Shaikh A*, Mayadeo NM**, Warke HS***.
(* Second Year Resident, ** Professor, *** Associate Professor, Department of Obstetrics and Gynecology, Seth GS Medical college and KEM Hospital, Mumbai, India.)
We describe the successful management of a 35-year-old gravida 3 para 2 living 2 woman who was diagnosed with chronic myeloid leukemia (CML) in the third trimester of pregnancy, with rheumatic heart disease (RHD) with severe mitral stenosis (MS) with moderate mitral regurgitation (MR) with trivial tricuspid regurgitation (TR) with pulmonary hypertension. She was started on hydroxyurea 500 mg twice daily and Inj Interferon 50 gm twice a week. Post-delivery she was started on Tab Imatinib 400 mg daily and hydroxyurea was stopped. Though hydroxyurea and imatinib are classified as category D drugs and interferon is category C drug in pregnancy, they were used only in third trimester due to CML, with a successful outcome.
Chronic myeloid leukemia is a clonal hematopoietic disorder characterized by the translocation and resultant production of the activated bcr-abl tyrosine kinase. This arises due to an exchange of genetic material between chromosomes 9 and 22. Pregnancy and CML is an uncommon event as CML occurs mostly in elderly females. Management of CML is difficult because of the detrimental effects on the mother and fetus. In our case, the condition was further aggravated by rheumatic mitral stenosis. We describe the successful management of pregnancy with hydroxyurea and imatinib in a case of rheumatic mitral stenosis in a patient who was diagnosed to have CML in the third trimester of her pregnancy.
A 35 year old female gravida 3, para 2 with previous 2 normal deliveries, was referred from a regional hospital with 35- 36 weeks’ gestation, in view of myeloid leukemoid reaction diagnosed for the first time during routine evaluation for right limb edema. Her WBC count was 87,900/cu mm with increased number of immature leucocyte series. Patient had a history of limb edema aggravated since last 15 days. Patient was referred to the regional cancer hospital and was advised observation till delivery, but was not started on any treatment.
On examination, she was averagely built and nourished; her vital parameters and systemic examination were unremarkable. On obstetric examination, uterus was 36 weeks’ size, cephalic presentation and fetal heart sounds were 148 beats per minute. Vaginal examination revealed a multiparous cervix; patient was not in labor. She was admitted and evaluated.
Hematology consultation was obtained and she was investigated. Her routine investigations showed hemoglobin of 9.9 gm %, severely elevated total WBC count of 56,900 /cu mm with differential leucocyte count as follows: neutrophils 45 %, basophils 3 %, eosinophils 1 %, lymphocytes 12 %, myeloblasts 6 %, and myelocytes and metamyelocytes 30 %. Her platelet count was 2.4 lakh/ cu mm. Peripheral blood smear and bone marrow aspiration showed presence of chronic myeloid proliferative disorder with myeloid leukemoid reaction. Molecular cytogenetics (FISH) showed presence of single fusion in 93% of total interphase cells.
Over the course of one week, her WBC count increased from 56,900 to 86,000/ cu mm hence she was started on cap hydroxyurea 500 mg twice daily with inj interferon 50 gm twice a week.
While investigating the cause of bilateral pedal edema with which the patient had presented, ECG was done which showed sinus tachycardia with right axis deviation and T wave inversion in lead III. Hence cardiology consultation was done and 2 D echo was performed; patient was detected to have RHD with severe MS with moderate MR with trivial TR with pulmonary hypertension with an ejection fraction of 60%; she was asymptomatic. She was started on inj furesemide 40 mg daily. As her serum TSH was 7.5, patient was also started on tab thyronorm 50 mcg daily.
Patient went in spontaneous labor; full term outlet forceps application was done to cut short second stage of labor. She delivered a healthy female child of 2.7 kg. Post-delivery there were no complications. She was started on tab imatinib 400 mg daily and cap hydroxyurea and inj interferon were stopped. Tab furesemide 40 mg daily was continued and tab metoprolol 50 mg daily was initiated. Breastfeeding was withheld as she was on imatinib, after consultation with neonatologist. Her further stay in the ward was uneventful and she was discharged on day 8 after delivery.
Chronic myeloid leukemia has low occurrence in pregnancy. It is mostly diagnosed in the second or third trimester in pregnancy.. Because of its chronic course, CML it is usually managed conservatively. Hydroxyurea and imatinib are classified as category D drugs and interferon is category C drug in pregnancy. However, nonteratogenic treatments during pregnancy are not very well defined hence leukapheresis, hydroxyurea, interferon alfa [3,4] and imatinib  can be used in the second or the third trimester. Our patient was an undiagnosed case of CML with rheumatic heart disease with severe MS with moderate MR with trivial TR with pulmonary hypertension for which she did not take any treatment until 35 weeks of pregnancy. Hydroxyurea is an S-phase antineoplastic agent which decreases the production of deoxyribonucleotides and causes release of free radicals due to their involvement in reduction of nucleoside diphosphates. There are no fetal malformations reported with hydroxyurea. Our patient received this in third trimester, along with interferon. Interferons, which are proteins secreted by the immune system, boost the immune system response and reduce the growth of cancer cells. She was started on imatinib therapy post- delivery, and she delivered a healthy baby. Imatinib is a bcr-abl tyrosine kinase inhibitor frequently used and is a better treatment for patients with CML. It inhibits the abl protein of non-cancer cells leading to tumor cell death. Leukapheresis is not currently recommended as maintenance therapy for these diseases as it is inconvenient, costly and time consuming.
Even though hydroxyurea and imatinib  are not considered totally safe for the treatment of CML in pregnancy and there is no effective data available about imatinib and breastfeeding in humans, it is still a necessary treatment in select cases. The result in our case was good and shows that even if started late in pregnancy and continued thereafter, there is a good maternal and fetal outcome.
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Shaikh A, Mayadeo NM, Warke HS. Chronic Myeloid Leukemia With Rheumatic Heart Disease In Pregnancy. JPGO 2017. Volume 4 No. 6. Available from: http://www.jpgo.org/2017/06/chronic-myeloid-leukemia-with-rheumatic.html