Abstract

Abstract 1688

Objective:

The introduction of several classes of targeted therapeutics for the treatment of chronic myelogenous leukemia (CML) raises the question of whether male fertility is affected and the degree of this affection, if any, among the different generations of tyrosine kinase inhibitors. When two drugs are equally effective, the drug with less toxic effect on fertility is favorable. Our aims were to evaluate semen parameters and pituitary gonadal function before and 4 months after starting tyrosine kinase inhibitors (TKI) namely, Dasatinib, Nilotinib, and Imatinib in patients with CML.

Design:

Prospective study.

Setting, Patients, Interventions:

We studied the effect of TKIs' first generation (Imatinib) and second generation ( Dasatinib and nilotinib) on semen parameters, endocrine functions in 20 euogonadal male patients with CML, and capacity to ejaculate, aged from 35 to 51 years. They were receiving either Imatinib, Dasatinib or Nilotinib as upfront therapy. We studied gonadotrophins (LH and FSH) and testosterone (T) secretion and evaluated sperm parameters before and after four months of using these TKIs.

Main Outcome Measures and Results:

Four months after starting TKIs there were significant decreases in serum testosterone, LH, FSH concentrations. The total sperm count, total and rapid progressive sperm motility, and % sperms with normal morphology decreased significantly versus before treatment. (table 1). After 4 months of therapy, Dasatinib effects on sperm count (SC), volume(SV), all sperm motilities and % of sperms with normal morphology(%NM) were significantly less harmful compared to Imatinib and Nilotinib. (Table 2).

Significant correlations were found between serum T concentrations and semen parameters before and after TKIs therapy including SC ( r = 0.658 and r = 0.73 respectively, p < 0.001), rapid progressive motility (r = 0.675 and r = 0.758 respectively p < 0.001), and the % NM(r = 0.752 and r = 0.834 respectively, p < 0.001). After TKIs therapy, LH were correlated significantly with T concentrations ( r = 0.434, p < 0.001) and SV and SC (r = 0.439 and r = 0.376 respectively, p: 0.01).

Conclusion:

Our study suggests that in patients with CML TKIs are associated with significant decrease of sperm parameters and decreased concentrations of serum T, LH, FSH. These potentially toxic effects on spermatogenesis are less prominent in patients treated with Dasatinib compared to Imatinib and Nilotinib. The mechanisms and pathways for these effects need further human and/or experimental studies.

Table 1.

Effect of TKIs on pituitary gonadal axis and sperm parameters

ALL GROUPS ON TKIs (n = 20)
BeforeAfter
Age (yr) 45.25 +/− 7.6 45.6 +/− 7.6 
LH (U/L) 6 +/− 1.75 4.6 +/− 1.14* 
FSH (U/L) 6.05 +/− 1.23 4.5 +/− 1.2* 
Testosterone (nmol/L) 16.41 +/− 2.1 13.49 +/− 1.65* 
Sperm Count (M/ml) 232 +/− 54 158 +/− 81* 
Sperm Volume (ml) 2.7 +/− 0.57 2.37 +/− 0.46 
Total PM (M/ml) 131 +/− 33 70 +/− 41* 
RPM (M/ml) 80 +/− 28 44.1 +/− 25* 
SPM (M/ml) 50.55 +/− 12.9 25.75 +/− 19.4* 
NPM (M/ml) 55.55 +/− 34.2 42.65 +/− 26.16* 
Immotile (M/ml) 46.8 +/− 23.4 44.75 +/− 23.56 
Normal Morphology % 46.8 +/− 23.4 41.95 +/− 10.3* 
ALL GROUPS ON TKIs (n = 20)
BeforeAfter
Age (yr) 45.25 +/− 7.6 45.6 +/− 7.6 
LH (U/L) 6 +/− 1.75 4.6 +/− 1.14* 
FSH (U/L) 6.05 +/− 1.23 4.5 +/− 1.2* 
Testosterone (nmol/L) 16.41 +/− 2.1 13.49 +/− 1.65* 
Sperm Count (M/ml) 232 +/− 54 158 +/− 81* 
Sperm Volume (ml) 2.7 +/− 0.57 2.37 +/− 0.46 
Total PM (M/ml) 131 +/− 33 70 +/− 41* 
RPM (M/ml) 80 +/− 28 44.1 +/− 25* 
SPM (M/ml) 50.55 +/− 12.9 25.75 +/− 19.4* 
NPM (M/ml) 55.55 +/− 34.2 42.65 +/− 26.16* 
Immotile (M/ml) 46.8 +/− 23.4 44.75 +/− 23.56 
Normal Morphology % 46.8 +/− 23.4 41.95 +/− 10.3* 
*

p < 0.01 after versus before treatment with TKIs.

Table 2:

Effect of different TKIs on pituitary gonadal axis and sperm count in the three groups

Imatinib group (n = 7)Dasatinib group (n = 7)Niolotinib group (n =6)
BeforeAfterBeforeAfterBeforeAfter
Age (yr) 44 +/− 9 44 +/− 8.9 46.1 +/− 8.7 46.49 +/− 8.7 46.2 +/− 5 46.5 +/− 5.2 
LH 7.7 +/− 1.4 5 +/− 1.15 5.3 +/− 1.1 5.14 +/− 0.9 4.8 +/− 1.17 3.5 +/− 0.55 
FSH 7.1 +/− 1.1 4.1 +/− 0.7 5.7 +/− 0.95 5.7 +/− 0.95 5.17 +/− 0.75 3.5 +/− 0.55 
Testosterone 18.3 +/− 1.33 13.2 +/− 1.12 15.6 +/− 1.7 14.8 +/− 1.7 15.1 +/− 1.63 12.33 +/− 1.13 
Sperm Count (M/ml) 220 +/− 55 88 +/− 16 271 +/− 46 256 +/− 44 202 +/− 36 123 +/− 24 
Sperm Volume (ml) 2.9 +/− 0.4 2.3 +/− 0.27 3 +/− 0.7 2.6 +/− 0.6 2.4 +/− 0.5 2.16 +/− 0.4 
Total PM (M/ml) 135 +/− 47 45 +/− 6.7 126 +/− 33 118.4 +/− 33 130.2 +/− 13 42.7 +/− 8.4 
RPM (M/ml) 88 +/− 38.9 31.3 +/− 9.4 80.3 +/− 25.6 72.6 +/− 19 70.2 +/− 14.4 25.8 +/− 7.3 
SPM (M/ml) 46.9 +/− 10.8 13.3 +/− 5.1 46.1 +/− 14.6 46 +/− 21 60 +/− 8.7 16.8 +/− 1.7 
NPM (M/ml) 43.6 +/− 31.2 20.3 +/− 7.2 83.9 +/− 26.6 71 +/− 21 36.5 +/− 25.9 35.5 +/− 10.7 
Immotile (M/ml) 42 +/− 12.1 23.1 +/− 7.2 61.3 +/− 29.8 65.7 +/− 20 35.5 +/− 19.1 45.5 +/− 17.4 
Normal Morphology % 57.6 +/− 3.2 41.6 +/− 4.6 54.4 +/− 3.7 52.4 +/− 2.2 54.2 +/− 4.6 30.2 +/− 7.2 
Imatinib group (n = 7)Dasatinib group (n = 7)Niolotinib group (n =6)
BeforeAfterBeforeAfterBeforeAfter
Age (yr) 44 +/− 9 44 +/− 8.9 46.1 +/− 8.7 46.49 +/− 8.7 46.2 +/− 5 46.5 +/− 5.2 
LH 7.7 +/− 1.4 5 +/− 1.15 5.3 +/− 1.1 5.14 +/− 0.9 4.8 +/− 1.17 3.5 +/− 0.55 
FSH 7.1 +/− 1.1 4.1 +/− 0.7 5.7 +/− 0.95 5.7 +/− 0.95 5.17 +/− 0.75 3.5 +/− 0.55 
Testosterone 18.3 +/− 1.33 13.2 +/− 1.12 15.6 +/− 1.7 14.8 +/− 1.7 15.1 +/− 1.63 12.33 +/− 1.13 
Sperm Count (M/ml) 220 +/− 55 88 +/− 16 271 +/− 46 256 +/− 44 202 +/− 36 123 +/− 24 
Sperm Volume (ml) 2.9 +/− 0.4 2.3 +/− 0.27 3 +/− 0.7 2.6 +/− 0.6 2.4 +/− 0.5 2.16 +/− 0.4 
Total PM (M/ml) 135 +/− 47 45 +/− 6.7 126 +/− 33 118.4 +/− 33 130.2 +/− 13 42.7 +/− 8.4 
RPM (M/ml) 88 +/− 38.9 31.3 +/− 9.4 80.3 +/− 25.6 72.6 +/− 19 70.2 +/− 14.4 25.8 +/− 7.3 
SPM (M/ml) 46.9 +/− 10.8 13.3 +/− 5.1 46.1 +/− 14.6 46 +/− 21 60 +/− 8.7 16.8 +/− 1.7 
NPM (M/ml) 43.6 +/− 31.2 20.3 +/− 7.2 83.9 +/− 26.6 71 +/− 21 36.5 +/− 25.9 35.5 +/− 10.7 
Immotile (M/ml) 42 +/− 12.1 23.1 +/− 7.2 61.3 +/− 29.8 65.7 +/− 20 35.5 +/− 19.1 45.5 +/− 17.4 
Normal Morphology % 57.6 +/− 3.2 41.6 +/− 4.6 54.4 +/− 3.7 52.4 +/− 2.2 54.2 +/− 4.6 30.2 +/− 7.2 

*p < 0.01 before versus after treatment,

#p < 0.01 between groups

Disclosures:

Yassin:Hamad medical corporation MRC: Employment, Research Funding. Soliman:Hamad medical corporation MRC: Employment, Research Funding. Elawa:Hamad medical corporation MRC: Employment, Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.