Long-term Imatinib Treatment does not Cause Testicular Toxicity in Male Adolescents with Chronic Myeloid Leukemia and in a Juvenile Rat Model

Abstract

Background: The impact of exposure to the tyrosine kinase inhibitor (TKI) imatinib (IMA) on the male reproductive endocrine system is still discussed controversially. We therefore investigated testosterone (Testo) and inhibin B (InB) in blood serum from male adolescents with chronic myeloid leukemia (CML) under long-term TKI treatment. Also long-term exposure to TKIs was studied in a juvenile rat model.

Methods: Serum was collected at 3 months intervals from 13 boys (age: 7.8–18.9 years, median: 12.8 years) with CML receiving TKI treatment over 3–58 months (median: 18 months). 4 weeks (w) old male rats were exposed, either chronically or intermittently, via the drinking water to a standard (SD) and a high dose (=2-fold SD) of IMA, dasatinib (DASA), or bosutinib (BOSU) over a 10 w period. Controls received water only. Animals were sacrificed after 2 w (prepubertal), 4 w (pubertal), and 10 w (postpubertal) of exposure. Testo and InB serum levels were measured by ELISA.

Results: Boys exhibited Testo and InB levels within normal age-related reference ranges and no pattern of rising or falling levels during TKI treatment could be observed. In rats, Testo levels under IMA exposure tended to be non-significantly lowered at postpubertal age compared to controls while no significant differences were found under DASA and BOSU exposure. Animals’ InB levels did not significantly differ from controls for all TKIs, at all doses, and by all application schemes tested.

Conclusion: With the limitation that the number of individuals tested was rather small, testicular toxicity due to TKI seems unlikely as no alterations of Testo and InB blood levels neither in male adolescent patients nor in rats under long-term TKI exposure was observed.

Zusammenfassung

Hintergrund: Die Langzeit-Nebenwirkung einer TKI-Therapie mit Imatinib (IMA) auf das männliche Reproduktionssystem wird kontrovers diskutiert. Wir untersuchten bei männlichen adoleszenten Patienten mit chronischer myeloischer Leukämie (CML) Testosteron (Testo) und Inhibin B (InB) Serumspiegel unter TKI-Therapie. Ebenfalls wurden Folgen der TKI-Langzeitexposition in einem etablierten Tiermodell untersucht.

Methode: Bei 13 Jungen (Alter: 7,8–18,9 Jahre, Median: 12,8 J) mit CML unter Standard TKI-Therapie wurden über 3–58 Monate (Median: 18 Monate) Serumproben in 3-monatlichen Intervallen untersucht. 4 Wochen (W) alte männliche Ratten wurden chronisch oder intermittierend über das Trinkwasser mit einer Standarddosis (SD) und einer Hochdosis (HD=2 × SD) von IMA, Dasatinib (DASA), oder Bosutinib (BOSU) über 10 W exponiert. Nach 2 W (präpubertär), 4 W (pubertär) und 10 W (postpubertär) Exposition wurde Serum gewonnen. Testo- und InhB-Spiegel wurden mittels ELISA ermittelt.

Ergebnisse: Testo- und InB-Serumspiegel der Jungen lagen innerhalb der altersabhängigen Refe­renzbereiche ohne steigenden oder abfallenden Trend unter TKI-Therapie. In Ratten zeigte die IMA-Exposition einen nicht signifikanten Trend zu reduzierten Testo-Spiegeln postpubertär; DASA und BOSU aber keinen Effekt. Die InB-Spiegel waren unter allen TKI, untersuchten Dosen und Applikationsschemata unverändert.

Schlussfolgerung: Trotz der geringen Zahl an Untersuchungen scheint eine testikuläre Toxi­zität durch TKIs unwahrscheinlich, da keine Veränderungen von Testo und InB Serumspiegeln in Jungen oder Ratten unter Langzeit-TKI Exposition beobachtet wurden.

Key words

CML - imatinib - boys - fertility - rat model

Schlüsselwörter

CML - imatinib - Jungen - Fertilität - Tiermodel

• References

• 1 Andersson AM, Juul A, Petersen JH et al. Serum inhibin B in healthy pubertal and adolescent boys: relation to age, stage of puberty, and follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol levels. J Clin Endocrinol Metab 1997; 82: 3976-3981
• 2 Abbott BL. Dasatinib: from treatment of imatinib-resistant or -intolerant patients with chronic myeloid leukemia to treatment of patients with newly diagnosed chronic phase chronic myeloid leukemia. Clin Ther 2012; 34: 272-281
• 3 Ault P, Kantarjian H, O’Brien S et al. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol 2006; 24: 1204-1208
• 4 Baccarani M, Deininger MW, Rosti G et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013 122. 872-884
• 5 Baker MA, Hetherington L, Curry B et al. Phosphorylation and consequent stimulation of the tyrosine kinase c-Abl by PKA in mouse spermatozoa: its implication during capacitation. Dev Biol 2009; 333: 57-66
• 6 Basciani S, De LG, Dolci S et al. Platelet-derived growth factor receptor beta-subtype regulates proliferation and migration of gonocytes. Endocrinology 2008; 149: 6226-6235
• 7 Chuah C. Imatinib does not impair gonadal function (Editorial). Leukemia Res 2012; 36: 262-263
• 8 Gambacorti-Passerini C, Tornaghi L, Cavagnini F et al. Gynaecomastia in men with chronic myeloid leukaemia after imatinib. Lancet 2003; 361: 1954-1956
• 9 Hensley ML, Ford JM. Imatinib treatment: specific issues related to safety, fertility, and pregnancy. Semin Hematol 2003; 40: 21-25
• 10 Kantarjian HM, Hochhaus A, Saglio G et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011; 12: 841-851
• 11 Mariani S, Basciani S, Arizzi M et al. PDGF and the testis. Trends Endocrinol Metab 2002; 13: 11-17
• 12 Mariani S, Basciani S, Fabbri A et al. Severe oligozoospermia in a young man with chronic myeloid leukemia on long-term treatment with imatinib started before puberty. Fertil Steril 2011; 95: 1120.e15-e17
• 13 Mauduit C, Hamamah S, Benahmed M. Stem cell factor/c-kit system in spermatogenesis. Hum Reprod Update 1999; 5: 535-545
• 14 Nurmio M, Toppari J, Zaman F et al. Inhibition of tyrosine kinases PDGFR and C-Kit by imatinib mesylate interferes with postnatal testicular development in the rat. Int J Androl 2007; 30: 366-376
• 15 Nurmio M, Kallio J, Toppari J et al. Adult reproductive functions after early postnatal inhibition by imatinib of the two receptor tyrosine kinases, c-kit and PDGFR, in the rat testis. Reprod Toxicol 2008; 25: 442-446
• 16 O’Brien S, Berman E, Borghaei H et al. Chronic Myelogenous Leukemia. J Natl Compr Canc Netw 2009; 7: 984-1023
• 17 Oweini H, Otrock ZK, Mahfouz RA et al. Successful pregnancy involving a man with chronic myeloid leukemia on dasatinib. Arch Gynecol Obstet 2011; 283: 133-134
• 18 Prasad AM, Ramnarayan K, Nalini K et al. Effect of imatinib on the biochemical parameters of the reproductive function in male Swiss albino mice. Indian J Pharmacol 2011; 43: 389-392
• 19 Pye SM, Cortes J, Ault P et al. The effects of imatinib on pregnancy outcome. Blood 2008; 111: 5505-5508
• 20 Ramasamy K, Hayden J, Lim Z et al. Successful pregnancies involving men with chronic myeloid leukaemia on imatinib therapy. Br J Haematol 2007; 137: 374-375
• 21 Ross DM, Branford S, Seymour JF et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013; 122: 515-522
• 22 Schultheis B, Nijmeijer BA, Yin H et al. Imatinib mesylate at therapeutic doses has no impact on folliculogenesis or spermatogenesis in a leukaemic mouse model. Leuk Res 2012; 36: 271-274
• 23 Seshadri T, Seymour JF, McArthur GA. Oligospermia in a patient receiving imatinib therapy for the hypereosinophilic syndrome. N Engl J Med 2004; 351: 2134-2135
• 24 Shash E, Bassi S, Cocorocchio E et al. Fatherhood during imatinib. Acta Oncol 2011; 50: 734-735
• 25 Stewart J, Turner KT. Inhibin B as a potential biomarker of testicular toxicity. Cancer Biomark 2005; 1: 75-91
• 26 Suttorp M, Millot F. Treatment of pediatric chronic myeloid leukemia in the year 2010: use of tyrosine kinase inhibitors and stem-cell transplantation. Hematology Am Soc Hematol Educ Program 2010; 2010: 368-376
• 27 Suttorp M, Eckardt L, Tauer JT et al. Management of Chronic Myeloid Leukemia in Childhood. Curr Hematol Malig Rep 2012; 7: 116-124
• 28 Tauer JT, Hofbauer LC, König S et al. Non-selective side effects of nonreceptor tyrosine kinase inhibitors (TKI). Klin Padiatr 2011; 223: A2
• 29 Ulmer A, Tauer JT, Suttorp M. Influence of tyrosine kinase inhibitors (TKIs) on endocrinological parameters. Klin Padiatr 2012; 224: A4
• 30 Ulmer A, Tauer JT, Glauche I et al. TK inhibitor treatment disrupts growth hormone axis: clinical observations in children with CML and experimental data from a juvenile animal model. Klin Padiatr 2013; 225: 120-126
• 31 Zawatski W, Lee MM. Male pubertal development: are endocrine-disrupting compounds shifting the norms?. J Endocrinol 2013; 218: R1-R12
• 32 Rendtorff R, Hohmann C, Reinmuth S et al. Hormone and Sperm Analyses after Chemo- and Radiotherapy in Childhood and Adolescence. Klin Padiatr 2010; 222: 145-149
• 33 Schweizer R, Blumenstock G, Mangelsdorf K et al. Prevalence and incidence of endocrine disorders in children: results of a survey in Baden-Wuerttemberg and Bavaria (EndoPrIn BB) 2000–2001. Klin Padiatr 2010; 222: 67-72