Aim of the paper was to assess the current status concerning the hazards of Imatinib therapy on the development of thyroid dysfunction.

Eligibility

After taking the Ethical Review Committee approval and informed consent from each patient before participation in the study, only 30 cancer patients met the following eligibility criteria were selected carefully:

1. Histologically proven CML with Philadelphia chromosome positive in chronic phase with no other evidence of distant metastases at the thyroid gland.

2. Who were euthyroid clinically (with normal hormonal profiles) preceding treatment with Imatinib. Patients with past history of any thyroid problems, on any thyroid therapy or any medications that may affect thyroid function, like; steroids, were excluded. Normal TFT were defined as; (TSH) ≤ 4.2 mIU/L; (FT4) 12.5–22 pmol/L and (T3) between 3.1 and 5.5 pmol/L.

Imatinib therapy & thyroid function assessment

All patients enrolled in this study, received imatinib orally as a first-line treatment on a standard schedule (initial dose 400 mg/ml, in a continuous manner). For the purpose of the study, total thyroid profiles TSH, Free T4, Free T3, Anti thyroid peroxidase (Anti TPO), and Anti thyroglobulin (Anti Tg) were obtained from each patient before and after 4 and 24 weeks for assessment of toxicity and remission, respectively).

Based on the last follow up, patients with hypothyroidism expressed by (high level of TSH and/or low FT3/FT4 while patients with thyroiditis expressed with high level of Anti-TPO.

STATISTICAL ANALYSIS

Statistical analysis was performed using SPSS version 16. Data presented as the mean±SD Pearson's correlation was used to assess the relationships between two variables to assess its strength as well as linear regression test.  The p-value

RESULTS

In this retrospective study, 30 patients with known diagnosed CML Philadelphia chromosome positive in chronic phase were enrolled. 10 patients with preexisting hypothyroidism were excluded, reduced the total number to 20 eligible patients, 9 were male (45%) and 11 (55%) were female with a mean age of 50 ± 11.9 years (Table 1).

The major percentage of the patients received imatinib therapy was 35% over 4 months while the lowest percentage among patients received Imatinib therapy was 5% over 2.6.8.11 months (Table 2).

9 out of 20 patients (45%) only expressed hypothyroidism (2 patients expressed clinically by fatigue and edema (22%), 4 (44%) showed subclinical hypothyroidism with a high TSH level, while the other 3 patients (33%) showed autoimmune thyroiditis confirmed by increased Antithyroid Anti-peroxidase (TPO) level.

Statistically, there is a high significant correlation between the undesirable hypothyroidism occurrence and duration of Imatinib therapy and 59% could be explained (R factor=0.76, R square=0.59, P-value=0.000) (Table 3).

A linear regression test was done to assess if there is a correlation between the hypothyroidism occurrence and the duration of the Imatinib therapy, it revealed a good linear correlation (Figure 1).

DISCUSSION

Although the mechanism by which TKIs cause thyroid dysfunction remains unclear. A limited number of studies have been performed to try to characterize the mechanism of9 out of 20 patients (45%) only expressed hypothyroidism (2 patients expressed clinically by fatigue and edema (22%), 4 (44%) showed subclinical hypothyroidism with a high TSH level, while the other 3 patients (33%) showed autoimmune thyroiditis confirmed by increased Antithyroid Anti-peroxidase (TPO) level.

Statistically, there is a high significant correlation between the undesirable hypothyroidism occurrence and duration of Imatinib therapy and 59% could be explained (R factor=0.76, R square=0.59, P-value=0.000) (Table 3).

A linear regression test was done to assess if there is a correlation between the hypothyroidism occurrence and the duration of the Imatinib therapy, it revealed a good linear correlation (Figure 1).

DISCUSSION

Although the mechanism by which TKIs cause thyroid dysfunction remains unclear. A limited number of studies have been performed to try to characterize the mechanism of TKI induced hypothyroidism, mostly coming from de Groot’s group [5,6]. 15 patients were treated with Imatinib and hypothyroidisms expressed only in nine patients while the others kept a normal thyroid hormone profile during the Imatinib therapy. Kim et al. [7], also reported alterations in thyroid function tests in 25% of patients received Imatinib. In our study which has nearly similar results as compared to de Groot groups, 9 out of 20 patients expressed clinical/subclinical hypothyroidism proved by elevated TSH and or low T3, T4.

Our study revealed significant changes at levels of T3, T4 and TSH during imatinib therapy at the time of follow up beyond 5 months, one of the designed goals in this long-time follow-up was the recognition of imatinib adverse effects. Druker et al. [8] did not mention any thyroid modifications in this evaluation.

Dora et al. [9] performed another study in 2008, all of the cases of CML on imatinib therapy underwent long follow up for more than six months, none of them showed thyroid dysfunction as well as in Mashahdi study in 2014, which showed normal levels of thyroid hormones, Anti TPO, before and during imatinib therapy [10].

Our study detected only 3 patients out of 20 with autoimmune thyroiditis proved by elevated level of TPO, other studies also reported the effects of other tyrosine kinase inhibitors, especially sunitinib on thyroid function. The abnormalities included autoimmune thyroiditis, transient or permanent hypothyroidism and increased dose of levothyroxine [7, 11, 12].

In spite of these significant changes of TFT among the patients during imatinib therapy, none of them induce to discontinue imatinib or induce levothyroxine treatment, all of these effects disappeared immediately after imatinib discontinuation. The main mechanism of imatinib-induced sub/or clinical hypothyroidism is still unknown but may be due to apoptosis which manifests initially by a destructive thyroiditis and then gradually progresses to be atrophic one.

CONCLUSION

As a result of this study with other relevant studies, which reported significant changes in thyroid function during long follow up duration of imatinib, it is now recommended that all patients starting therapy with TKIs have their thyroid function test before and during imatinib therapy.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.