Influence of CYP3A5 and SLCO1 on Imatinib Response Among Egyptian Patients with Chronic Myeloid Leukemia in Chronic Phase
Authors: El Baiomy Mohamed Ali , Aref Salah , El-Ghonemy Mohamed 
Published: October 2019

Background

Imatinib (IM) was approved as a molecular target tyrosine kinase inhibitor (TKI) drug that selectively inhibits BCR/ABL1 tyrosine kinase which causes Philadelphia-positive chronic myeloid leukemia (CML) and so far has been one of the first-choice treatment option in CML with excellent results. However, only a proportion of patients achieve major molecular response. Hence, the need to find whether there are some factors that affect the response to treatment is essential. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. This study aimed to investigate the frequencies of mutational status of CYP3A5 and SLCO1 in CML patients undergoing imatinib treatment and to determine whether these two genes could predict the response to imatinib therapy in CML patients.

Subjects and methods

We investigated the mutational status of SLCO1 and CYP3A5 by Polymerase Chain Reaction followed by restricted fragment length polymorphism in 62 Philadelphia positive newly diagnosed Egyptian CML patients in chronic phase; 39 males (62.9%) and 23 females (37.1%). All patients received imatinib therapy and were followed up for at least one and half year. The response to imatinib therapy was evaluated by recording the hematological response, cytogenetic response at 3rd then 6th month and molecular response at 12th month according to the European Leukemia Net criteria. Results

Twenty-eight patients (45.2%) were CYP3A5 wild versus 34 patients (54.8%) mutant while 26 patients (41.9%) were SLCO1 wild versus 36 patients (58.1%) mutant. 85.7% of patients with wild CYP3A5 had low & intermediate Sokal score versus 76.5% of mutant CYP3A5 patients had low & intermediate Sokal score with non-significant relation (p = 0.3). There was a significant relation between mutation in CYP3A5 and poor performance state (PS) of the patients at presentation; 89.3% of patients with wild CYP3A5 had good PS versus 61.8% in the mutant group with (p = 0.01). After 3 month of imatinib therapy there was no significant relation between CYP3A5 mutational state and response to therapy however, 85.7% of patients with wild CYP3A5 reached optimal & suboptimal response versus 79.4% in the mutant group with non-significant difference (p = 0.5). We had 51 patients that continued on imatinib till 6th month of therapy whereas 11 patients shifted to 2nd line TKI after imatinib failure. 87.5% of patients with wild CYP3A5 reached optimal & suboptimal response versus 66.7% in the mutant group with difference reaching significance (p = 0.07). We have 39 patients continued imatinib therapy till 12 month whereas 12 patients shifted to 2nd line TKI after imatinib failure. 71.4% of patients with wild CYP3A5 reached MMR at 12th month of treatment however only 22.2% of mutant CYP3A5 patients reached major molecular response (MMR) with significant difference (p = 0.002). Patients with wild SLCO1 were significantly had low & intermediate Sokal score (p = 0.04). However there was no significant correlation between SLCO1 mutational state and performance state or response to imatinib therapy.

Conclusion

CYP3A5 mutant gene was associated with poor imatinib efficacy while the SLCO1 gene was not associated with the response to imatinib treatment in Egyptian patients with CML in chronic phase.

Disclosures

No relevant conflicts of interest to declare.