The Effect of Nilotinib in Chronic Myeloid Leukemia Treatment Dose on Spermatogenesis and Folliculogenesis in a Healthy Mouse Model

Introduction&Aim:Chronic myeloid leukemia (CML) is a hematopoietic pluripotent stem cell disease where myeloid cells lead to uncontrolled proliferation. Current treatment of Ph (+) CML is based on the inhibition of tyrosine kinase inhibitors (TKI), especially second generation drugs. Majority of CML patients are male and 46% of them are between 20 and 64 years of age. Therefore, it is conceivable that inhibition of c-kit or PDGFR by TKI may have deleterious effects on spermatogenesis or folliculogenesis, resulting in male or female subfertility. Aim of this study is to determine the effect of nilotinib on spermatogenesis and folliculogenesis which is used routinely to treat CML.

Materyal&Method: Here we present the results of testicular and ovarian changes after nilotinib administration to five-week old male and female C57bI6 mice. Mice received 0.4 mg of nilotinib per day dissolved in the drinking water for 2 months. Control group received only drinking water. Treatment dose was determined according to the clinical studies regarding the plasma concentrations (20 mg/kg, orally). After sacrification of both groups, testicular and ovarian tissues were fixed and parafin sections were stained with hematoxylene-eosin. In the ovaries, the follicles were counted and their developmental stages were recorded from the serial sections. In the testes, 24 seminiferous tubules with approximately circular cross-sectional profiles were assessed using a classification according to the degree of spermatogenic activity to generate a mean score for each mouse. In addition, tubule diameters were measured using an eyepiece micrometer to provide an additional indication of the level of function.

Results:There was less distance between the cortex and medulla than normal, and the follicles were widely scattered instead of organized in a normal hierarchy from the least mature at the periphery to the largest growing stages towards the medulla. The numbers of follicles were significantly different between nilotinib and control groups (268±110 vs. 170±60; p= 0.03). Virtually every seminiferous tubule from all animals had active spermatogenesis with either spermatids or spermatozoa present. Mean tubular diameter measurements were 190,61±8,33 vs. 194,32±7,26 in control and nilotinib groups, respectively (p=0.475). Spermatogenic activity index were not significantly different between control and nilotinib groups (3.1 vs. 3.4; p=0.241).

Conclusion: Unlike the manufacturer’s results; we showed the supression of folliculogenesis and prevention of spermatogenesis during the long-term nilotinib treatment. Our results indicate that nilotinib, within the dose of CML treatment regimen, may create gonadotoxicity and therefore its usage may be an indication for fertility preservation. In the second part of our ongoing study, we are investigating the effect of nilotinib on fertility and teratogenicity.