Correspondence
Oligospermia in a Patient Receiving Imatinib Therapy for the Hypereosinophilic Syndrome
N Engl J Med 2004; 351:2134-2135November 11, 2004
- Article
To the Editor:
We report the development of oligospermia in a young man treated with imatinib for the hypereosinophilic syndrome. Imatinib was developed as a selective inhibitor of the BCR-ABL tyrosine kinase that is constitutively activated in chronic myeloid leukemia (CML). It also potently inhibits other normal cellular tyrosine kinases, c-abl, c-arg, and the receptors for platelet-derived growth factor (PDGF) and stem-cell factor (c-kit). Imatinib has been successfully used therapeutically against these kinases in other malignant diseases, including the hypereosinophilic syndrome.1
The role of these tyrosine kinases in normal cellular function is still being elucidated, and their inhibition by imatinib may contribute to unintended effects. For example, c-abl–deficient mice have impaired fertility, lymphopenia, and altered gastrointestinal motility, and animals lacking c-kit have various alterations in spermatogenesis.2,3
In clinical experience to date, imatinib has been asociated with adverse effects of rash, nausea, diarrhea, superficial edema, myelosuppression, muscle cramps, and elevated levels of hepatic transaminases.4 Altered c-kit activity may be involved in the development of changes in skin.4 Gynecomastia has also been associated with imatinib therapy, possibly through inhibition of c-kit and the PDGF receptor, leading to the impaired production of testosterone.5
A developmentally normal patient, now 18 years of age, was diagnosed with hypereosinophilic syndrome in October 2002. At that time, he was treated with hydroxyurea (3 g per day), prednisolone (60 mg per day), and interferon alfa (3 million units). He was referred to our institution for consideration of imatinib therapy. Semen was cryopreserved in December 2002 (volume, 3.2 ml; count, 20 million per milliliter, with 40 percent showing moderate motility). Imatinib therapy was commenced at 400 mg per day for one month, then, owing to lack of response, escalated to 600 mg per day for five months, and continues at 800 mg per day. A semen analysis performed in December 2003 showed marked oligospermia (volume, 2.5 ml; sperm count, <1 million per milliliter, with 25 percent showing low motility and 75 percent complete immotility). The patient took no other medications between the two semen analyses, and his hypereosinophilic syndrome was in remission. The testosterone levels were normal.
Imatinib has revolutionized the treatment of CML and gastrointestinal stromal tumors. Its role in other tumors continues to be investigated. Oligospermia has not previously been recognized as an adverse effect of imatinib, although the role of the escalated dose used to treat this patient is unclear. We believe that the risk of impaired fertility should be considered when patients are counseled before imatinib therapy is initiated, and pretreatment storage of semen should be considered. More studies of the effect of imatinib on male fertility are needed to ascertain the true incidence of this phenomenon.
5 ReferencesTara Seshadri, M.B., B.S.
John F. Seymour, M.B., B.S.
Grant A. McArthur, M.B., B.S., Ph.D.
Peter MacCallum Cancer Centre, Melbourne 2003, Australia
john.seymour@petermac. org 1
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- Citing Articles (17)
Citing Articles
1
Charles Chuah. (2011) Imatinib does not impair gonadal function. Leukemia Research
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Beate Schultheis, Bart A. Nijmeijer, H. Yin, Roger G. Gosden, Junia V. Melo. (2011) Imatinib mesylate at therapeutic doses has no impact on folliculogenesis or spermatogenesis in a leukaemic mouse model. Leukemia Research
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Emad Shash, Simona Bassi, Emilia Cocorocchio, Giovanni Maria Colpi, Saverio Cinieri, Fedro Alessandro Peccatori. (2011) Fatherhood during imatinib. Acta Oncologica 50:5, 734-735
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Avi Leader, Michael Lishner, Jennia Michaeli, Ariel Revel. (2011) Fertility considerations and preservation in haemato-oncology patients undergoing treatment. British Journal of Haematology 153:3, 291-308
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Crystal Heim, Kayla Minniear, Christina Tenenhaus Dann. (2011) Imatinib has deleterious effects on differentiating spermatogonia while sparing spermatogonial stem cell self renewal. Reproductive Toxicology 31:4, 454-463
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Stefania Mariani, Sabrina Basciani, Andrea Fabbri, Luciano Agati, Salvatore Ulisse, Carla Lubrano, Giovanni Spera, Lucio Gnessi. (2011) Severe oligozoospermia in a young man with chronic myeloid leukemia on long-term treatment with imatinib started before puberty. Fertility and Sterility 95:3, 1120.e15-1120.e17
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Jane Apperley. (2009) CML in pregnancy and childhood. Best Practice & Research Clinical Haematology 22:3, 455-474
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Christopoulos, Constantinos, Dimakopoulou, Vasiliki, Rotas, Evangelos, . (2008) Primary Ovarian Insufficiency Associated with Imatinib Therapy. New England Journal of Medicine 358:10, 1079-1080
Full Text9
Issa J. Dahabreh, Stavroula Giannouli, Christine Zoi, Katerina Zoi, Michael Voulgarelis, Haralampos M. Moutsopoulos. (2007) Management of Hypereosinophilic Syndrome. Medicine 86:6, 344-354
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Matko Kalac, Alfonso Quintás-Cardama, Radovan Vrhovac, Hagop Kantarjian, Srdan Verstovsek. (2007) A critical appraisal of conventional and investigational drug therapy in patients with hypereosinophilic syndrome and clonal eosinophilia. Cancer 110:5, 955-964
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Amy D. Klion. (2007) Approach to the Therapy of Hypereosinophilic Syndromes. Immunology and Allergy Clinics of North America 27:3, 551-560
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Karthik Ramasamy, Janet Hayden, ZiYi Lim, Ghulam J. Mufti, Aloysius Y. L. Ho. (2007) Successful pregnancies involving men with chronic myeloid leukaemia on imatinib therapy. British Journal of Haematology 137:4, 374-375
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Andrew Grigg, Timothy Hughes. (2006) Role of Allogeneic Stem Cell Transplantation for Adult Chronic Myeloid Leukemia in the Imatinib Era. Biology of Blood and Marrow Transplantation 12:8, 795-807
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Ayalew Tefferi, Mrinal M. Patnaik, Animesh Pardanani. (2006) Eosinophilia: secondary, clonal and idiopathic. British Journal of Haematology 133:5, 468-492
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Ziyad Al Aly, Jennifer M. Philoctête Ashley, Mary E. Gellens, Esther A. González. (2005) Thrombotic thrombocytopenic purpura in a patient treated with imatinib mesylate: True association or mere coincidence?. American Journal of Kidney Diseases 45:4, 762-768
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(2005) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 14:3, i-xii
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A. Tefferi. (2005) Modern Diagnosis and Treatment of Primary Eosinophilia. Acta Haematologica 114:1, 52-60
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