Oligospermia in a Patient Receiving Imatinib Therapy for the Hypereosinophilic Syndrome
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《新英格兰医药杂志》
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.
Tara 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
Drs. Seymour and McArthur report having received honoraria from Novartis, the manufacturer of imatinib.
References
Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201-1214.
Tybulewicz VL, Crawford CE, Jackson PK, Bronson RT, Mulligan RC. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 1991;65:1153-1163.
Mauduit C, Hamamah S, Benahmed M. Stem cell factor/c-kit system in spermatogenesis. Hum Reprod Update 1999;5:535-545.
Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist 2004;9:271-281.
Gambacorti-Passerini C, Tornaghi L, Cavagnini F, et al. Gynaecomastia in men with chronic myeloid leukaemia after imatinib. Lancet 2003;36:1954-1956.
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.
Tara 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
Drs. Seymour and McArthur report having received honoraria from Novartis, the manufacturer of imatinib.
References
Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201-1214.
Tybulewicz VL, Crawford CE, Jackson PK, Bronson RT, Mulligan RC. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 1991;65:1153-1163.
Mauduit C, Hamamah S, Benahmed M. Stem cell factor/c-kit system in spermatogenesis. Hum Reprod Update 1999;5:535-545.
Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist 2004;9:271-281.
Gambacorti-Passerini C, Tornaghi L, Cavagnini F, et al. Gynaecomastia in men with chronic myeloid leukaemia after imatinib. Lancet 2003;36:1954-1956.