.444), the percent of PB basophils (P = 0.140), the absolute blast count in PB (P = 0.324), and the percent of PB (P = 0.257) or BM blasts (P = 0.225).
Patients' response to treatment at the sixth month
At the sixth month, the mean TLC was 24.1 ± 57 × 10 9 /l (range = 2.7-260), the mean hemoglobin was 11 ± 1.46 g/dl (range = 6.1-14), and the mean platelet count was 250.3 ± 135.2 ×10 9 /l (range = 96-870). Out of the 48 patients enrolled in this study, 45 (93.8%) patients were in CP, whereas three (6.2%) patients were in AP/BP after 6 months. Eleven (22.9%) patients did not achieve CHR, whereas 37 (77.1%) patients achieved CHR. Regarding the cytogenetic response, nine (18.8%) patients achieved CCgR, eight (16.7%) patients achieved partial cytogenetic response (PCgR), eight (16.7%) patients achieved minor cytogenetic response, 13 (27.1%) patients achieved minimal cytogenetic response, and 10 (20.8%) patients achieved no cytogenetic response. Regarding the molecular response, MMolR was achieved only in eight (16.7%) patients, whereas the remaining 40 (83.3%) patients did not achieve MMolR or complete molecular response. Regarding the response to first-line imatinib, eight (16.7%) patients had optimal response, seven (14.6%) had warning response, and 33 (68.8%) had failure of response.
Histamine levels in patients and controls at 6 months
The mean histamine level in CML patients at the sixth month was 3.5 ± 1.6 ng/ml (range = 1-8.5), which was significantly lower than that at diagnosis (P < 0.001) ([Figure 1]b). The mean histamine level in CML patients at 6 months was also significantly higher than that in controls (P < 0.001) ([Figure 1]c).
Comparison of the histamine level at 6 months among patient groups
There was no significant difference among patients younger and older than 45 years, among male and female patients, and among patients in CP and those in AP/BP at the sixth month. In contrast, patients with clonal cytogenetic abnormalities had a significantly higher mean histamine level at the sixth month compared with those lacking them (P = 0.006) ([Table 4]).
Correlation of the histamine level at 6 months with other disease parameters
The histamine level at 6 months correlated significantly with the sixth month PCR for BCR-ABL (r = 0.487; P < 0.001). The sixth-month histamine level did not correlate significantly with TLC (P = 0.124), hemoglobin (P = 0.767), and platelets (P = 0.075).
Comparison of histamine levels at 6 months among remission and response groups
Mean histamine levels at 6 months differed significantly among patients with and without CHR (3.2 ± 1.3 vs. 4.3 ± 2.2 ng/ml, respectively; P = 0.043) ([Figure 2]a). They also differed significantly among patients with CCgR (2.1 ± 0.7 ng/ml), PCgR (3.2 ± 1.1 ng/ml), minor cytogenetic response (3.6 ± 1.5 ng/ml), minimal cytogenetic response (3.8 ± 1.3 ng/ml), and no cytogenetic response (4.5 ± 2.2 ng/ml) (P = 0.021) ([Figure 2]b) and among patients with MMolR and no molecular response (2.1 ± 0.7 vs. 3.7 ± 1.6 ng/ml, respectively; P = 0.006) ([Figure 2]c). It also differed significantly among TKI response groups (optimal, warning, failure) (2.1 ± 0.7 vs. 2.9 ± 1.2 vs. 3.9 ± 1.6 ng/ml, respectively; P = 0.007) ([Figure 3]).
|Figure 2 A comparison of histamine levels at the sixth month (a) between chronic myeloid leukemia (CML) patients who achieved and did not achieve complete hematological response (CHR) (P = 0.043), (b) between CML patients with complete cytogenetic response (CCgR), partial cytogenetic response (PCgR), minor cytogenetic response (mCgR), minimal cytogenetic response (minCgR), and no cytogenetic response (noCgR) (P = 0.021), and (c) between CML patients with major molecular response (MMolR) and no molecular response (P = 0.006).|
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|Figure 3 A comparison of histamine levels at the sixth month between chronic myeloid leukemia (CML) patients who achieved optimal, warning, and failure response to tyrosine kinase inhibitors (TKIs) (P = 0.007).|
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| Discussion|| |
Histamine is a specific product of basophils and is highly upregulated in CML , . Histidine decarboxylase (HDC) is the key enzyme involved in histamine generation. This enzyme is expressed in basophil-committed progenitors and in mature basophils. Interleukin-3, a major differentiation factor for basophils, has been reported to induce the expression of HDC and thus the synthesis of histamine in myeloid progenitors  . In CML cells, BCR-ABL induces the expression of HDC and, in turn, the synthesis of histamine. In line with this observation, imatinib was found to counteract BCR-ABL-induced expression of HDC and synthesis of histamine  . Also, rare patients with high basophil counts (>20%) have developed urticarial eruptions after taking imatinib, presumably because of the histamine release from basophils  .
In this study, we tried to determine the significance of measuring the serum histamine level in CML patients treated with TKIs. Our results regarding the comparison of the histamine level in patients and controls at diagnosis are in agreement with those of Agis et al.  , who showed significantly higher levels in patients than in controls. Also, the baseline levels were significantly higher in AP/BP patients than in CP patients in that study  . This was also found in our study, but the increase was not significant. This difference can be attributed to the lower frequency of patients in AP/BP in our study (12.5 vs. 22.5%). Moreover, the authors found a good correlation between baseline histamine levels and absolute numbers of basophils  , which was also found in our study together with the correlation with the initial TLC and the percent of BM basophils.
Despite the fact that Agis et al.  were not able to demonstrate significant correlations between histamine and BCR-ABL at the sixth month, the histamine level at the sixth month correlated significantly with the sixth month PCR for BCR-ABL in our study. This difference can be attributed to the serial performance of PCR for BCR-ABL from the third to the 24th month in the other study  , whereas it was performed once at the sixth month in our study, which in turn suggests cautious interpretation of our results. Also, about 55% of the patients receiving imatinib in that study were pretreated with interferon-α and/or stem cell transplantation, which may have influenced their histamine and PCR values  . Hence, we disagree with those authors regarding considering the histamine level as an additional MRD parameter.
Agis et al.  also performed a comparison of histamine levels between patients achieving and not achieving CCgR at 3-month intervals starting from the third to the 24th month, and the comparison was significant at the sixth and the 12th months. As patients achieving either a CCgR or a PCgR have a significantly better 5-year progression free survival, event free survival and overall survival  , we preferred to compare sixth-month histamine levels between all remission groups defined by the European Leukemia Net  , and we found a significant difference between groups. Both studies showed a significant difference in histamine levels between patients who achieved and who did not achieve MMolR at the sixth month.
To our knowledge, this is the first report comparing histamine levels among TKI response groups. Histamine levels differed significantly among patients with optimal, warning, and failure of response. These findings point to the possibility of using histamine as a marker for tracking cytogenetic and molecular remissions in CML patients and for the early detection of warning or failure of response to TKIs. However, further assessments of remission and response were needed at 12 months and later as a gain or loss of remission, and response may occur eventually  . Also, we did not study histamine levels in patients who have or lack BCR-ABL1 mutations, which are major causes for treatment failure and progression. The presence of imatinib-resistant BCR-ABL1 kinase domain mutations may necessitate changing the therapy  . Other studies focusing on these points are further needed.
| Conclusion|| |
We found that the serum histamine level may serve as a cheap early predictor of cytogenetic and molecular remission and of optimal, warning, and failure of response in CML patients treated by imatinib. However, we could not encourage measuring serum histamine as an alternative to PCR for BCR-ABL for the monitoring of MRD.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]