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CORRESPONDENCE
Year : 2013  |  Volume : 9  |  Issue : 3  |  Page : 484-486

Chronic myeloid leukemia with pregnancy: Successful management of pregnancy and delivery with hydroxyurea and imatinib continued till delivery


1 Department of Obstetrics and Gynaecology, Vardhman Mahaveer Medical College and Safdarjung Hospital, New Delhi, India
2 Department of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Mumbai, India
3 Department of Anaesthesiology, Vardhman Mahaveer Medical College and Safdarjung Hospital, New Delhi, India

Date of Web Publication8-Oct-2013

Correspondence Address:
Usha Yadav
Department of Obstetrics and Gynaecology, Vardhman Mahaveer Medical College and Safdarjung Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.119305

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 > Abstract 

The concomitant occurrence of pregnancy and chronic myeloid leukemia is uncommon. We describe the successful management of a 30-year-old G3 P0, A2 woman who was diagnosed to have chronic myelogenous leukemia (CML) in the third trimester of her pregnancy with intra-uterine growth retardation and oligohydroamnios. She was started on hydroxyurea and imatinib, and was continued till delivery and beyond. The use of imatinib did not have any adverse effects on the fetus, except for low birth weight and low APGAR at birth, but the later progress of the child was normal. We conclude that imatinib and hydroxyurea can be continued even at the third trimester in a pregnant lady with CML, if necessary.

Keywords: Chronic myeloid leukemia, hydroxyurea, imatinib, pregnancy


How to cite this article:
Yadav U, Solanki SL, Yadav R. Chronic myeloid leukemia with pregnancy: Successful management of pregnancy and delivery with hydroxyurea and imatinib continued till delivery. J Can Res Ther 2013;9:484-6

How to cite this URL:
Yadav U, Solanki SL, Yadav R. Chronic myeloid leukemia with pregnancy: Successful management of pregnancy and delivery with hydroxyurea and imatinib continued till delivery. J Can Res Ther [serial online] 2013 [cited 2019 Nov 13];9:484-6. Available from: http://www.cancerjournal.net/text.asp?2013/9/3/484/119305


 > Introduction Top


Chronic myelogenous leukemia (CML) is a myeloproliferative disorder with clonal expansion of transformed primitive hematopoietic progenitor cells. This genetic anomaly arises from an exchange of genetic material between chromosomes 9 and 22, which results in the fusion of the breakpoint cluster region (bcr) and the Abelson leukemia virus (abl) genes. Simultaneous presentation of pregnancy and CML is an uncommon event, because CML presents mostly in elderly patients. The management of CML during pregnancy is a challenging task because of the potential adverse effects of chemotherapy on the mother and teratogenicity in the fetus. We describe the successful management of pregnancy with hydroxyurea and imatinib in a patient who was diagnosed to have CML in the third trimester of her pregnancy.


 > Case Report Top


A 30-year-old and 45 kg female (G3 P0, A2) presented at obstetric services at 32 weeks of pregnancy with complaints of decreased appetite and easy fatigability. On history, she was also having swelling and pain on the left upper quadrant of the abdomen. She had history of two first trimester spontaneous abortions. On examination, she was poorly built and nourished, her pulse rate was 88 per minute and blood pressure (BP) was 124/87 mmHg. On systemic examination, huge splenomegaly (10 cm below costal margins) was present. Liver was not palpable. On obstetrical examination, upper border of uterus was at the umbilicus level and had cephalic presentation. The fetal heart rate was 130 per minute and regular and the uterus was relaxed with reduced liquor. Rest of her systemic examination was unremarkable. Her routine investigations showed hemoglobin of 10.2 g%, total leucocyte count of 256,000 per cubic mm with differential leucocyte count showing neutrophils 46%, lymphocytes 03%, eosinophils 02%, myelocyte 22%, metamyelocyte 18% and band cells 09%. Her platelet count was 3.5 lacs per cubic mm. Hematology consultation was obtained and she was further investigated. Peripheral blood smear showed red blood cell normocyte predominant, with anisocytosis, poikilocytosis, few target cells and mild erythropenia. Marked leucocytosis with premature cells of myeloid series was present. Chromosomal analysis done by fluorescence in situ hybridization for bcr/abl translocation assay showed 46 XX, translocation (9;22) (q34;q11) confirmatory of CML. She was started on oral hydroxyurea 500 mg twice daily, tab. allopurinol 300 mg once daily and tab. imatinib 400 mg once daily. She was posted for elective cesarean section at 37 weeks. A 2 kg weight male baby was delivered and the baby had APGAR score of 5 and 7 at 1 and 5 min, respectively. The baby was shifted to the neonatal nursery. After uterus and skin closure, the patient was shifted to the post-anesthesia care unit. Her immediate post-operative period was uneventful. She was shifted to the post-operative obstetric ward. Breast feeding was withheld. Her further stay in the ward was also uneventful. She was discharged on the sixth post-operative day with advice to continue medical treatment for CML and withhold breast feeding.


 > Discussion Top


Chronic myeloid leukemia in pregnancy is a rare condition (1:100,000). [1] Diagnosis during pregnancy is mostly made in the second or third trimesters because the early symptoms are non-specific. Because of its chronic course, it is usually managed conservatively during pregnancy by leukapheresis, [2] hydroxyurea, [3] interferon, [4] and imatinib. [5] Pregnancy per se does not affect CML, but there are the risks of leukostasis and placental insuffiency with consequent low birth weight, premature delivery and increased mortality. [6] Our patient was an undiagnosed case of CML with massive splenomegaly, for which she did not take any treatment until 32 weeks of pregnancy. She had a history of abortions during the first trimester and oligohydroamnios and intra-uterine growth retardation in the current pregnancy. Cytotoxic treatment for CML during pregnancy poses a very difficult therapeutic dilemma, with variable immediate and late effects on the fetus. The immediate effect includes abortive and teratogenic effects; and less common late effects includes gonadal and endocrinological disorders and growth and development disorders involving the central nervous system. These risks are concentrated in the first trimester and depend on the chemotherapeutic agents used. [7],[8]

Tyrosine kinases are critical signaling molecules for the cellular regulation of proliferation, differentiation, survival, function and motility. Due to their fundamental role in cell biology, possible, adverse effects by a more or less specific inhibition of tyrosine kinases in pregnancy and early infancy could be expected. [9] Schwartzberg et al. [10] showed the adverse effect on a mice model with ablm1 mutations, resulting in increased perinatal mortality, runtedness, abnormal spleen, head and eye development and dysfunctions of the immune system.

There are many human case reports showing evaluation of the outcome of pregnancy while on imatinib, and most cases have involved successful pregnancies after the drug is withdrawn. Our patient was started on imatinib therapy during the third trimester of pregnancy, and she delivered an otherwise healthy but low birth weight baby. In pre-clinical toxicologic and carcinogenic studies, imatinib has been shown to have positive genotoxic effects in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), in an in vitro mammalian cell assay (mouse lymphoma) and in an in vivo rat micronucleus assay. [11] There is lack of adequate control trails for the usefulness of imatinib in pregnancy. There are many human case reports showing evaluation of the outcome of pregnancy while on imatinib, and most cases have involved successful pregnancies after the drug is withdrawn. Our patient was started on imatinib therapy during the third trimester of pregnancy, and she delivered an otherwise healthy but low birth weight baby. One hundred and eighty women were evaluated by Pye et al. [12] for the effect of imatinib, who were exposed to treatment during pregnancy; outcomes were available for 125 patients. In total, 50% delivered a healthy baby, 28% elected to have a termination and 14% had a miscarriage. Cole et al. [13] reported a 21-year-old woman on imatinib and conducted a review of total 217 pregnancies on imatinib therapy. Of these, 171 pregnancies completed at term, 24 had spontaneous abortions and outcomes in 62 patients were unknown.

The important factors in management of CML with pregnancy are time of diagnosis, clinical tolerance of the disease and the adverse effects of the drugs on the mother and the child. [7]

Imatinib, a bcr-abl tyrosine kinase inhibitor, is currently the best medical treatment available for patients with CML. In pre-clinical animal studies, imatinib was found to be teratogenic and associated with impaired spermatogenesis. Therefore, it is recommended that women should use effective contraception during imatinib therapy to prevent pregnancy. Currently, there are few case reports showing successful pregnancy outcome while the patient was on imatinib therapy. Hydroxyurea has been used successfully without any teratogenicity of fetal malformations reported. [3],[4] Busulfan also has been used successfuly in CML during pregnancy, but fetal malformations have been reported. [7]

Leukapheresis is an attractive short-term alternative to chemotherapy for the pregnant patient. [2] It causes a rapid lowering of high total leucocyte counts. Because it is inconvenient, costly and time-consuming, leukapheresis is not currently recommended as maintenance therapy for these diseases.

In conclusion, although hydroxyurea and imatinib cannot be considered totally safe for the treatment of CML in pregnancy, the results in our case showed that if these are started late in pregnancy and continued thereafter, it can result in better maternal and fetal outcome.

 
 > References Top

1.Lichtman M, Liesveld J. Acute myelogenous leukemia. In: Beutler E, Lichtman M, Coller B, et al., editors. Williams Hematology. 6 th ed., Vol. 1047. New York, USA: McGraw-Hill; 2001. p. 1074-84.  Back to cited text no. 1
    
2.Ali R, Ozkalemkaº F, Ozkocaman V, Ozçelik T, Ozan U, Kimya Y, 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.  Back to cited text no. 2
    
3.Celiloglu M, Altunyurt S, Undar B. Hydroxyurea treatment for chronic myeloid leukemia during pregnancy. Acta Obstet Gynecol Scand 2000;79:803-4.  Back to cited text no. 3
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4.Baykal C, Zengin N, Coºkun F, Güler N, Ayhan A. Use of hydroxyurea and alpha-interferon in chronic myeloid leukemia during pregnancy: A case report. Eur J Gynaecol Oncol 2000;21:89-90.  Back to cited text no. 4
    
5.Martin J, Ramesh A, Devadasan L, Palaniappan, Martin JJ. An uneventful pregnancy and delivery, in a case with chronic myeloid leukemia on imatinib. Indian J Med Paediatr Oncol 2011;32:109-11.  Back to cited text no. 5
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6.Firas AS, Demeckova E, Mistrik M. Leukemia in pregnancy. Bratisl Lek Listy 2008;109:364-6.  Back to cited text no. 6
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7.Ali R, Ozkalemkaº F, Ozçelik T, Ozkocaman V, Ozan U, Kimya Y, 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.  Back to cited text no. 7
    
8.Delmer A, Rio B, Bauduer F, Ajchenbaum F, Marie JP, Zittoun R. Pregnancy during myelosuppressive treatment for chronic myelogenous leukemia. Br J Haematol 1992;82:783-4.  Back to cited text no. 8
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9.Henkes M, van der Kuip H, Aulitzky WE. Therapeutic options for chronic myeloid leukemia: Focus on imatinib (Glivec, Gleevectrade mark). Ther Clin Risk Manag 2008;4:163-87.  Back to cited text no. 9
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10.Schwartzberg PL, Stall AM, Hardin JD, Bowdish KS, Humaran T, Boast S, et al. Mice homozygous for the ablm1 mutation show poor viability and depletion of selected B and T cell populations. Cell 1991;65:1165-75.  Back to cited text no. 10
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11.Gleevec (Imatinib Mesylate): Description and Clinical Pharmacology. Available from: http://www.druglib.com/druginfo/gleevec/description_pharmacology/. [Last accessed on 2012 Nov 15].  Back to cited text no. 11
    
12.Pye SM, Cortes J, Ault P, Hatfield A, Kantarjian H, Pilot R, et al. The effects of imatinib on pregnancy outcome. Blood 2008;111:5505-8  Back to cited text no. 12
    
13.Cole S, Kantarjian H, Ault P, Cortés JE. Successful completion of pregnancy in a patient with chronic myeloid leukemia without active intervention: A case report and review of the literature. Clin Lymphoma Myeloma 2009;9:324-7.  Back to cited text no. 13
    



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