|Year : 2014 | Volume
| Issue : 2 | Page : 305-308
Utility of the trough plasma imatinib level monitoring at two time points in patients with the chronic myeloid leukemia-chronic phase
Sanjeev Kumar Sharma1, Suman Kumar1, AR Vijayakumar2, Tulika Seth1, Pravas Mishra1, Manoranjan Mahapatra1, Sudha Sazawal1, T Velpandian2, Renu Saxena1
1 Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Ocular Pharmacology and Pharmacy, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||14-Jul-2014|
Department of Hematology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Introduction: Plasma imatinib levels vary widely in patients with the chronic myeloid leukemia-chronic phase, and studies have shown improved hematological, cytogenetic, and molecular responses in patients with the higher trough imatinib levels.
Materials and Methods: We analyzed 50 consecutive patients with the chronic myeloid leukemia-chronic phase and performed plasma imatinib levels at 1 month and 12 months and correlated them with complete hematological response at 3 months and molecular response at 12 months, respectively.
Results: Trough plasma imatinib levels at 1 month correlated well with complete hematological response at 3 months (P = 0.007) and levels at 12 months correlated with molecular response at 12 months (P = 0.04). Compliance to imatinib also significantly correlated with imatinib levels at 1 month (P = 0.0008) and imatinib levels at 12 months (P = 0.0002).
Conclusion: Plasma imatinib levels may be of benefit in patients not achieving desired response at defined time intervals. The plasma level monitoring also helps in the assessment of drug compliance.
结果：血浆波谷伊马替尼水平在1个月与3个月完全血液学反应相关性很高（P = 0.007），12个月水平与12个月的分子反应水平相关性也极好（P = 0.04）。依从性与伊马替尼水平相关性也极好，1个月（P = 0.0008）12个月（P = 0.0002）。
Keywords: Chronic myeloid leukemia; compliance; molecular response; trough plasma imatinib levels.
|How to cite this article:|
Sharma SK, Kumar S, Vijayakumar A R, Seth T, Mishra P, Mahapatra M, Sazawal S, Velpandian T, Saxena R. Utility of the trough plasma imatinib level monitoring at two time points in patients with the chronic myeloid leukemia-chronic phase. J Can Res Ther 2014;10:305-8
|How to cite this URL:|
Sharma SK, Kumar S, Vijayakumar A R, Seth T, Mishra P, Mahapatra M, Sazawal S, Velpandian T, Saxena R. Utility of the trough plasma imatinib level monitoring at two time points in patients with the chronic myeloid leukemia-chronic phase. J Can Res Ther [serial online] 2014 [cited 2019 Nov 14];10:305-8. Available from: http://www.cancerjournal.net/text.asp?2014/10/2/305/136583
| > Introduction|| |
Response to imatinib (IM) is assessed by monitoring hematological, cytogenetic, and molecular markers at regular intervals; however, the role of therapeutic drug monitoring in the management of CML is controversial. Most of the previous studies on IM monitoring have correlated the response with only a single time point measurement of plasma IM levels. ,,,,, Studies by Larson et al.  and Picard et al.  have suggested that trough plasma imatinib levels more than 1000 ng/mL are associated with the improved response rate. Another important factor related to the response to imatinib is the adherence to imatinib therapy, ,, as patients with poor compliance have poor response rates. In this study, we tried to analyze if monitoring of plasma imatinib levels at two time points could help in the better management of patients with CML-CP.
| > Materials and methods|| |
The study was conducted by the Departments of Hematology and Ocular Pharmacology and Pharmacy, All India Institute of Medical Sciences, New Delhi. Fifty consecutive recently diagnosed adult patients with CML-CP were included in the study. The study was approved by the ethical committee of the Institute. Written informed consent was taken from the patients participating in the study. The diagnosis of CML-CP was made by clinical, hematological, and molecular analysis. CML patients on treatment other than imatinib or on higher dose of imatinib, and patients with CML-accelerated phase and blast crises were excluded. The renal and liver functions were assessed prior to starting imatinib in all patients. Molecular analysis included RT-PCR for BCR-ABL,  which was done in the Molecular Laboratory of Hematology department. RNA was extracted from whole blood using Qiagen kits (Qiagen, GmbH, Germany) and reversely transcribed to cDNA with random hexamers (Roche diagnostics, GmbH Germany). The quality of cDNA was assessed by amplification of the β2 microglobulin gene. RT-PCR was performed (C1000 Thermal Cycler, BIO-RAD) for the amplification of P210 BCR-ABL using the primers. Real time PCR (Rotor Gene 3000, Corbet Research, Australia) was performed using TaqMan probes and primers designated for BCR-ABL fusion transcript (Professional Biotech, India). BCR-ABL transcript quantification was expressed as percentage of the control gene. All patients were treated with imatinib 400 mg daily (Gleevec® Novartis Pharmaceuticals). Patients were also permitted to receive hydroxyurea and allopurinol during the initial part of treatment, if total leukocyte counts were high. Trough plasma imatinib levels were evaluated at two time points, one month and 12 months after starting Imatinib. Plasma imatinib levels were quantified in the High Precision Bio-analytical Laboratory of Department of Ocular Pharmacology and Pharmacy. Briefly, patient's blood samples were collected 24 h after the last imatinib dose, in ETDA vials and were subjected for centrifugation to collect plasma. The collected plasma was stored at -86°C until the analysis. Ultra Performance Liquid Chromatography (UPLC) (Accela, Thermo Electron Corp, Waltham, MA, USA) connected with ESI-LC-MS/MS (4000 Q-Trap, Applied Biosystem, Foster city, CA, USA) was used for the quantification of the analyte. A validated hydrophilic interaction chromatography method was employed for separation (ZIC HILIC, Merck, Germany) and quantification of imatinib using the MRM transition of 494.3/394.1. In this analysis sulfadimethoxine (311/156) was used as an internal standard. Calibration curve was plotted using drug-free plasma spiked with varying concentrations of imatinib for its quantification from patient's samples.
Response to imatinib was assessed by hematological and molecular parameters as per the standard of care for such patients already being practiced at our center and as per standard guidelines. , The hemogram was performed every 15 days for initial 3-6 months, and then monthly once complete hematological response (CHR) achieved. The compliance of the patient to drug as well as the side effects of imatinib was noted. CHR was defined as TLC <10 × 10 9 /L, platelet count <450 × 10 9 /L, peripheral smear showing no immature cells and basophils <5% with no organomegaly or extramedullary disease. Molecular response (MR) at 12 months was measured by RQ-PCR for BCR-ABL transcripts and levels <1% were considered equivalent to complete cytogenetic response, as per recommended guidelines. , Compliance was defined as the total number of days imatinib taken by the patient over 1 year. , Patients with compliance less than 90% were considered as poorly compliant.
Statistical analysis included t-test and Mann-Whitney test for assessing the difference in continuous outcome between two groups and Chi-square test was used to assess the difference in categorical outcome between two groups.
| > Results|| |
The mean age of presentation was 33.7 years (range14-70 years). There were 37 males and 13 females [Table 1]. Median duration of illness before presentation to the hospital was 3.6 months (range 10 days to 12 months). Median duration of illness was 2 months in patients who achieved CHR at 3 months versus 3.2 months in patients who did not achieve CHR at 3 months (Mann-Whitney test, P = 0.09). Whereas, the median duration of illness was 3 months in patients who achieved MR at 12 months versus 4 months in patients who did not achieve MR at 12 months (Mann-Whitney test, P = 0.04).
|Table 1: Characteristic features of the patients in the study group (n=50)|
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There was no correlation of trough plasma imatinib levels at 1 month (P = 0.75) and 12 months (P = 0.73) with the Sokal score. But there was a significant correlation of the Sokal score with months to achieve CHR (P = 0.01), a patient with a low Sokal score (<0.8) achieved CHR earlier, compared to patients with a high Sokal score (>1.2) (P = 0.049, linear regression analysis).
There was significant correlation between plasma IM levels at 1 month (IM 1) and CHR at 3 months (P = 0.007, t test), with mean trough plasma IM 1 for patients who achieved CHR within 3 months of 1546.4 ± 596.1 ng/mL (458-2980 ng/mL) compared to 1105.24 ± 521.9 ng/mL (range 261-2010 ng/mL) for those who did not achieve CHR at 3 months [Figure 1]. 47.1% of patients with IM1 <1000 ng/mL achieved MR versus 63.6% of patients with IM1 ≥1000 ng/mL (OR: 1.97, 95 CI: 0.61-6.41). There was a significant correlation between plasma imatinib levels at 12 months (IM 12) and molecular response at 12 months (P = 0.04, t test) [Figure 2] with 72.4% (21/29) patients with IM 12 ≥1000 ng/mL achieving RQ-PCR for BCR-ABL ≤1% compared to 38% (8/21) patients with IM levels <1000 ng/mL. Those patients who achieved CHR at 3 months were 3.27 times more likely to achieve MR at 12 months (i.e., BCR-ABL <1%) (95% CI: 1.03-10.42). Imatinib levels at 1 month showed a trend toward achieving the molecular response at 12 months (P = 0.64, t test).
|Figure 1: Boxplot chart showing imatinib levels at 1 month (IM1) in patients who achieved complete hematological response at 3 months|
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|Figure 2: Boxplot chart showing imatinib levels at 12 months in patients who had molecular response (BCR-ABL by RQ-PCR) ?1% or >1%|
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Compliance to IM significantly correlated with IM1 (P = 0.0008) and IM 12 (P = 0.0002). Patients with compliance ≥90% had mean IM12 levels 1339.8 ng/mL (± 604.2) compared to 837.1 ng/mL (±512.6) in poorly compliant patients (P = 0.008). Compliance was significantly higher in patients whose IM levels were ≥1000 ng/mL at both 1 month and 12 months (97.5%) compared to patients whose imatinib levels were <1000 ng/mL at the these two time points (86.9%) (P = 0, t test). Compliance also significantly correlated with MR (P = 0.02). A patient was more likely to achieve MR if there was good compliance (≥90%) at 12 months (95% CI: 0.057-0.79).
Eleven out of 25 (44%) patients had adverse effects (both hematological and nonhematological) when IM levels were higher at both time points (1 and 12 months) compared to 2 out of 11 (18.2%) when IM levels were lower at both time points. There was no significant correlation between plasma imatinib levels and adverse effect profile. The major side effects noted were-myalgia-10, pedal edema/facial puffiness-3, skin pigmentation-4, nausea-1, and gynaecomastia-1. Cytopenias, irrespective of plasma imatinib levels, developed in 9 (18%) patients and were managed by transient drug interruptions.
| > Discussion|| |
Trough plasma IM levels measured at single time point, either 1 month or 12 months after start of Imatinib, have been correlated with cytogenetic and molecular response in CML-CP patients. ,,,,, Patients with poor response to standard dose of imatinib may respond to higher doses. This can be explained by an increased plasma level achieved by higher doses, signifying the need to maintain a minimum trough IM level to achieve desired response.  A study by Forrest et al.  failed to show any correlation between trough IM levels and the response rate. We analyzed the response to IM with serial monitoring of trough plasma IM levels at two time points (1 month and 12 months). There was no effect of weight, age, or sex of the patient on the IM levels in our study. Similarly, Peng et al.  had also found no significant correlation between body weight or body surface area and imatinib exposure whereas a subanalysis of data by Larson et al.,  from 351 patients in the IRIS trial identified a weak correlation between trough IM levels and both body weight and body surface area.
In our study, there was significant correlation between plasma imatinib levels at 1 month and CHR at 3 months (P = 0.007). There was also a significant correlation between plasma imatinib levels at 12 months and molecular response at 12 months (P = 0.04). Data from studies by Larson et al.  and Picard et al.  have also shown a correlation between imatinib trough plasma concentration and clinical response. Maintaining imatinib blood concentrations above 1000 ng/mL may be associated with improved outcomes. Larson et al.,  correlated mean trough plasma imatinib concentrations at day 29 of imatinib treatment with cytogenetic and molecular responses, event-free survival, and adverse event rates over 5 years of treatment in the phase III IRIS study. Response rates were significantly lower in patients with lower trough plasma imatinib levels.
The median compliance rate of our patients was 95.7%. Marin et al.,  evaluated the adherence rate with response rate in which there was a strong correlation between compliance and molecular response. Similarly, a study by Ganesan et al.  has shown that nonadherence to imatinib is associated with poor event-free survival. We evaluated the possible association of compliance with plasma levels of Imatinib. Patients with better compliance in our study were more likely to have higher plasma imatinib levels and higher response rates. This could mean that plasma levels could be a surrogate marker for assessing compliance.
In our study, there was no significant difference in the adverse effect profile of patients with imatinib levels. Similarly, in the IRIS study, adverse event rates were similar among the patients with different trough plasma imatinib concentrations. 
[Table 2] highlights the salient features observed in our study. This being an observational study, the imatinib dose was not increased based on the plasma imatinib levels. The limitation of the study was that molecular response at 12 months was used to assess the response (equivalent to complete cytogenetic response) and bone marrow examination was not performed for cytogenetic studies and to look for additional chromosomal abnormalities.
| > Conclusion|| |
The trough plasma imatinib level at 1 month correlated with CHR at 3 months and trough plasma imatinib levels at 12 months with molecular response at 12 months. Thus, it appeared that serial plasma level monitoring could be useful in dictating therapy. Moreover, the plasma imatinib levels in our study also correlated with compliance. This highlights the importance of the previous studies that have shown that poor compliance leads to poor outcome. Among patients who do not achieve the satisfactory landmarks of response, monitoring of trough IM levels can be performed, to ensure that this is not the factor leading to poor response alongside standard evaluation of cytogenetic, molecular, and mutational analysis. The plasma level monitoring at random time points could thus provide an alternative means to assessing compliance in a patient.
| > Acknowledgement|| |
We are thankful to Dr. Sandeep Sharma and Aashna Sharma for formatting the manuscript.
| > References|| |
|1.||Larson RA, Druker BJ, Guilhot F, O′Brien SG, Riviere GJ, Krahnke T, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: A subanalysis of the IRIS study. Blood 2008;111:4022-8. |
|2.||Picard S, Titier K, Etienne G, Bernard MA, Lassalle R, Marit G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007;109:3496-9. |
|3.||Faber E, Friedeckỳ D, Mièová K, Divoká M, Katrincsáková B, Rozmanová S, et al . Imatinib dose escalation in two patients with chronic myeloid leukemia, with low trough imatinib plasma levels measured at various intervals from the beginning of therapy and with suboptimal treatment response, leads to the achievement of higher plasma levels and major molecular response. Int J Hematol 2010;91:897-902. |
|4.||Sakai M, Miyazaki Y, Matsuo E, Moriuchi Y, Hata T, Fukushima T, et al. Long-term efficacy of imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: A report by the Nagasaki CML Study Group. Int J Hematol 2009;89:319-25. |
|5.||Chen C, Wang W, Xu C, Hou M, Wang L, Liu C, et al. Monitoring of plasma concentration of imatinib mesylate in patients with chronic myeloid leukemia. Zhonghua Xue Ye Xue Za Zhi 2011;32:450-3. |
|6.||Singh N, Kumar L, Meena R, Velpandian T. Drug monitoring of imatinib levels in patients undergoing therapy for chronic myeloid leukaemia: Comparing plasma levels of responders and non-responders. Eur J Clin Pharmacol 2009;65:545-9. |
|7.||Goldman JM. How I treat chronic myeloid leukemia in the imatinib era. Blood 2007;110:2828-37. |
|8.||Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: An update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009;27:6041-51. |
|9.||Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010;28:2381-8. |
|10.||Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: Review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28-37. |
|11.||Noens L, van Lierde M, De Bock R, Verhoef G, Zachée P, Berneman Z, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: The ADAGIO study. Blood 2009;113:5401-11. |
|12.||Kantarjian HM, Talpaz M, O′Brien S, Giles F, Garcia-Manero G, Faderl S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003;101:473-5. |
|13.||Forrest DL, Trainor S, Brinkman RR, Barnett MJ, Hogge DE, Nevill TJ, et al. Cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia are correlated with Sokal risk scores and duration of therapy but not trough imatinib plasma levels. Leuk Res 2009;33:271-5. |
|14.||Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 2005;44:879-94. |
|15.||Ganesan P, Sagar TG, Dubashi B, Rajendranath R, Kannan K, Cyriac S, et al. Nonadherence to Imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am J Hematol 2011;86:471-4. |
[Figure 1], [Figure 2]
[Table 1], [Table 2]