Chronic Myeloid Leukemia In Pregnancy Case presentation Dr. Quraish Karim Consultant Ob/Gyn Tawam Hospital 31st March 2013 Objectives:n n n n Learning Objectives. Background. Case presentation. Discussion. Learning Objectives: n To share and learn more about uncommon medical disorders with pregnancy as there is no established evidence nor guideline of managements. n Management depend on small case series and case reports. Background Chronic Myeloid leukemia (CML) Colonal bone marrow stem cells disorder-Proliferation of mature granulocytes and their precursors. n ↑ unregulated growth of predominantly myeloid cells in the bone marrow and blood.(1,2) n Myeloproliferative disease with chromosomal translocationPhiladelphia chromosome. n Epidemiology n n n n n Leukemia incidence :1 to 75,000-100,000 . 10% of them are CML. Affects middle aged> younger age group. CML 15-20% of adult leukemia in westren.(9) Risk- exposure to radiation (as in Nagasaki and Hiroshima) (3) Clinical presentation n n n Asymptomatic Incidental finding of leukocytosis Non-specific ¡ n n n n Malaise, Low grade fever and excessive sweating, Gout, weight loss Splenomegaly in >50%, hepatomegaly or both. ↑ infection Anemia Thrombocytopenia or thrombocytosis. (1, 2,10) Classification n n n n Based on clinical and lab findings into: Chronic phase (for several years) accelerated phase blast crisis which is the terminal phase of CML (acute leukemia) (2) Cont. n n One of the drivers of the progression from chronic phase through acceleration and blast crisis is the new chromosomal abnormalities (in addition to the Philadelphia chromosome). Some patients may already be in the accelerated phase or blast crisis by the time they are diagnosed. Chronic phase n n In 85% of patients at the time of presentation Usually asymptomatic or have mild symptoms Accelerated phase n WHO Criteria define it by any of the following (5,6) ¡ ¡ ¡ ¡ ¡ ¡ n 10-19% of myloblast in the blood or bone marrow >20% of basophils Platelets count <10,000 unrelated to therapy Platelets count >1,000,000 unresponsive to therapy Cytogenetic with new abnormality in addition to Philadelphia chromosome Increasing WBC or splenomegaly Significant as it signals that the disease is progressing and transformation to blast crisis is imminent. Blast crises n n Behave like acute leukemia with rapid progression and short survival Diagnosed if any of the following is present: ¡ ¡ ¡ >20% of myloblast or lymphoblast in blood or bone marrow Large clusters of blasts in BM or biopsy Development of chloroma ( solid focus of leukemia outside BM) (7) Path physiology n n n t(9,22) - Philadelphia chromosome BCR gene from chromosome 22 is fused with ABL gene on chromosome 9 The fusion gene bcr-abl generate a tyrosin kinase protein (1) Path physiology cont… n n n speeding up cell cycle ,cell division and inhibits DNA repair genetic abnormality Tyrosin kinase inhibitors (imatinib mesylate)- inhibit the activity of BCRABL protein . (8) Effect of pregnancy on leukemia n n No adverse effect Adverse consequences if chemotherapy is withheld for fear of damaging the fetus . Effect of leukemia on pregnancy n related to ¡ ¡ n n n n disease process chemotherapy Infection hemorrhage fetal loss (14% in CML vs. 33% in acute leukemia) Congenital malformation specially with the use of cytotoxic during first trimester (4) Diagnosis n CBC ¡ ¡ ↑ granulocytes Basophiles and eosinophils are almost universally ↑ . marked leukocytosis with granulocyte left shift n n Bone marrow as a part of evaluation of CML BM morphology is insufficient to diagnose Bone marrow film at 400X magnification demonstrates clear dominance of granulopoiesis. The number of eosinophils and megakaryocytes is increased. n Diagnosed by Philadelphia chromosome.(2) ¡ ¡ ¡ cytogenetic FISH PCR FISH Cont. n Few patients without molecular evidence of bcr-abl fusion , classified as having an undifferentiated myelodysplastic/ myeloproliferative disorder, their clinical course tends to be different from patients with CML. Treatment n Goals to induce remission ¡ Hematological remission-normal CBC and clinical examination ¡ Cytogenetic 0% ph-positive cells ¡ Molecular –PCR negative for BCR/ABL for cure and prolonged survival. Management of chronic myeloid leukemia (CML) during pregnancy n n n n Challenge. Careful counseling . No absolute indications to termination of pregnancy. Management in tertiary hospital. Treatment cont. No interventions -close observation-Risk of progression. (14) n Delayed treatment –start in second trimester. n Medical. n Surgical . n Medical treatment n Tyrosin kinase inhibitor (15) ¡ ¡ ¡ ¡ ¡ ¡ First line therapy (Imatinib, Dasatinib, Nilotinib) Used with adequate contraception. Stopped in pregnancy category D by the FDA may ↑ risk of serious fetal abnormalities or spontaneous abortion. Advised against breastfeed Alternatives to TK inhibitors in pregnancy: n Leukaphoresis ¡ ¡ ¡ ¡ For short interval Avoid teratogenic drugs Adverse effects: time consuming, expensive, ↑infection and thrombosis and hypotension . Reports of successful pregnancy.(11 ) Alternatives to TK inhibitors in pregnancy: n Hydroxy urea(12) ¡ ¡ ¡ ¡ ¡ n Inhibit DNA synthesis ↑miscarrage ↑stillbirth ↑IUGR Congenital malformation Interferon- alfa (13) ¡ ¡ Dose not inhibit DNA synthesis Relatively safe during pregnancy. Medical treatment: n Previously anti-metabolite alkylating agent and interferon alfa 2b and steroids were used Treatment continued: n Bone marrow transplantation ¡ ¡ ¡ n Initial treatment before advent of TK inhibitor Can often be curative High mortality rate ( in 2010 <5%) (8) Surgery. Rare. Prognosis n n Not differ from non-pregnant Median survival time ¡ ¡ n 98 months in low risk people 42 months in high risk people Overall survival 90% after 5 years.(9) Case presentation Ø Ø Ø Ø Ø Mrs. W. Q. Palestinian. 22 years Primigravida Chronic Myeloid Leukemia (CML) 2 months before pregnancy. Clinical Presentations : n n n n urinary tract infection for 3 weeks duration, Leucocytosis . CBC : -WBC 10800000/ml -Hb 10.2 gm/dl -Plt. Count 469000/ml Preipheral Blood Smear , -5-7%blast cells, -6-8% promelocytes - 12%myelocytes -15%metamyeloctes Coagulation study and ESR are normal Referred to Tawam Hospital: n n n n As a case of leukemia for further management. Admitted to Hematology Unit. O/E : Fever, pallor and splenomegaly. Treatment: ¡ ¡ ¡ Supportive measures. USS ,BM biopsy ,cytogenetic and HLA typing Hydroxy urea. Contin. n n n n n n n BMB : CML in chronic phase. USS :splenomegaly 15cm CT: splenomegaly Discharge home F/U in hematology clinic Treat. Interferon alpha (INF) 3million units / m,x3/week. Counseled against pregnancy. Hematology Clinic f/u: n n n WBC decreasing, her response to treatment is good. 5 weeks pregnancy. Advise to stop INF until finish first trimester then restart Obstetric-Medicine f/u: n n n n Booked at 7 weeks. Asymptomatic ,apart from symptoms of early pregnancy. Normal booking tests. WBC 9000/ml,HB 10 gm/dl, Plt count 255000/ml, CRP 3,CMP normal. Plan: n n n n n Seen regularly with CBC ,CMP with each visit Restart interferon at 14 weeks . Postnatal suppression of lactation. Postnatal chemotherapy. Reliable contraception. Antenatal f/u: n n Normal anomaly scan at 18 weeks then at 22 weeks . At 26 weeks she developed Iron deficiency anemia . ¡ ¡ ¡ HB 9 gm/dl,WBC 10000/ml,Plt 255000/ml LFT high AST 108 and ALT 65 No gestational diabetes Antenatal f/u: n n n n Normal grown baby At 36 weeks ,seen on weekly basis with CTG. At term ,she was stable clinically and obstetrically Pre anesthetic consultation. Intrapartum management: n Lab tests with in normal range. n Epidural analgesia Spontaneous vaginal delivery at term + . Girl baby 3.5 kg with good APGAR score. Bleeding from the site of Epidural catheter responding to pressure dressing. n n n Postnatal Course: n n n n n n n Reviewed by hematologist. HB 12 gm/dl, WBC 5500/ml,plt 164000,normal CMP and coagulation profile. Lactation suppressed. Discharge home . 2 weeks f/u in hematology clinic Contraception – depoprovera Start TKI (Imatinib). Discussion Thank you References n 1-^ a b c d Faderl S, Talpaz M, Estrov Z, Kantarjian HM (1999). "Chronic myelogenous leukemia: biology and therapy". Annals of Internal Medicine 131 (3): 207–219. PMID 10428738. n 2- ^ a b c d e f Tefferi A (2006). "Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era". Hematology Am Soc Hematol Educ Program 2006: 240–245. doi:10.1182/asheducation-2006.1.240. PMID 17124067 n 3-^ Moloney WC (1987). "Radiogenic leukemia revisited". Blood 70 (4): 905–908. PMID 3477299. n 4- Slade R, James DK. Pregnancy and maternal malignant hametological disorders. In: turner TL, ed. Perinatal hametological problems. 1991: 23-38 n 5- ^ a b c Tefferi A, Thiele J,et.al, Vardiman JW (2007). "Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert pane". Blood 110 (4): 1092–1097. doi:10.1182/blood-2007-04-083501. PMID 17488875. References: n 6- ^ Vardiman J, Harris N, Brunning R (2002). "The World Health Organization (WHO) classification of the myeloid neoplasms". Blood 100 (7): 2292–302. doi:10.1182/blood-2002-04-1199. PMID 12239137. http://www.bloodjournal.org/cgi/content/full/100/7/2292. Retrieved 2007-09-22. n 7- ^ Karbasian Esfahani M, Morris EL, Dutcher JP, Wiernik PH (2006). "Blastic phase of chronic myelogenous leukemia". Current Treatment Options in Oncology 7 (3): 189– 199. doi:10.1007/s11864-006-0012-y. PMID 16615875. ^ n 8- a b c d Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet (2007). "Chronic myeloid leukaemia". Lancet 370 (9584): 342–50. doi: 10.1016/S0140-6736(07)61165-9. PMID 17662883. n 9-^ Druker BJ, Guilhot F, O'Brien SG et al. (2006). "Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia". New England Journal of Medicine 355 (20): 2408–2417. doi:10.1056/NEJMoa062867. PMID 17151364. http://content.nejm.org/cgi/content/full/355/23/2408. n 10-Nicholson HO Leukemia and pregnancy.j Obsestet Gynecol Br Commonwealth 1968;75:517-20. References: n 11-Ali R., Ozkalemkas F, Ozkocaman V, 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. 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