European Journal of Cardiovascular Medicine

Tyrosine kinase inhibitors (TKIs) are a group of drugs that disrupt signal transduction pathways of protein kinases through various modes of inhibition. The approval of the first TKI, imatinib, in 2001 marked a significant advancement in the treatment of chronic myeloid leukemia (CML), leading to the evolution of cancer chemotherapy into the current era of targeted therapy. TKIs are now considered the standard of care for several cancers, with CML being a prominent example where TKIs are the preferred treatment regardless of the stage of the disease.

TKIs function by inhibiting tyrosine kinase enzymes, which can be classified into receptor tyrosine kinases, non-receptor tyrosine kinases, and dual specificity kinases. Currently, the United States Food and Drug Administration (FDA) has approved over 50 FDA TKIs for use. Adverse drug events of TKIs are generally dose-dependent and are associated with specific side effect profiles unique to each drug. Due to similarities in drug targets, different classes of TKIs may produce similar side effects. Common side effects shared by TKIs include cutaneous drug reactions, fatigue, fever, gastrointestinal disturbances, cardiovascular side effects (such as hypertension), and endocrine-related issues like thyroid dysfunction.

CML is a myeloproliferative neoplasm caused by the reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the BCR-ABL1 fusion gene, which drives the disease process. CML represents a rare haematological malignancy with remarkable responses to targeted therapy. TKIs are presently used in the management of CML patients at any stage. There are 6 TKIs approved and in use for CML treatment, categorized into three generations:

1st generation – Imatinib

2nd generation – Dasatinib, Nilotinib, Bosutinib, and Radotinib

3^rd generation – Ponatinib

These drugs vary in their pharmacological profiles. Clinical, haematological, cytogenetic, and molecular responses are used to assess the response of CML patients to these drugs and reflect the leukemic burden in these patients. TKIS are known to produce thripid dysfunction, and it is a well-documented side effect of TKIS used to treat solid tumours, but there is a paucity of studies to validate this side effect in haematological malignancies. This study tried to confirm the hypothesis that thyroid dysfunction is induced by tyrosine kinase inhibitors used to treat CML, and whether there is any correlation with the molecular response attained by these patients.

Study design:

The study was a cross-sectional observational study that followed a protocol approved by the institute's ethics committee before its execution.

The flow of the study:

The study was conducted in a tertiary care hospital in New Delhi, India. Patients were follow-up cases of chronic myeloid leukaemia on tyrosine kinase inhibitors in remission. The records of these patients were reviewed, which especially included whether the patient was on any anti-thyroid drug or thyroid supplementation drug, and the type of molecular response the patient was in. We include patients of the age of more than 18 years of any gender with chronic myeloid leukaemia on tyrosine kinase inhibitors for more than 18 months with the molecular response (major and deep molecular response). we exclude Patients with pre-existing thyroid alterations based on previous records, Patients on thyroid hormone supplement therapy or anti-thyroid drugs or any other drug-altering thyroid function test other than TKI such as amiodarone, lithium, selective serotonin reuptake inhibitors, rifampin…. etc., Patients with nephropathy of any cause, chronic liver illness was also excluded from the study. Eligible patients were included in the study and were subjected to a history targeted at symptoms of hypothyroidism or hyperthyroidism with examination of the thyroid gland and thyroid function tests using chemiluminescent microparticle immunoassay. The thyroid function test included serum-free T3, free T4 and TSH levels. Along with the thyroid function test, molecular response, which was previously documented, was confirmed by running RT-PCR of the peripheral blood for BCR-ABL transcripts.

Interpretation of test results:

Hypothyroidism: elevated serum TSH level with reduced serum-free T4 level.

Hyperthyroidism: reduced serum TSH level with elevated serum-free T4 level.

Sub-clinical hypothyroidism: elevated serum TSH level with normal serum T4 level.

Molecular response (MR) was defined according to the European Leukemia Network guidelines – Major Molecular Response (MMR) was defined as BCR-ABL1 IS transcripts less than 0.1%, and Deep Molecular Response (DMR) was defined as BCR-ABL1 IS transcripts less than 0.01%. Both MMR and DMR patients were assessed for thyroid function.

The test results were interpreted and then subjected to statistical analysis.

Statistical analysis:

Sample size: The sample size was calculated using Openepi version 3.2 with a confidence level of 95%. The p-value was set at 34.8% from the study by Rodia R et al²⁸. The absolute precision was defined as 10% (0.1). Z = 1.96; q = 1-p = 0.652.

n = Z² pq / d²

The calculated sample size (n) is 87.

Analysis of data:

The categorical variables were presented as numbers, while the quantitative data were shown as means ± standard deviation (SD) and as medians with the 25th and 75th percentiles (interquartile range). The normality of the data was assessed using the Kolmogorov-Smirnov test. For cases where the data did not meet the criteria for normal distribution, nonparametric tests were employed. The following statistical tests were utilised for the analysis of the results:

1. Associations between quantitative variables that were not normally distributed were analysed using the Mann-Whitney test for two groups and the Kruskal-Wallis test for more than two groups.
2. Associations between qualitative variables were analysed using the Chi-Square test. Fisher's exact test was applied when any cell had an expected value of less than 5.

Data entry was performed using Microsoft Excel 2021, and the final analysis was conducted with the Statistical Package for the Social Sciences (SPSS) software, version 29.0, produced by IBM, Chicago, USA. A p-value of less than 0.05 was regarded as statistically significant.

In our study, most of the patients were male, and the mean age of the population was 50.4 years. The youngest patient was 26 years old, and the eldest was 78 years old. The majority of the patients received imatinib, and most of the patients were in deep molecular response. Abnormal thyroid function test was observed in 75/100 patients with hypothyroidism being the most common abnormality (Table 1).

Table 1 CML patients’ characteristics and thyroid profile observed during TKIs therapy

y

*Hypothyroidism includes both sub-clinical and clinical hypothyroidism

DMR – deep molecular response, MMR – major molecular response.

Out of 75 patients with abnormal thyroid function tests, 70 were observed to have hypothyroidism. Among these, 37 patients were clinically hypothyroid, with 27 in deep molecular response and 10 in major molecular response. 33 patients were sub-clinically hypothyroid, with 24 in deep molecular response and 9 in major molecular response. Additionally, 5 patients were hyperthyroid, all of whom were in major molecular response. Finally, 25 patients had a normal thyroid profile (Figure 1).

Figure 1

Out of 37 patients with clinical hypothyroidism, 7 did not show symptoms, while the remaining 30 did. Among the 33 patients with sub-clinical hypothyroidism, 4 displayed symptoms, and the other 29 were asymptomatic. Additionally, 5 patients were diagnosed with hyperthyroidism, with 4 showing symptoms and 1 being asymptomatic. Notably, 2 out of the 4 hypothyroid patients displayed thyroid eye signs (Figure 2).

Figure 2

CH- Clinical hypothyroidism; SH – Subclinical hypothyroidism; N – Normal; HYP – Hyperthyroidism;

The results showed a significant association between thyroid function tests and molecular response, specifically deep and major molecular responses. There was a notable correlation between serum TSH level (p < 0.001) and free T3 level (p = 0.047) with both deep and major molecular responses. In this study, p < 0.05 was considered statistically significant (Table 2).

Table 2 Association of thyroid function test with molecular response of the study participants

#Student’s t-test

*p-value <0.05 statistically significant

In analysing the thyroid profile alongside the molecular response, a significant association was discovered between hyperthyroidism and both molecular responses, with a p-value of 0.008. Additionally, a significant association was observed between patients with a normal thyroid profile and both molecular responses, with a p-value of 0.013 (table 3).

Table 3

*p-value

<0.05 statistically significant.

**Fisher’s exact p-value <0.05 statistically significant.

CH- Clinical hypothyroidism; SH – Subclinical hypothyroidism; N – Normal; HYP – Hyperthyroidism.

Chronic myeloid leukaemia is a clonal myeloproliferative neoplasm characterised by an unregulated expansion of myeloid cells in the bone marrow. The driving force behind the disease process is the reciprocal translocation between chromosomes 9 and 22, leading to the formation of the oncoprotein BCR-ABL1, which produces a dysregulated tyrosine kinase. The discovery of this dysregulated tyrosine kinase led to the development of targeted cancer therapy. Imatinib, the first tyrosine kinase inhibitor developed for use in CML, was approved in the year 2001. Since then, various tyrosine kinase inhibitors have been developed for the management of CML as well as other malignancies and non-malignant conditions. Tyrosine kinase has various side effects, ranging from simple GI disturbances to secondary malignancies, but one of the side effects of interest is thyroid dysfunction produced by tyrosine kinase inhibitors. TKIs have anti-proliferative and anti-angiogenic properties. The exact incidence of thyroid dysfunction caused by tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia (CML) is currently unknown. However, case series have indicated that up to 90% of patients receiving TKIs may develop thyroid dysfunction. In contrast, TKIs used for treating solid tumors show a very high incidence of thyroid dysfunction as well. The proposed mechanisms for thyroid dysfunction induced by tyrosine kinase inhibitors include thyroiditis, autoimmunity, inhibition of vascular endothelial growth factor receptor (VEGFR), and blockade of iodine uptake. In our study, we studied the thyroid profile in patients with CML receiving tyrosine kinase inhibitors. Our study was a cross-sectional observational study in which 100 patients who were diagnosed with chronic myeloid leukaemia were taken as the study group. All these patients were receiving tyrosine kinase inhibitors and were either in major or deep molecular response. The molecular responses of these patients were assessed by performing Real-time polymerase chain reaction of the peripheral blood of these patients. Patients with pre-existing thyroid function abnormalities were ruled out by going through their previous records of thyroid function tests and asking them whether they were on thyroid hormone supplements.

The annual incidence of chronic myeloid leukaemia (CML) is reported to be 0.7-1.0 cases per 100,000 population based on data from several European CML registries. The average age at diagnosis of CML is between 57 and 60 years, and the male-to-female ratio ranges from 1.2 to 1.7. The prevalence of CML is not well established, but it is estimated to be 10-12 cases per 100,000 population. In India, the reported incidence of CML has varied from 0.8 to 2.2 cases per 100,000 population, but these figures are based on a registry that doesn't distinguish between acute and chronic forms of myeloid leukemia. However, this incidence is lower compared to the data from registries in the US, Europe, and Australia. This raises questions about the incidence of CML in India, especially given the country's high population density. In our study most of the patients were male and the mean age of the population was 50.4 years. Usually in Indian centers even though 2^nd generation TKI’s are preferred than imatinib in both attaining remission and side effect profile, imatinib is still the preferred first line drug. Imatinib is dosed at 400mg per day. In our centre, usually, patients who are newly diagnosed with CML are started on imatinib, but in some centres in India, patients are directly started on second-generation TKI such as nilotinib, which is dosed at 300mg twice daily. In our study out of 100 patients 65 patients were on imatinib and 35 patients were on nilotinib. In all these patients, there was no prior history of use of any other TKI. Hence, from our study, we concluded that the majority of our patients were started on imatinib as first-line therapy, and a significant portion of patients were started on nilotinib as first-line drug therapy. We attribute this selection of TKI 1^st gen VS 2^nd gen to the drug affordability of our patients. Measuring the molecular response is the current modality of monitoring response to therapy when compared to earlier used methods such as monitoring spleen size, blasts in peripheral blood, etc. once the patient has been initiated on tyrosine kinase inhibitors then RT-PCR of peripheral blood is usually done at 3 months interval until the patient reaches the desirable molecular response. The ideal or desirable molecular response is the major molecular response achieved at the 12^th month after initiation of therapy. After achieving such a molecular response, monitoring of the response is usually done at 2-3 times per year. Observations from our study showed majority of the patients in both deep and major molecular response were on imatinib. TKI causes endocrine side effects such as thyroid dysfunction, hyperparathyroidism, adrenal insufficiency, hypo/hyperglycemia, hypogonadism, alteration of bone mineral density, and the list keeps adding on. In our study, 75/100 patients had thyroid function test abnormality; of these patients, 37 were clinically hypothyroid, 33 were sub-clinically hypothyroid, and 5 were hyperthyroid. So, our study concludes that thyroid dysfunction is seen with the use of tyrosine kinase inhibitors, and hypothyroidism is the most frequently observed thyroid function test abnormality. In our study, 37 patients were clinically hypothyroid, of whom 30 patients had symptoms of hypothyroidism and 7 patients were asymptomatic for hypothyroidism. 33 patients were sub-clinically hypothyroid, with 4 patients having symptoms of hypothyroidism, and the rest of the 29 patients were asymptomatic. 5 patients were hyperthyroid, of which 4 were symptomatic and 1 was asymptomatic. Interestingly, in our study, it was observed that 2/4 patients with symptoms of hyperthyroidism had thyroid eye signs. These eye findings were then re-confirmed by specialist opinion from an ophthalmologist. Our study concludes that most of the patients with clinical hypothyroidism and hyperthyroidism are symptomatic for thyroid dysfunction. There is only one study in the literature that associated molecular response with drug adverse effects in CML patients; hence, our study is a standalone study. Our study concludes that there is a significant association between thyroid function test and molecular response with significant association between thyroid profile and molecular response.

Limitations:

The duration for which the patients were on tyrosine kinase inhibitors could not be traced; hence, a linear correlation between the thyroid dysfunction and the duration of therapy could not be drawn. The selection of patients into the study was made on the basis of reviewing previous records of thyroid function tests and whether the patients were on any anti-thyroid or thyroid supplementary drugs. Hence, there was no available baseline thyroid function test for comparison. The protocol was a cross-sectional observational study; hence, an etiological workup was not considered. The protocol was designed to only consider whether symptoms of hypothyroidism or hyperthyroidism were present. Individual symptoms could not be taken into account, as symptoms of thyroid dysfunction are not specific.

1. Thomson RJ, Moshirfar M, Ronquillo Y. Tyrosine Kinase Inhibitors. StatPearls Publishing; 2023.
2. Osman AEG, Deininger MW. Chronic Myeloid Leukemia: Modern therapies, current challenges and future directions. Blood Rev [Internet]. 2021;49(100825):100825. Available from: http://dx.doi.org/10.1016/j.blre.2021.100825
3. Berman E. How I treat chronic-phase chronic myelogenous leukemia. Blood [Internet]. 2022;139(21):3138–47. Available from: http://dx.doi.org/10.1182/blood.2021011722
4. Shyam Sunder S, Sharma UC, Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduct Target Ther [Internet]. 2023;8(1). Available from: http://dx.doi.org/10.1038/s41392-023-01469-6
5. Caldemeyer L, Dugan M, Edwards J, Akard L. Long-term side effects of tyrosine kinase inhibitors in chronic myeloid leukemia. Curr Hematol Malig Rep [Internet]. 2016;11(2):71–9. Available from: http://dx.doi.org/10.1007/s11899-016-0309-2
6. Manouchehri A, Kanu E, Mauro MJ, Aday AW, Lindner JR, Moslehi J. Tyrosine kinase inhibitors in leukemia and cardiovascular events: From mechanism to patient care. Arterioscler Thromb Vasc Biol [Internet]. 2020;40(2):301–8. Available from: http://dx.doi.org/10.1161/atvbaha.119.313353
7. Kennedy JA, Hobbs G. Tyrosine kinase inhibitors in the treatment of chronic-phase CML: Strategies for frontline decision-making. Curr Hematol Malig Rep [Internet]. 2018;13(3):202–11. Available from: http://dx.doi.org/10.1007/s11899-018-0449-7
8. Assouline S, Lipton JH. Monitoring response and resistance to treatment in chronic myeloid leukemia. Curr Oncol [Internet]. 2011;18(2):71–83. Available from: http://dx.doi.org/10.3747/co.v18i2.391
9. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia [Internet]. 2020;34(4):966–84. Available from: https://www.nature.com/articles/s41375-020-0776-2
10. Senapati J, Sasaki K, Issa GC, Lipton JH, Radich JP, Jabbour E, et al. Management of chronic myeloid leukemia in 2023 – common ground and common sense. Blood Cancer J [Internet]. 2023;13(1):1–12. Available from: https://www.nature.com/articles/s41408-023-00823-9
11. Shanmuganathan N, Hiwase DK, Ross DM. Treatment of chronic myeloid leukemia: assessing risk, monitoring response, and optimizing outcome. Leuk Lymphoma [Internet]. 2017;58(12):2799–810. Available from: https://pubmed.ncbi.nlm.nih.gov/28482729/
12. Fallahi P, Ferrari SM, Vita R, Di Domenicantonio A, Corrado A, Benvenga S, et al. Thyroid dysfunctions induced by tyrosine kinase inhibitors. Expert Opin Drug Saf [Internet]. 2014;1–11. Available from: http://dx.doi.org/10.1517/14740338.2014.913021
13. Illouz F, Braun D, Briet C, Ulrich Schweizer, Rodien P. ENDOCRINE SIDE-EFFECTS OF ANTI-CANCER DRUGS: Thyroid effects of tyrosine kinase inhibitors. Eur J Endocrinol [Internet]. 2014;171(3):R91–9. Available from: https://academic.oup.com/ejendo/article-abstract/171/3/R91/6661461?redirectedFrom=fulltext&login=false
14. Torino F, Barnabei A, Paragliola R, Baldelli R, Appetecchia M, Corsello SM. Thyroid dysfunction as an unintended side effect of anticancer drugs. Thyroid [Internet]. 2013;23(11):1345–66. Available from: http://dx.doi.org/10.1089/thy.2013.0241
15. Brown RL. Tyrosine kinase inhibitor-induced hypothyroidism: incidence, etiology, and management. Target Oncol [Internet]. 2011;6(4):217–26. Available from: http://dx.doi.org/10.1007/s11523-011-0197-2
16. Tremblay D, Yacoub A, Hoffman R. Overview of myeloproliferative neoplasms. Hematol Oncol Clin North Am [Internet]. 2021;35(2):159–76. Available from: http://dx.doi.org/10.1016/j.hoc.2020.12.001
17. Thapa B, Fazal S, Parsi M, Rogers HJ. Myeloproliferative Neoplasms. StatPearls Publishing; 2023.
18. Nangalia J, Green AR. Myeloproliferative neoplasms: from origins to outcomes. Hematology Am Soc Hematol Educ Program [Internet]. 2017;2017(1):470–9. Available from: https://ashpublications.org/hematology/article/2017/1/470/21094/Myeloproliferative-neoplasms-from-origins-to
19. Harrison’s principles of internal medicine. 20th ed. McGraw-Hill Education/Medical; 2018.
20. Eden RE, Coviello JM. Chronic Myelogenous Leukemia. StatPearls Publishing; 2023.
21. Sillaber C, Mayerhofer M, Agis H, Sagaster V, Mannhalter C, Sperr WR, et al. Chronic myeloid leukemia: Pathophysiology, diagnostic parameters, and current treatment concepts. Wien Klin Wochenschr [Internet]. 2003;115(13–14):485–504. Available from: https://pubmed.ncbi.nlm.nih.gov/13677268/
22. Benchikh S, Bousfiha A, El Hamouchi A, Soro SGC, Malki A, Nassereddine S. Chronic myeloid leukemia: cytogenetics and molecular biology’s part in the comprehension and management of the pathology and treatment evolution. Egypt J Med Hum Genet [Internet]. 2022;23(1). Available from: http://dx.doi.org/10.1186/s43042-022-00248-2
23. Deininger MWN, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood [Internet]. 2000;96(10):3343–56. Available from: https://ashpublications.org/blood/article/96/10/3343/180994/The-molecular-biology-of-chronic-myeloid-leukemia
24. Thompson PA, Kantarjian HM, Cortes JE. Diagnosis and treatment of chronic myeloid leukemia in 2015. Mayo Clin Proc [Internet]. 2015;90(10):1440–54. Available from: http://dx.doi.org/10.1016/j.mayocp.2015.08.010
25. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring. Am J Hematol [Internet]. 2020;95(6):691–709. Available from: http://dx.doi.org/10.1002/ajh.25792
26. Quintás-Cardama A, Cortes JE. Chronic myeloid leukemia: Diagnosis and treatment. Mayo Clin Proc [Internet]. 2006;81(7):973–88. Available from: http://dx.doi.org/10.4065/81.7.973
27. Volume 2023 issue 1 [Internet]. Ashpublications.org. Available from: https://ashpublications.org/hematology/issue/2023/1
28. Rodia R, Pani F, Caocci G, La Nasa G, Simula MP, Mulas O, et al. Thyroid autoimmunity and hypothyroidism are associated with deep molecular response in patients with chronic myeloid leukemia on tyrosine kinase inhibitors. J Endocrinol Invest [Internet]. 2022;45(2):291–300. Available from: http://dx.doi.org/10.1007/s40618-021-01613-5
29. Singha H, Chakrabarty SK, Sherpa PL, Saha S. A study to assess tyrosine kinase inhibitors induced thyroid dysfunction in newly diagnosed chronic myeloid leukemia patients. J Assoc Physicians India [Internet]. 2023;71(1):1. Available from: https://pubmed.ncbi.nlm.nih.gov/37116025/  
30. Yoshizato T, Nannya Y, Yoshiki Y, Nakamura F, Imai Y, Ichikawa M, et al. Nilotinib-induced hypothyroidism in a patient with chronic myeloid leukemia. Int J Hematol [Internet]. 2011;93(3):400–2. Available from: https://pubmed.ncbi.nlm.nih.gov/21347645/
31. Malhotra A, Gupta R, Mahajan S. Tyrosine kinase inhibitors induced thyroid dysfunction: myth or reality? Rep Pract Oncol Radiother [Internet]. 2023;28(4):463–7. Available from: https://pubmed.ncbi.nlm.nih.gov/37795229/  
32. Abdel-Rahman O, Fouad M. Risk of thyroid dysfunction in patients with solid tumors treated with VEGF receptor tyrosine kinase inhibitors: a critical literature review and meta analysis. Expert Rev Anticancer Ther [Internet]. 2014;14(9):1063–73. Available from: https://pubmed.ncbi.nlm.nih.gov/24927771/
33. Nearchou A, Valachis A, Lind P, Akre O, Sandström P. Acquired hypothyroidism as a predictive marker of outcome in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors: A literature-based meta-analysis. Clin Genitourin Cancer [Internet]. 2015;13(4):280–6. Available from: https://pubmed.ncbi.nlm.nih.gov/25442773/
34. Mannavola D, Coco P, Vannucchi G, Bertuelli R, Carletto M, Casali PG, et al. A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab [Internet]. 2007;92(9):3531–4. Available from: https://pubmed.ncbi.nlm.nih.gov/17595247/
35. Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med [Internet]. 2006;145(9):660. Available from: https://pubmed.ncbi.nlm.nih.gov/17088579/
36. Degroot J, Zonnenberg B, Plukker J, Vandergraaf W, Links T. Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther [Internet]. 2005;78(4):433–8. Available from: https://pubmed.ncbi.nlm.nih.gov/16198662/
37. Allahyari A, Salehi F, Kaboli M, Sadeghi M. Evaluation of Thyroid Dysfunction during Imatinib Therapy in Chronic Myeloid Leukemia. Iranian Journal of Blood and Cancer 2016; 8 (1) :9-12 URL: http://ijbc.ir/article-1-648-en.html
38. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring. Am J Hematol [Internet]. 2022;97(9):1236–56. Available from: http://dx.doi.org/10.1002/ajh.26642
39. Deininger MW, Shah NP, Altman JK, Berman E, Bhatia R, Bhatnagar B, et al. Chronic myeloid leukemia, version 2.2021, NCCN clinical practice Guidelines in oncology. J Natl Compr Canc Netw [Internet]. 2020;18(10):1385–415. Available from: https://jnccn.org/view/journals/jnccn/18/10/article-p1385.xml
40. Ganesan P, Kumar L. Chronic myeloid leukemia in India. J Glob Oncol [Internet]. 2017;3(1):64–71. Available from: http://dx.doi.org/10.1200/jgo.2015.002667
41. Lokesh KN, Pehalajani JK, Loknatha D, Jacob LA, Babu MCS, Rudresha AH, et al. CML in elderly: Does age matter? Indian J Hematol Blood Transfus [Internet]. 2020;36(1):47–50. Available from: https://pubmed.ncbi.nlm.nih.gov/32174690/
42. Meena L, Kumar S, Gupta V, Bharti A, Gupta V, Shukla J. A study to determine the clinical, hematological, cytogenetic, and molecular profile in CML patient in and around Eastern UP, India. J Family Med Prim Care [Internet]. 2019;8(7):2450. Available from: https://pubmed.ncbi.nlm.nih.gov/31463275/
43. Fachi MM, Tonin FS, Leonart LP, Rotta I, Fernandez-Llimos F, Pontarolo R. Haematological adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukaemia: A network meta‐analysis. Br J Clin Pharmacol [Internet]. 2019;85(10):2280–91. Available from: http://dx.doi.org/10.1111/bcp.13933
44. McLigeyo A, Rajab J, Ezzi M, Oyiro P, Bett Y, Odhiambo A, et al. Cytopenia among CML patients on imatinib in Kenya: Types, grades, and time course. Adv Hematol [Internet]. 2020;2020:1–5. Available from: https://pubmed.ncbi.nlm.nih.gov/32454829/
45. Reksodiputro AH, Syafei S, Prayogo N, Karsono B, Rinaldi I, Rajabto W, et al. Clinical characteristics and hematologic responses to Imatinib in patients with chronic phase myeloid leukemia (CML) at Cipto Mangunkusumo Hospital. Acta Med Indones [Internet]. 2010;42(1):2–5. Available from: https://pubmed.ncbi.nlm.nih.gov/20305324/
46. Sarah A, Dondi E, De Francia S. Tyrosine kinase inhibitors: the role of pharmacokinetics and pharmacogenetics. Expert Opin Drug Metab Toxicol [Internet]. 2023;19(11):733–9. Available from: http://dx.doi.org/10.1080/17425255.2023.2277758
47. Deininger MW. Molecular monitoring in CML and the prospects for treatment-free remissions. Hematology Am Soc Hematol Educ Program [Internet]. 2015;2015(1):257–63. Available from: https://ashpublications.org/hematology/article/2015/1/257/20723/Molecular-monitoring-in-CML-and-the-prospects-for
48. Malagola M, Iurlo A, Abruzzese E, Bonifacio M, Stagno F, Binotto G, et al. Molecular response and quality of life in chronic myeloid leukemia patients treated with intermittent TKIs: First interim analysis of OPTkIMA study. Cancer Med [Internet]. 2021;10(5):1726–37. Available from: http://dx.doi.org/10.1002/cam4.3778
49. Lodish, M. B., & Stratakis, C. A. (2010). Endocrine side effects of broad-acting kinase inhibitors. Endocrine-Related Cancer, 17(3), R233–R244. https://doi.org/10.1677/erc-10-0082
50. Kim TD, Schwarz M, Nogai H, Grille P, Westermann J, Plöckinger U, et al. Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia. Thyroid [Internet]. 2010;20(11):1209–14. Available from: http://dx.doi.org/10.1089/thy.2010.0251