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Journal of Clinical Oncology, Vol 24, No 23 (August 10), 2006: pp. 3812-3813 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.9310
Imatinib and PregnancyDivision of Hematology, Department of Internal Medicine, Uludag University School of Medicine, Bursa, Turkey To the Editor: We read with great interest the article by Ault et al1 in a recent issue of Journal of Clinical Oncology, describing the results of pregnancy among patients with chronic myeloid leukemia (CML) treated with imatinib. We would like to add some points and bring attention to some questions concerning imatinib and pregnancy. Tyrosine kinases (TKs) are one of the most critical groups of signaling molecules for the cellular regulation of proliferation, differentiation, survival, function, and motility, and various tumors overexpress TKs, leading to uncontrolled mitogenic signals to the neoplastic cells. Imatinib (Gleevec or Glivec; Novartis, Basel, Switzerland) is a small-molecule tyrosine kinase inhibitor active against BCR-ABL, c-ABL, ARG, PDGF-r, and c-KIT.2 Although imatinib has been used primarily for cancers such as CML, use of imatinib has demonstrated that tyrosine kinase inhibitors can have a wide therapeutic window and heralds the era of targeted cancer and noncancer disease therapy. Information about the effects of drugs on the developing embryo is derived primarily from animal experiments and case reports describing the outcomes of pregnancies complicated with drug. Some drugs can be teratogenic in some animal species, but not in humans. In preclinical studies imatinib was found to be teratogenic in rats, but not in rabbits, and impaired spermatogenesis was observed in rats, dogs, and monkeys; however, there was no evidence that imatinib was genotoxic. These observations lead to concerns that men treated with imatinib may have reduced sperm counts. Clinical experience has not shown this to be true because male patients who were receiving treatment of imatinib were partners in 18 pregnancies and four healthy infants. Owing to teratogenicity data in rats (causing exencephaly or encephalocele, and absent or reduced frontal and absent parietal bones), it is recommended that women treated with imatinib be aware of the potential teratogenicity of imatinib, and effective contraception should be used during imatinib therapy to prevent pregnancy.2 Hensley and Ford2 reported 26 pregnancies (15 in clinical trials, 11 in nonclinical trials) among women taking imatinib. Most of the patients opted for elective therapeutic abortions, and only three patients carried their pregnancies to term. Two infants were healthy, and one infant had hypospadias. Recently, eight patients with CML who became pregnant while receiving imatinib therapy were reported from different areas of the world.3-7 All of the fetuses had been exposed to imatinib during the first trimester, and four fetuses have also been exposed to imatinib during the second and third trimesters. Six of the reported eight pregnancies proceeded to term with healthy infants, and two were terminated with unsatisfactory outcomes—one had spontaneous abortion4 and the other had a dead fetus with meningocele.7 More recently, Ault et al1 reported their experience on 19 pregnancies involving 18 patients (10 female and eight male patients) who conceived while receiving imatinib for the treatment of CML. Three pregnancies (involving two female patients and one male patient) ended in spontaneous abortion, and one patient had an elective abortion. All other pregnancies were uneventful. Two of 16 infants had minor abnormalities at or shortly after birth (hypospadias in one and rotation of small intestine in another) that were surgically repaired. The reported outcomes of pregnancies under treatment of imatinib are satisfactory, but do not indicate that imatinib can be safely recommended during the first trimester of gestation. What can we do if a patient with CML after having achieved a molecular remission, or another patient receiving imatinib for a different disease wishes to become involved in a pregnancy? Since we know the outcome of discontinuation of imatinib therapy after achieving a molecular remission, shall we use imatinib in the second or third trimester? What can we do in the event of inadvertent conception on imatinib therapy? Although it is difficult to answer these questions, in light of reported cases, we conclude that patients who are under treatment of imatinib at the moment of conception may have normal pregnancies. We think that each case should be examined individually in terms of the aggressiveness of the disease, and decisions should to be individualized. In conclusion, in the face of complicated pregnancy with imatinib, both social and humanitarian factors should be considered, and the main aim should be to ensuer a healthy mother and a healthy infant in both the short- and long-term. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Ault P, Kantarjian H, O'Brien S, et al: Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol 24:1204-1208, 2006 2. Hensley ML, Ford JM: Imatinib treatment: Specific issues related to safety, fertility, and pregnancy. Semin Hematol 40:21-25, 2003[Medline] 3. Heartin E, Walkinshaw S, Clark RE: Successful outcome of pregnancy in chronic myeloid leukemia treated with imatinib. Leukemia Lymphoma 45:1307-1308, 2004[CrossRef][Medline] 4. AlKindi S, Dennison D, Pathare A: Imatinib in pregnancy. Eur J Haematol 74:535-537, 2005[CrossRef][Medline] 5. Ali R, Ozkalemkas F, Ozcelik T, et al: Pregnancy under treatment of imatinib and successful labor in a patient with chronic myelogenous leukemia (CML): Outcome of discontinuation of imatinib therapy after achieving a molecular remission. Leuk Res 29:971-973, 2005[CrossRef][Medline] 6. Prabhash K, Sastry PSRK, Biswas G, et al: Pregnancy outcome of two patients with imatinib. Ann Oncol 16:1983-1984, 2005 7. Choudhary DR, Mishra P, Kumar R, et al: Pregnancy on imatinib: Fatal outcome with meningocele. Ann Oncol 17:178-179, 2006 Related Reply
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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