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Pregnancy under treatment of imatinib and successful labor in a patient with chronic myelogenous leukemia (CML)
Leukemia Research 29 (2005) 971–973
Case report
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 a , Ulk¨ ¨ ¨ ¸ elik a , Vildan Ozkocaman ¨ ¨ u Ozan a , Yalc¸ın Rıdvan Ali a, ∗ , Fahir Ozkalemkas ¸ a , T¨ulay Ozc Kimya b , Nilg¨un K¨oksal c , Tuna G¨ulten d , Tahsin Yakut d , Ahmet Tunalı a a
Division of Hematology, Department of Internal Medicine, Uludag University School of Medicine, Bursa, Turkey b Department of Obstetrics and Gynecology, Uludag University School of Medicine, Bursa, Turkey c Division of Neonatology, Department of Pediatrics, Uludag University School of Medicine, Bursa, Turkey d Department of Medical Genetics, Uludag University School of Medicine, Bursa, Turkey Received 1 January 2005 Available online 16 February 2005
Abstract Because of the teratogenicity data in rats, it is recommended that women treated with imatinib should be aware of the potential teratogenicity of imatinib and effective contraception should be used during imatinib therapy to prevent pregnancy. We describe successful pregnancy and delivery, without any congenital anomaly, in a patient with CML under treatment of imatinib. The fetus had been exposed to imatinib for 8 weeks. The patient remained off treatment during gestation and cytogenetic relapse of CML (5 months after discontinuation of imatinib therapy) developed at seventh month of gestation. © 2005 Elsevier Ltd. All rights reserved. Keywords: Chronic myelogenous leukemia; Pregnancy; Imatinib
1. Introduction The pregnancy of a patient with a neoplastic disease requiring cytotoxic treatment poses a very difficult therapeutic dilemma. A related problem arises when a woman becomes pregnant during or shortly after receiving chemotherapy, due to the side effects of most cytotoxic agents. Most information on this subject stems from animal experiments, but there are relatively few data on human abnormalities. Imatinib entered clinical trials in 1998 and has since been shown to induce dramatic hematologic and cytogenetic responses in CML [1]. Whether imatinib therapy may be discontinued safely in patients who achieve complete remission is the important and unanswered question at the present time [2,3]. Because of ∗
Corresponding author. Tel.: +90 224 4428400; fax: +90 224 4428060. E-mail address: [email protected] (R. Ali).
0145-2126/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2005.01.009
the teratogenicity data in rats, it is recommended that women treated with imatinib should be aware of the potential teratogenicity of imatinib and effective contraception should be used during imatinib therapy to prevent pregnancy [4]. We describe successful pregnancy and labor under treatment of imatinib in a patient with CML, and the outcome of discontinuation of imatinib therapy after achieving a molecular remission.
2. Case report A 44-year-old woman was admitted with fatigue, back and bone pain, unexplained weight loss of 4 months duration and abdominal discomfort. On initial examination, she was found to have pale appearance and a spleen palpable 15 cm below the left costal margin. The WBC were 281 × 109 l−1 with
972
R. Ali et al. / Leukemia Research 29 (2005) 971–973
24% neutrophils, 21% bands, 17% metamyelocytes, 24% myelocytes, 1% promyelocyte, 5% basophils, 8% eosinophils and 2% pyknotic erythroblasts. The hemoglobin was 7.9 g/dl and the platelet count 580 × 109 l−1 . A bone marrow specimen demonstrated marked granulocytic hyperplasia and marrow cells contained the Philadelphia (Ph) chromosome. Chronic phase CML diagnosis was made. After reduction of WBC with hydroxyurea, imatinib at a dose of 400 mg daily was started for treatment of CML. The patient achieved hematological and cytogenetic complete remission within 3 months. On the fifth month of imatinib therapy, she was presented with nausea and vomiting. Her pregnancy test was found positive and ultrasound scan confirmed a viable fetus of 8 weeks. Imatinib was stopped immediately. Detailed fetal abnormality scanning did not demonstrate any cause for concern. Her history revealed that she had developed four spontaneous abortions in 1992, 1995, 1998 and 2001. All of them developed during 8–10 weeks of gestation. Detailed investigations did not reveal any evidence for spontaneous abortions such as systemic lupus erythematosus, antiphospholipid syndrome, thrombophilia and toxoplasmosis. Since the family did not have a baby, the patient and her family had demands on the continuity of the pregnancy and also they did not allow permission for any invasive procedure or medical abortion. Detailed information about the disease and imatinib, and possible complications of them were given. Her written informed consent was obtained for the continuity of the pregnancy with supportive therapy and leukapheresis [1,5], if required, on the following weeks. The patient remained off treatment during gestation. Five months after discontinuation of imatinib therapy (seventh month of gestation) she had 10% metaphases positive for the Ph chromosome by fluorescence in situ hybridization (FISH). Hematologic relapse was observed at sixth month of discontinuation of therapy (eighth month of gestation). Her hematologic condition did not progress (Hb > 11 g/dl; WBC < 50 × 109 l−1 ; platelet < 500 × 109 l−1 ) during gestation. Fetal growth on ultrasound was normal and amniotic fluid volume was within normal limits. Labor was induced at 38th week of gestation. A healthy girl, weighing 3200 g, 51 cm in length with Apgar score of 9, was delivered vaginally. The infant’s general examination and blood count were within normal limits. Macroscopic examination of the placenta was normal. The patient’s WBC at the labor were 15 × 109 l−1 , hemoglobin 11 g/dl and platelet counts 220 × 109 l−1 . Any prenatal or postnatal complication did not occur. The infant’s transfontanel, abdominal and hip ultrasonography, echocardiography and chromosomal analysis were normal. The baby is healthy and growing normally.
3. Discussion The management of leukemia during pregnancy is a difficult problem because of the potential effects of the therapy on the mother and fetus. Therapeutic approaches of leukemia
complicated with pregnancy may be different from those usually used to treat this disease. The differences are modified by several variables, including time of diagnosis, type of leukemia, clinical tolerance of the disease, toxic effects of the drugs on mother and child and the decision of family [1,5,6]. While CML may not need to be treated immediately and pregnancy does not appear to affect the course of CML, there is still a risk of leukostasis as well as the risk of placental insufficiency with consecutive below-normal fetal birth weight, increased fetal prematurity and increased mortality if CML is left untreated for the duration of the pregnancy [1]. Through rational drug development, imatinib; Gleevec or Glivec (formerly STI571), a bcr-abl tyrosine kinase inhibitor offers a new hope for expanded options for patients with CML. Efficacy and place of imatinib on CML is discussed thoroughly in the literature. In preclinical studies, imatinib was teratogenic in rats, but not rabbits. Because of the teratogenicity data in rats, it is recommended that women treated with imatinib should be aware of the potential teratogenicity of imatinib and effective contraception should be used during imatinib therapy to prevent pregnancy [4]. There are few data about imatinib therapy during pregnancy in humans [4,7,8]. The most critical period for teratogenicity is the first trimester because this period correlates with the stage of active organogenesis. Hence, many authors advise against the use of anti-neoplastic agents during the first trimester [1,5,6,9,10]. The case that we reported was under treatment of imatinib for 5 months and the fetus had been exposed to imatinib for 8 weeks. The child was morphologically normal, her growth and development were normal and no congenital anomaly was established to date (2 months). The child was breast-fed for 1 month, because imatinib therapy was restarted. In animals, imatinib or its metabolites were extensively excreted in milk. It is not known whether imatinib is excreted in human milk, therefore, it was suggested that women taking imatinib should not breast-feed [8]. Recently Heartin et al. [7] reported the first successful pregnancy and labor in a patient with CML under treatment of imatinib. To our knowledge, the case that we reported is the second healthy pregnancy under imatinib treatment and healthy outcome without any congenital anomaly in the English literature. The patient we presented has been married for 14 years. She had four spontaneous abortions; all of them being in the first trimester and the cause for these abortions was not identified. After all these years she could have a baby “incidentally” after imatinib therapy. Since there was no identified cause in the past for her relapsing aborts, her developing pregnancy and delivering a healthy baby after imatinib therapy is interesting and requires much more concern. Whether imatinib therapy may be discontinued safely in patients who achieve complete remission is important and unanswered question at the present time. Our case discontinued the imatinib therapy because of pregnancy and 5 months after discontinuation of therapy she had 10% Ph-positive metaphases by fluorescence in situ hybridization. But hematologic relapse was observed at the sixth month of discontin-
R. Ali et al. / Leukemia Research 29 (2005) 971–973
uation of therapy (eighth month of gestation). Our and other author’s [2,3] experience illustrates the need for continued therapy with imatinib after achieving molecular remission. In conclusion, human’s pregnancy is complex, more experience and studies are required for predicting about imatinib therapy in human pregnancy and it cannot be recommended at the present time to discontinue therapy for patients who achieve a molecular remission with imatinib.
References ¨ ¨ ¨ ¸ elik T, Ozan U, ¨ Kimya Y, [1] Ali R, Ozkalemkas F, Ozkocaman V, Ozc et al. Successful pregnancy and delivery in a patient with chronic myelogenous leukemia (CML), and management of CML with leukapheresis during pregnancy: a case report and review of the literature. Jpn J Clin Oncol 2004;34:215–7. [2] Mauro MJ, Druker BJ, Maziarz RT. Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission. Leuk Res 2004;28S1:S71–3.
973
[3] Cortes J, O’Brien S, Kantarjian H. Discontinuation of imatinib therapy after achieving a molecular response. Blood 2004;104: 2204–5. [4] Hensley ML, Ford JM. Imatinib treatment: specific issues related to safety, fertility, and pregnancy. Semin Hematol 2003;40: 21–5. ¨ ¨ ¨ ¸ elik T, [5] Ali R, Ozkalemkas ¸ F, Ozkocaman V, B¨ulb¨ul-Bas¸kan E, Ozc ¨ et al. Successful labor in the course of chronic lymphocytic Ozan U, leukemia (CLL) and management of CLL during pregnancy with leukapheresis. Ann Hematol 2004;83:61–3. ¨ ¨ ¸ elik T, Ozkocaman ¨ ¨ Kimya Y, [6] Ali R, Ozkalemkas F, Ozc V, Ozan U, et al. Maternal and fetal outcomes in pregnancy complicated with acute leukemia: a single institutional experience with 10 pregnancies at 16 years. Leuk Res 2003;27:381–5. [7] Heartın E, Walkinshaw S, Clark RE. Successful outcome of pregnancy in chronic myeloid leukemia treated with Imatinib. Leuk Lymphoma 2004;45:1307–8. [8] Glivec-Clinical monograph. Basel, Switzerland: Novartis Pharma AG; 2004. [9] Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol 2004;5:283–91. [10] Buerkers TE, Lallas TA. Chemotherapy in pregnancy. Obstet Gynecol Clin North Am 1998;25:323–9.
Case report
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 a , Ulk¨ ¨ ¨ ¸ elik a , Vildan Ozkocaman ¨ ¨ u Ozan a , Yalc¸ın Rıdvan Ali a, ∗ , Fahir Ozkalemkas ¸ a , T¨ulay Ozc Kimya b , Nilg¨un K¨oksal c , Tuna G¨ulten d , Tahsin Yakut d , Ahmet Tunalı a a
Division of Hematology, Department of Internal Medicine, Uludag University School of Medicine, Bursa, Turkey b Department of Obstetrics and Gynecology, Uludag University School of Medicine, Bursa, Turkey c Division of Neonatology, Department of Pediatrics, Uludag University School of Medicine, Bursa, Turkey d Department of Medical Genetics, Uludag University School of Medicine, Bursa, Turkey Received 1 January 2005 Available online 16 February 2005
Abstract Because of the teratogenicity data in rats, it is recommended that women treated with imatinib should be aware of the potential teratogenicity of imatinib and effective contraception should be used during imatinib therapy to prevent pregnancy. We describe successful pregnancy and delivery, without any congenital anomaly, in a patient with CML under treatment of imatinib. The fetus had been exposed to imatinib for 8 weeks. The patient remained off treatment during gestation and cytogenetic relapse of CML (5 months after discontinuation of imatinib therapy) developed at seventh month of gestation. © 2005 Elsevier Ltd. All rights reserved. Keywords: Chronic myelogenous leukemia; Pregnancy; Imatinib
1. Introduction The pregnancy of a patient with a neoplastic disease requiring cytotoxic treatment poses a very difficult therapeutic dilemma. A related problem arises when a woman becomes pregnant during or shortly after receiving chemotherapy, due to the side effects of most cytotoxic agents. Most information on this subject stems from animal experiments, but there are relatively few data on human abnormalities. Imatinib entered clinical trials in 1998 and has since been shown to induce dramatic hematologic and cytogenetic responses in CML [1]. Whether imatinib therapy may be discontinued safely in patients who achieve complete remission is the important and unanswered question at the present time [2,3]. Because of ∗
Corresponding author. Tel.: +90 224 4428400; fax: +90 224 4428060. E-mail address: [email protected] (R. Ali).
0145-2126/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2005.01.009
the teratogenicity data in rats, it is recommended that women treated with imatinib should be aware of the potential teratogenicity of imatinib and effective contraception should be used during imatinib therapy to prevent pregnancy [4]. We describe successful pregnancy and labor under treatment of imatinib in a patient with CML, and the outcome of discontinuation of imatinib therapy after achieving a molecular remission.
2. Case report A 44-year-old woman was admitted with fatigue, back and bone pain, unexplained weight loss of 4 months duration and abdominal discomfort. On initial examination, she was found to have pale appearance and a spleen palpable 15 cm below the left costal margin. The WBC were 281 × 109 l−1 with
972
R. Ali et al. / Leukemia Research 29 (2005) 971–973
24% neutrophils, 21% bands, 17% metamyelocytes, 24% myelocytes, 1% promyelocyte, 5% basophils, 8% eosinophils and 2% pyknotic erythroblasts. The hemoglobin was 7.9 g/dl and the platelet count 580 × 109 l−1 . A bone marrow specimen demonstrated marked granulocytic hyperplasia and marrow cells contained the Philadelphia (Ph) chromosome. Chronic phase CML diagnosis was made. After reduction of WBC with hydroxyurea, imatinib at a dose of 400 mg daily was started for treatment of CML. The patient achieved hematological and cytogenetic complete remission within 3 months. On the fifth month of imatinib therapy, she was presented with nausea and vomiting. Her pregnancy test was found positive and ultrasound scan confirmed a viable fetus of 8 weeks. Imatinib was stopped immediately. Detailed fetal abnormality scanning did not demonstrate any cause for concern. Her history revealed that she had developed four spontaneous abortions in 1992, 1995, 1998 and 2001. All of them developed during 8–10 weeks of gestation. Detailed investigations did not reveal any evidence for spontaneous abortions such as systemic lupus erythematosus, antiphospholipid syndrome, thrombophilia and toxoplasmosis. Since the family did not have a baby, the patient and her family had demands on the continuity of the pregnancy and also they did not allow permission for any invasive procedure or medical abortion. Detailed information about the disease and imatinib, and possible complications of them were given. Her written informed consent was obtained for the continuity of the pregnancy with supportive therapy and leukapheresis [1,5], if required, on the following weeks. The patient remained off treatment during gestation. Five months after discontinuation of imatinib therapy (seventh month of gestation) she had 10% metaphases positive for the Ph chromosome by fluorescence in situ hybridization (FISH). Hematologic relapse was observed at sixth month of discontinuation of therapy (eighth month of gestation). Her hematologic condition did not progress (Hb > 11 g/dl; WBC < 50 × 109 l−1 ; platelet < 500 × 109 l−1 ) during gestation. Fetal growth on ultrasound was normal and amniotic fluid volume was within normal limits. Labor was induced at 38th week of gestation. A healthy girl, weighing 3200 g, 51 cm in length with Apgar score of 9, was delivered vaginally. The infant’s general examination and blood count were within normal limits. Macroscopic examination of the placenta was normal. The patient’s WBC at the labor were 15 × 109 l−1 , hemoglobin 11 g/dl and platelet counts 220 × 109 l−1 . Any prenatal or postnatal complication did not occur. The infant’s transfontanel, abdominal and hip ultrasonography, echocardiography and chromosomal analysis were normal. The baby is healthy and growing normally.
3. Discussion The management of leukemia during pregnancy is a difficult problem because of the potential effects of the therapy on the mother and fetus. Therapeutic approaches of leukemia
complicated with pregnancy may be different from those usually used to treat this disease. The differences are modified by several variables, including time of diagnosis, type of leukemia, clinical tolerance of the disease, toxic effects of the drugs on mother and child and the decision of family [1,5,6]. While CML may not need to be treated immediately and pregnancy does not appear to affect the course of CML, there is still a risk of leukostasis as well as the risk of placental insufficiency with consecutive below-normal fetal birth weight, increased fetal prematurity and increased mortality if CML is left untreated for the duration of the pregnancy [1]. Through rational drug development, imatinib; Gleevec or Glivec (formerly STI571), a bcr-abl tyrosine kinase inhibitor offers a new hope for expanded options for patients with CML. Efficacy and place of imatinib on CML is discussed thoroughly in the literature. In preclinical studies, imatinib was teratogenic in rats, but not rabbits. Because of the teratogenicity data in rats, it is recommended that women treated with imatinib should be aware of the potential teratogenicity of imatinib and effective contraception should be used during imatinib therapy to prevent pregnancy [4]. There are few data about imatinib therapy during pregnancy in humans [4,7,8]. The most critical period for teratogenicity is the first trimester because this period correlates with the stage of active organogenesis. Hence, many authors advise against the use of anti-neoplastic agents during the first trimester [1,5,6,9,10]. The case that we reported was under treatment of imatinib for 5 months and the fetus had been exposed to imatinib for 8 weeks. The child was morphologically normal, her growth and development were normal and no congenital anomaly was established to date (2 months). The child was breast-fed for 1 month, because imatinib therapy was restarted. In animals, imatinib or its metabolites were extensively excreted in milk. It is not known whether imatinib is excreted in human milk, therefore, it was suggested that women taking imatinib should not breast-feed [8]. Recently Heartin et al. [7] reported the first successful pregnancy and labor in a patient with CML under treatment of imatinib. To our knowledge, the case that we reported is the second healthy pregnancy under imatinib treatment and healthy outcome without any congenital anomaly in the English literature. The patient we presented has been married for 14 years. She had four spontaneous abortions; all of them being in the first trimester and the cause for these abortions was not identified. After all these years she could have a baby “incidentally” after imatinib therapy. Since there was no identified cause in the past for her relapsing aborts, her developing pregnancy and delivering a healthy baby after imatinib therapy is interesting and requires much more concern. Whether imatinib therapy may be discontinued safely in patients who achieve complete remission is important and unanswered question at the present time. Our case discontinued the imatinib therapy because of pregnancy and 5 months after discontinuation of therapy she had 10% Ph-positive metaphases by fluorescence in situ hybridization. But hematologic relapse was observed at the sixth month of discontin-
R. Ali et al. / Leukemia Research 29 (2005) 971–973
uation of therapy (eighth month of gestation). Our and other author’s [2,3] experience illustrates the need for continued therapy with imatinib after achieving molecular remission. In conclusion, human’s pregnancy is complex, more experience and studies are required for predicting about imatinib therapy in human pregnancy and it cannot be recommended at the present time to discontinue therapy for patients who achieve a molecular remission with imatinib.
References ¨ ¨ ¨ ¸ elik T, Ozan U, ¨ Kimya Y, [1] Ali R, Ozkalemkas F, Ozkocaman V, Ozc et al. Successful pregnancy and delivery in a patient with chronic myelogenous leukemia (CML), and management of CML with leukapheresis during pregnancy: a case report and review of the literature. Jpn J Clin Oncol 2004;34:215–7. [2] Mauro MJ, Druker BJ, Maziarz RT. Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission. Leuk Res 2004;28S1:S71–3.
973
[3] Cortes J, O’Brien S, Kantarjian H. Discontinuation of imatinib therapy after achieving a molecular response. Blood 2004;104: 2204–5. [4] Hensley ML, Ford JM. Imatinib treatment: specific issues related to safety, fertility, and pregnancy. Semin Hematol 2003;40: 21–5. ¨ ¨ ¨ ¸ elik T, [5] Ali R, Ozkalemkas ¸ F, Ozkocaman V, B¨ulb¨ul-Bas¸kan E, Ozc ¨ et al. Successful labor in the course of chronic lymphocytic Ozan U, leukemia (CLL) and management of CLL during pregnancy with leukapheresis. Ann Hematol 2004;83:61–3. ¨ ¨ ¸ elik T, Ozkocaman ¨ ¨ Kimya Y, [6] Ali R, Ozkalemkas F, Ozc V, Ozan U, et al. Maternal and fetal outcomes in pregnancy complicated with acute leukemia: a single institutional experience with 10 pregnancies at 16 years. Leuk Res 2003;27:381–5. [7] Heartın E, Walkinshaw S, Clark RE. Successful outcome of pregnancy in chronic myeloid leukemia treated with Imatinib. Leuk Lymphoma 2004;45:1307–8. [8] Glivec-Clinical monograph. Basel, Switzerland: Novartis Pharma AG; 2004. [9] Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol 2004;5:283–91. [10] Buerkers TE, Lallas TA. Chemotherapy in pregnancy. Obstet Gynecol Clin North Am 1998;25:323–9.