Imatinib mesylate has become an important therapy in the management of chronic myeloid leukemia (CML). It has an excellent safety profile, but animal studies have shown that it is potentially teratogenic. This drug is not recommended for use during pregnancy or if the patient plans to conceive. There are very few reports of outcome of pregnancy conceived while on imatinib. We report two cases of pregnancies that were conceived while the patient was on imatinib, and the patients continued to take imatinib until term.
Case 1
A 30-year-old woman presented in February 2004 with pain in the abdomen for 1.5 years. On examination the patient was found to have 4 cm splenomegaly below the costal margin, and was investigated for the same. Her hemogram and bone marrow aspiration were suggestive of chronic myeloproliferative disorder. Cytogenetics showed Philadelphia chromosome-positive in all 15 metaphases analyzed. The patient was diagnosed as having CML. She was started on hydroxyurea to reduce her white blood cell count, and was started on imatinib mesylate 400 mg/day. She was also counseled about contraception and the risk to the fetus if she became pregnant. She was in complete hematological response after 1 month. The patient returned monthly for regular check-ups and hemograms. Four months after regular follow-up she wanted to continue treatment with her local physician. She was given a letter regarding this, with an instruction to return after 3 months for follow-up to assess the response hematologically and cytogenetically. In fact, she returned after 5 months, and reported that she was following up with her obstetrician and her last ultrasound showed an 8-month-old normal fetus. She had not stopped imatinib since it was started. This suggested that the fetus had been exposed to imatinib since it was started. The case was discussed in the clinic and it was decided to continue imatinib as the fetus had already been exposed to imatinib in all three trimesters, and the patient's CML was well controlled. The key period of embryogenesis occurs between weeks 3 and 10 of post-conception life. Stem cell populations for major organ systems are determined between this period. We had no information on how the CML would behave if imatinib was stopped. Subsequently, the patient delivered a normal healthy baby. At present the patient is in complete hematological response and major cytogenetic response.
Case 2
A 27-year-old woman presented in November 2002 with low-grade fever, anorexia and weakness for 4 months. On examination she had splenomegaly up to the umbilicus. Her hemogram and bone marrow aspiration suggested chronic myeloproliferative disorder. Cytogenetics study showed Philadelphia chromosome. She was diagnosed as having CML. She was started on hydroxyurea. Her white blood cell count was controlled. She had refused to take interferon and she was not willing to undergo bone marrow transplant. She was started on imatinib 400 mg/day in January 2004 when it became available in our country. She was counseled about contraception and the risk to the fetus if she became pregnant. She achieved complete hematological response after 3 weeks. She was initially followed up at our hospital for 3 months. Susequently, she wanted to continue treatment nearer her home. She returned after 1 month. She was in complete hematological response. She then returned again after 6 months with a 1-month-old baby. She had a normal delivery and her baby is normal. She had continued to take imatinib even after she was known to be pregnant. She was in complete hematological remission but there was no cytogenetic response. Her imatinib dose has been increased to 600 mg/day.
Discussion
Pregnancy and cancer is a complex situation. Often treatment cannot be delayed. When chemotherapy is needed urgently, this typically requires termination of pregnancy [1]. Many patients with CML have been reported to have had a successful pregnancy. However, there is a paucity of data regarding CML patients on imatinib mesylate becoming pregnant and completing pregnancy [1
]. Twenty-four pregnancies have been reported among female patients with CML on imatinib mesylate. Only four of them proceeded to term; most of the other patients opted for elective therapeutic abortions. Out of these four patients, three had normal infants and one infant had hypospadias. In three of these patients imatinib was stopped after pregnancy was detected. One patient who relapsed with blast crisis imatinib had to be restarted. This patient who had to continue with imatinib had a normal infant [2
].
Imatinib has been found to be antiangiogenic in animal models. This antiangiogenic effect is mediated by platelet-derived growth factor receptor (PDGFR); however, it does not affect human umbilical vein endothelial cells as they do not express PDGFR. Imatinib has been found to be teratogenic in rats at dose above 100 mg/kg but not at doses up to 60 mg/kg. The teratogenic effect observed are encephalocele, anencephaly, and reduced and absent parietal bones in animal studies. Female rats also experienced early fetal resorption.
Imatinib is not genotoxic but it has been suggested that it leads to a decrease in spermatozoa counts. This has been confirmed as 18 pregnancies have been reported in partners of male patients on imatinib with four normal deliveries. A few reports also confirm that it decreases spermatozoa counts in human [2].
Pregnancy does not affect the course of CML as was observed in both our cases. However, the effect of pregnancy on the efficacy of imatinib is not known [3]. Both of our cases had a complete hematological response, one of them had major cytogenetic response and the other patient did not have any cytogenetic response. More data are needed to address this issue.
We follow the recommendation that women of reproductive age who have been started on imatinib should use effective contraception. However, the present two cases in our study and other cases in the literature suggest that if a patient inadvertently conceives while on imatinib, the pregnancy can evolve uneventfully. However, these apparently normal children need to be followed up to look for any long-term side-effects if any.
Tata Memorial Hospital, Medical Oncology, Mumbai, India
* E-mail: kp_madhusingh{at}yahoo.com
References
1. Heartin E, Walkinshaw S, Clark RE. Successful outcome of pregnancy in chronic myeloid leukemia treated with imatinib. Leuk Lymphoma 2004; 45: 13071308.[CrossRef][ISI][Medline]
2. Hensley ML, Ford JM. Imatinib treatment: Specific issues related to safety, fertility and pregnancy. Semin Hematol 2003; 40: 2125.[CrossRef][ISI][Medline]
3. Ali R, Ozkalemkas F, Ozkocaman V et al. Successful pregnancy and delivery in a patient with chronic myelogenous leukemia (CML), and mamagement of CML with leukapheresis during pregnancy: a case report and review of the literature. Jpn J Clin Oncol 2004; 34: 215217.
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