CML pada Kehamilan,leukemia kronik .pptx

Cml

1. Pregnancy in Two Patients with Chronic Myeloid Leukimia DIVISION OF HEMATOLOGY AND MEDICAL ONCOLOGY DEPARTMENT OF INTERNAL MEDICINE MEDICAL FACULTY HASANUDDIN UNIVERSITY Wahyudi Pratama Harli Dimas Bayu SERIAL CASE AUGUST 202 1

2. VISI Menjadi pusat pendidikan yang unggul , mandiri dan bermartabat untuk menghasilkan Dokter Spesialis Ilmu Penyakit Dalam yang berkualitas dan mampu bersaing secara regional, nasional maupun global pada tahun 2025, dengan didukung oleh sumber daya manusia yang professional dan bertanggung jawab .

3. MISI Menyelenggarakan Pendidikan di bidang Ilmu Penyakit Dalam dan riset Memberikan pelayanan Kesehatan di bidang Ilmu Penyakit Dalam dengan pendekatan kultural dan budaya secara paripurna dan bermutu Meningkatkan kuantitas dan kualitas penelitian dasar dan aplikatif Ilmu Penyakit Dalam yang bertaraf Internasional Menciptakan sistem manajemen Program Studi Ilmu Penyakit Dalam yang transparan , akuntabel , responsible, independent, terintegrasi dan berkeadilan

4. INTRODUCTION Chronic myeloid leukemia (CML)  a myeloproliferative malignancy in the form of excessive expansion of pluripotent cells and is characterized by a reciprocal translocation between chromosomes 9 and 22 , hereinafter known as the Philadelphia chromosome (Ph). Frazer R, Irvine A, McMullin M. Chronic Myeloid Leukaemia in The 21st Century. Ulster Med J. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring. American Journal of Hematology.

5. The incidence of CML is approximately 1-2 per 100,000 population per year Median age of presentation is 45 to 55 years , approximately 17% of cases occur in the age group of 20-44 years. M : F = 2:1 The incidence of leukemia in pregnancy is about 1 in 75,000–100,000 pregnancies . Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring. American Journal of Hematology. Chowdhury T, Jereen I, Chowdhury T. Pregnancy with chronic myeloid leukemia: case report and literature review. 2020

6. Simultaneous presentation of pregnancy and CML is an uncommon event . The management of CML during pregnancy is a challenging task both for the patient and the physician because of the potential adverse effects of chemotherapy on the mother and teratogenicity in the fetus. We hereby report the successful management of pregnancy in two woman who was diagnosed to have CML in the first trimester of pregnancy.

7. PATIENT’S IDENTITY (I) Name : MRS . R Age : 35 years old Address : Makassar Occupation : Enterpreneur Religion : Moeslem Ethnic : Buginese Marriage Status : Married Hospital : Grestelina R oom : Outpatient Clinic Reg. N umber : 175747

8. HISTORY TAKING The patient is currently receiving therapy for Chronic myeloid leukemia that has been experienced since May 2016  the patient is routinely treated with Imatinib 200 mg per day. Previously, the patient had been treated with hydroxyurea for 1 month while waiting for the results of the BCR-ABL examination. The history of complaints for the first time of treatment : bruises on the thighs, migraine and Weakness

9. HISTORY TAKING The patient had achieved a major molecular response of about 1 year in molecular response. When the patient came for treatment, the patient was found to be 4-6 weeks pregnant  Stop TKI until the patient gave birth At 36 weeks of gestation there was a hematologic relapse  recommended for leukopheresis  refused due to cost reasons  the patient was closely monitored  the patient gave birth with normal delivery by induction  baby is healthy and no malformation.

10. PHYSICAL EXAMINATION VITAL SIGN

11. Head : Normocephal , straight black hair, difficult to remove. Eyes : I socor pupils, 2.5 mm / 2.5 mm diameter, direct and indirect light reflexes have a normal impression, no conjunctiva anemic , no icteric s c lera Ears : No secretions appear Nose : Normal form, no secretions, no epistaxis Mouth : Papillary atrophy is absent, tonsils and pharynx not hiperemis Neck : JVP R+0 cmH 2 O (30 o ) , no lymph node enlargement PHYSICAL EXAMINATION

12. T horax: I : Symmetrical, left is the same as the right P : No pain. The tumor mass is not palpable. P : Percussion is sonor at hemithorax bilateral A : broncho vesicular breathing, no ronch i , no wheezing. Heart: I : Ictus cordis is not appears . P : Ictus cordis is not palpable . P : dullness sound, cardiac border within normal limit A : Regular S1-S2 heart sounds , no gallops, no murmurs PHYSICAL EXAMINATION

13. Abdomen: I : flat, follow breathing movements. A : N ormal Intestinal peristal tic . P : Liver are not papable . spleen are palpable scuffner 2, soft consistency, blunt edges, not pain at papable , tenderness is absent, tumor mass is not palpable P : Tympani, ascites does not exist, Shifting dullnes ( - ) Extremities: Superior Extrimity : no tremor and no erythema palmaris Inferior extrimity : no edema and no erythema palmarris Rectal toucher is not checked PHYSICAL EXAMINATION

14. LABORATORY EXAMINATION 17/5/2016 24/10/16 23/11/16 23/12/16 23/02/17 19/02/18 13/02/20 (UK 36 minggu ) 06/07/20(Post Partum) 20/01/21 01/07/21 WBC 188.130 8300 8100 7500 8900 11.300 32.470 7890 16.230 26.700 NEUT 75 60.3 45.3 50.6 53.0 64.7 68.7 67.2 74.5 75.1 LYMP 12 28.0 44.7 37.8 40.1 25.8 19.6 21.8 17.0 13.3 MONO 7 6.8 6.6 7.3 3.9 6.2 3.2 10.0 4.7 8.3 EO 5 2.8 1.8 2.7 2.3 2.7 3.1 0.6 1.4 2.4 BASO 1 2.1 1.6 1.6 0.06 0.06 5.4 0.4 0.4 0.9 HGB 9.9 11.9 12,7 13.0 12.3 12.1 12.3 11.7 10.2 14.8 HCT 29.7 36 38 39 36 36 36.3 37.8 37.9 47.5 MCV 85.1 85 84 85 89 94 79.3 85.7 74.5 88.6 MCH 28.4 29 28 28 30 32 26.9 26.5 28.9 27.6 MCHC 33.3 33 33 33 34 34 33.9 31.0 37.7 31.1 PLT 1.030.000 299.000 279.000 243.000 264.000 229.000 1.366.000 297.000 490.000 760.000

15. PERIPHERAL BLOOD SMEAR May 19 2016, Grestelina Hospital : Erythrocytes: Normocytic Normochrome, Anisocytosis, Polychromacy (+), Inclusion Body, Normoblast (+). Leukocytes : The number is greatly increased . The myeloid series is predominated. Found all series of Maturation stages. Myeloblast (+) Platelets: Decreased number, normal morphology Impression: Suspected Chronic Myeloid Leukemia (CML)

16. BONE MARROW ASPIRATION May 19 2016 Cellularity : Hyper cellular Erythropoietic : Normal activity, found erythroid precursors. Leukopoietic : Increased activity, found myeloid precursor, 12% myeloblast Thrombopoetic : Normal activity, megakaryocytes are found Plasma cell : Found ME Ratio : 8 : 1 Impression : Chronic Myeloblastic Leukemia in acceleration phase

17. POLYMERASE CHAIN REACTION (PCR) BCR-ABL Qualitative Status (20/06/2016) B3a2 transcript detected (p210/major breakpoint cluster region) BCR-ABL Quantitative (PCR) BCL-ABR Quantitative Date 12/2016 6/2017 12/2017 6/2018 12/2018 6/2019 Transcripts International standard (IS) >1% <1% <1% <1% <0,1% <0,1%

18. PATIENT’S IDENTITY (II) Name : Ny. A Age : 38 years old Address : Makassar Occupation : Housewife Religion : Moeslem Ethnic : Buginese Marriage Status : Married Hospital : RS WS R oom : Palem Atas 202 Reg. N umber : 618977 Admission D ate : 01 – 11 - 2020

19. HISTORY TAKING Patient was diagnosed with CML since July 2013 based on bone marrow punction . At the first, patient was complaint of enlarged stomach that experienced since 1 month ago and be slowly. Patient went to the obstetrician and diagnosed with intra-abdominal tumor so she was consulted for a digestive surgery. From the results of abdominal CT scan, the impression of hepatosplenomegaly was obtained and on routine blood tests there was a very high increase in leukocytes so patient was consulted to the Medical Oncology Hematology department. In the first 6 months, the patient received Hydroxyurea therapy and was tested for BCR-ABL with a positive result in January 2014 and started therapy with Imatinib Mesilate 200mg / 12h / orally.

20. HISTORY TAKING History of pregnancy P3A2. Her first pregnancy was in 2009 and had an miscarried at 6 weeks of gestation. Second pregnancy in June 2018 and miscarriage at 8 weeks pregnant at that time the patient did not know about her pregnancy . The third pregnancy was at 4 weeks of gestation in October 2019 and stopped treatment during the first trimester with strict routine blood control and continued treatment in the second trimester until now. The patient gave birth with section caesarean to her first child and alive in May 2020 with a BBL of 2500 grams and there were no congenital abnormalities. He was hospitalized in September 2020 because of a decrease in Hb and platelets and received 8 units of PRC transfusions and 8 units of TC. There was no prior history of treatment except at the time of abortion and the patient delivered her first child.

21. After giving birth the patient's condition worsened, the results of bone marrow aspiration showed a progression from the chronic phase to the blast crisis phase with the morphology of acute myeloid leukemia (AML M2) and on January 1, 2021 the patient was reported to have died. HISTORY TAKING

22. PHYSICAL EXAMINATION VITAL SIGN

23. Head : Normocephal , straight black hair, difficult to remove. Eyes : I socor pupils, 2.5 mm / 2.5 mm diameter, direct and indirect light reflexes have a normal impression, pale conjunctiva , no icteric sklera Ears : No secretions appear Nose : Normal form, no secretions, no epistaxis Mouth : Papillary atrophy is absent, tonsils and pharynx not hiperemis Neck : JVP R+0 cmH 2 O (30 o ) , no lymph node enlargement PHYSICAL EXAMINATION

24. T horax: I : Symmetrical, left is the same as the right P : No pain. The tumor mass is not palpable. P : Percussion is sonor at hemithorax bilateral A : broncho vesicular breathing, no ronch i , no wheezing. Heart: I : Ictus cordis is not appears . P : Ictus cordis is not palpable . P : dullness sound, cardiac border within normal limit A : Regular S1-S2 heart sounds , no gallops, no murmurs PHYSICAL EXAMINATION

25. Abdomen: I : flat, follow breathing movements. A: N ormal Intestinal peristal tic . P: Liver are not papable . spleen are palpable scuffner 2, soft consistency, blunt edges, not pain at palpable , tenderness is absent, tumor mass is not palpable P: Tympani, ascites does not exist, Shifting dullnes ( - ) Extremities: Superior Extrimity : no tremor and erythema palmaris Inferior extrimity : no edema , multiple nodule palpable, black to blue colour, hard consistency , localate , tenderness is absent Rectal toucher : normal contraction of anal sphincter , slippery mucosa, ampulla containing stolsel. Handscoens: yellowish stool,no blood . PHYSICAL EXAMINATION

26. PHYSICAL EXAMINATION

27. CT-Abdomen Without Contrast (16/7/13) Liver: Enlarged with parenchymal density within normal limits. There was no visible vascular dilatation and bile duct. No SOL density appears GB: The walls are not thickened. No SOL density appears Pancreas: Parenchyma size and density within normal limits Lien: Enlarged, parenchyma density within normal limits. No SOL density appears Both Kidneys: Parenchyma size and density within normal limits. There was no visible PSC dilation. No SOL density appears VU: Not scanning Bowel loops were scan within normal limits Intact bones Conclusion : Hepatosplenomegaly

28. Thorax X-ray (1/11/20) Bronchovascular pattern within normal limits There is no specific proces and nodular lesions in either lung There are compaction of both hilar Cor : enlarged impression with CTI 0.58, concave cardiac waist, lifted apex , calcified aorta Both sinuses and diaphragm are good Intact bones Conclusion : Cardiomegaly with atheroscelrosis of the aorta Suspect hilar lymphadenopathy Pulmo within normal limits

29. LABORATORY EXAMINATION 11/4/16 16/10/17 13/7/18 (M) 30/7/18 17/12/18 17/6/19 (P) 26/9/19 (P) 31/10/19 2/1/20 23/5/20 (B) 11/9/20 19/9/20 1/11/20 8/11/20 WBC 10.600 21.900 85.000 39.300 11.800 9.100 9.500 11.900 125.500 35.000 64.300 35.500 87.400 48.500 NEUT 61,8 63 54,5 47,4 29,9 43,9 56,8 60,2 67,9 87,6 24,0 53,1 59,1 54,3 LYMP 25,0 14,8 21 18,9 44,1 47,8 35,9 34,0 5,4 4,3 44,0 23,8 15,3 26,8 MONO 11,4 8,0 24,1 23,6 8,5 5,9 5,5 4,2 21,8 5,2 19,5 10,7 24,5 12,5 EO 1,1 0,1 0,2 0,1 0,6 0,7 0,8 0,7 0,1 0,0 1,0 0,1 0,9 0,1 BASO 0,7 14,1 0,2 10,0 1,99 1,7 1,0 0,9 4,8 2,9 11,5 12,3 0,2 6,3 HGB 14,1 13,0 4,0 9,9 8,2 13,5 13,0 13,5 5,2 11,4 3,9 13,7 2,2 9,7 HCT 45 41 12 30 25 40 38 40 16 33 12 42 6 28 MCV 94 98 114 90 107 110 109 110 116 103 113 90 80 85 MCH 30 31 37 30 35 37 38 37 38 36 36 30 28 29 MCHC 32 32 32 33 32 34 35 34 33 35 32 33 35 34 PLT 224.000 291.000 12.000 18,000 24.000 145.000 157.000 143.000 124.000 153.000 51.000 37.000 32.000 21.000

30. LABORATORY EXAMINATION Pemeriksaan Hasil Nilai Rujukan PT 12,0 10-14 detik INR 1,17 - APTT 16,7 22,0-30,0 detik GDS 135 140 mg/dl Ureum 29 mg/dl 10-50 mg/dl Kreatinin 0,79 mg/dl L : <1,3 P:<1,1 mg/dl S GOT 2 <3 8 U/L SGPT 27 41 U/L Natrium 136 136-145 mmol/L Kalium 3,5 3,5-5,1 mmol/L Klorida 103 97-111 mmol/L

31. PERIPHERAL BLOOD SMEAR July 18 2013 : Erythrocytes : Anisocytosis , Normochrome , Erythroblast (+) Leukocytes : Greatly increased. All stages of development of granulocyte series cells appear Thrombosites : A little less Conclusion : Suspected Chronic Myeloid Leukemia (CML)

32. BONE MARROW ASPIRATION July 18 2013 Cellularity : Increasing Erythropoitik : Depressed Granulopoitic : Hyperactive Thrombopoytic : Active M : E : Increasing Impression : Chronic Myeloblastic Leukemia

33. BONE MARROW ASPIRATION November 5 2020 Cellularity : Hypercellular Erythropoietic : decreased activity, found erythroid precursors one by one, found dyseritropoesis Leukopoietic : Increased activity, predominance of myeloid series cells, very minimal maturation, 40% myeloblast Thrombopoetik : decreased activity, megakaryocytes were not found Plasma cell : Found Mitosis : Found ME Ratio : Very increased Impression : Chronic Myeloblastic Leukemia in Blast Crisis (Morphology of Acute Myeloid Leukemia (AML) M2)

34. CASE TIMELINE Second Patient Imatinib Mesilate BCR-ABL (+) Abdominal enlargment Splenomegaly Pregnancy 4-6 weeks Start Hydroxiurea for 1 month BMP: CML PCR BCR-ABL <0,1% SI 36 weeks pregnancy : leukocytosis and thrombocytosis -> refused to leucopheresis Delivery birth (normal labor) May 20 16 December 2018 January 2020 June 2019 January 2020 PCR BCR-ABL > 1% SI December 201 6 PCR BCR-ABL < 1% SI December 201 7 June 20 16 Start Hydroxiurea almost 6 month BMP: CML January 20 14 July 2013 Imatinib Mesilate BCR-ABL (+) June 2018 Misscariage f or second time September 2019 4 weeks Pregnancy Delivery birth ( Caesaria ) Mei 2020 First Patient X Continue imatinib December 2019 X

35. DISCUSSION

36. Patient was admitted to the hospital with the chief complaint of fatigue that has been felt continuously and worsened with activities . There is no history of bleeding. Physical examination and radiology imagine  Hepatosplenomegaly Complete blood count  leukocytosis There is history of treatment with chief complaint of weakness accompanied by bruises on the body . No history of bleeding. Physical examination  S plenomegaly Complete blood count  leukocytosis dan thrombocytosis 1 st Patient 2 nd Patient

37. 1 st Patient RT-PCR Qualitative  B3a2 transcript detected (p210/major breakpoint cluster region) 2 nd Patient RT-PCR Qualitative  BCR-ABL B2A2 fusion appears in the 305 bp aplicon product resulting in p210 protein expression Most of the patients (95%) had a typical BCR-ABL1 transcript subtype that was e13a2 (b2a2), e14a2 (b3a2) or the expression of both simultaneously. The transcripts e13a2 and e14a2 encode the P210 protein BCR-ABL1, although with slightly different sizes . Patients with e14a2 (b3a2) transcripts had significantly higher platelet counts than those with e13a2(b2a2) transcripts. Bintoro S. CHRONIC MYELOID LEUKEMIA Perkembangan Baru dalam Tata Laksana dan Implikasi Terhadap Ketahanan Hidup . 1st ed. Surabaya: Airlangga University Press; 2019

38. CLASSIFICATION Accelerated phase Blast phase WHO ELN WHO ELN Spleen Persisting or increasing splenomegaly unresponsive to therapy - - WBC Count Persisting or increasing WBC count (10x109/L) unresponsive - - Blast cells 10-19% 15-29% >=20% >=30% Basophils >20% >20% - - Platelet count >1000x109/L uncontrolled therapy - - - <100x109/L unrelated to therapy yes - - Hochhaus A, Saussele S, Rosti G, Mahon F, Janssen J, Hjorth-Hansen H et al. Chronic myeloid leukaemia : ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2017

39. CLASSIFICATION Accelerated phase Blast phase WHO ELN WHO ELN CCA/Ph+ Any new clonal abberation during therapy Additional clonal chromosal abnormalities in Ph cells at diagnosis that include “major route” abnormalities (second Ph, trisomy 8, isochromosome 17q, trisomy 19, complex karyotype or abnormalities of 3q26.2 present - Extramedullary involvement - - present present Provosional response to TKI criteria Haematological resistance to the first TKI (or failure to achieve a complete haematological response to the first TKI ) or any haemotological , cytogenetic or molecular indications of resistance to 2 sequential TKIs or occurrence of 2 or more mutation in BCR-ABL1 during TKI Hochhaus A, Saussele S, Rosti G, Mahon F, Janssen J, Hjorth-Hansen H et al. Chronic myeloid leukaemia : ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2017

40. MANIFESTATION AND STAGING Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring. American Journal of Hematology Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. American Journal of Hematology

41. DISEASE PROGRESSION Frazer R, Irvine A, McMullin M. Chronic Myeloid Leukaemia in The 21st Century. Ulster Med J.

42. DIAGNOSIS persistent unexplained leukocytosis (or occasionally thrombocytosis ) the presence of the Philadelphia (Ph) chromosome abnormality , the t(9;22)(q34;q11), by routine cytogenetics , the Ph related molecular BCR-ABL1 abnormalities by fluorescence in situ hybridization (FISH) or by molecular studies . Bone marrow aspiration is mandatory for all patients in whom CML is suspected Qualitative PCR is useful for diagnosing CML ; Quantitative PCR is ideal for monitoring residual disease. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring. American Journal of Hematology.

43. DIAGNOSTIC AND MONITOR RESPONSE Hochhaus A, Saussele S, Rosti G, Mahon F, Janssen J, Hjorth-Hansen H et al. Chronic myeloid leukaemia : ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2017

44. Hochhaus A, Saussele S, Rosti G, Mahon F, Janssen J, Hjorth-Hansen H et al. Chronic myeloid leukaemia : ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2017

45. Hochhaus A, Saussele S, Rosti G, Mahon F, Janssen J, Hjorth-Hansen H et al. Chronic myeloid leukaemia : ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2017

46. 1 st Patient History of CML since 4 years ago. Bone Marrow Aspiration : CML in Accelerated Phase (Myeloblast 12%) Treatment with imatinib 200mg/24hours/oral Patient was achieved MMR  1 years GA 4 weeks  Continuing the pregnancy by accepting the risk  Stop TKI until the patient gives birth. Patient refused to do leukapheresis when hematologic relapse occured  Financial Problem 2 nd Patient History of CML since 7 years ago. Bone Marrow Aspiration : (7/2013) CML in Chronic Phase  (11/2020) CML in Blast Crisis (Myeloblast 40%, Morphology Acute Myeloid Leukemia (AML) M2). Treatment with imatinib 200mg/12hours/oral the molecular response of therapy has never been examined  Financial Problem GA 4-6 weeks > Continuing the pregnancy by accepting the risk  stop TKI in the 1st trimester and continue in the 2nd trimester until now TKIs have been associated with teratogenic effects and are likely unsafe for use during pregnancy. Imatinib use in the first trimester was associated with spontaneous abortion and congenital malformations. Additionally, there are case reports of adverse outcomes associated with the use of both dasatinib and nilotinib. more recently it has been suggested that TKIs may be safe for use in the second or third trimester of pregnancy. Staley E, Simmons S, Feldman A, Lorenz R, Marques M, Williams L et al. Management of chronic myeloid leukemia in the setting of pregnancy: when is leukocytapheresis appropriate? A case report and review of the literature. Transfusion. 2017

47. MANAGEMENT CML IN PREGNANCY So there are 2 issues how to treat CML in pregnancy : CML with unplanned pregnancy CML with planned pregnancy When we start and stop TKI treatment ? What we need to follow up and evaluate ?

48. MANAGEMENT CML IN PREGNANCY CML CP PHASE AP/BP PHASE *start chemotherapy immediatly PRE PUBERTAL POST PUBERTAL Late trimester First trimester Start TKIs Already under TKI Newly diagnosed Offer early delivery if feasible Offer termination Madabhavi I, Sarkar M, Modi M, Kadakol N. Pregnancy Outcomes in Chronic Myeloid Leukemia: A Single Center Experience. Journal of Global Oncology. 2019; Chowdhury T, Jereen I, Chowdhury T. Pregnancy with chronic myeloid leukemia: case report and literature review. 2020

49. MANAGEMENT CML IN PREGNANCY Already under TKI Newly diagnosed Unplanned pregnancy Planned pregnancy Counsil about risk and benefit of TKIs on fertility and pregnancy offer sperm and oocyte cryopreservation Start TKIs Council about the risks and benefits of TKIs on fertility and pregnancy-> STOP TKIs 1 st trimester : leukapheresis (to maintain WBC <100x109/L and platelet <500x109/L 2 nd trimester : Leukapharesis , consider INF alfa 3 rd trimester : Leukapharesis , consider INF alfa Madabhavi I, Sarkar M, Modi M, Kadakol N. Pregnancy Outcomes in Chronic Myeloid Leukemia: A Single Center Experience. Journal of Global Oncology. 2019; Chowdhury T, Jereen I, Chowdhury T. Pregnancy with chronic myeloid leukemia: case report and literature review. 2020

50. MANAGEMENT CML IN PREGNANCY Planned pregnancy If patient is CMR/MMR for >= 2 years : Stop TKIs after counseling about the risks and benefits at onset of menstrual cycle Allow a few days of washout period before conceiving Consider observation with regular disease monitoring with full blood counts and RT- qPCR Planning an elective pregnancy Continous CMR/MMR Loss of CMR/MMR Observe/no treatment Leukapheresis 1 st trimester, INF alfa+leukapharesis 2 nd and 3 rd trimester If patient is in CHR or better Oocyte collection for future assited conception Stop TKI at onset of menstrual cycle Start IVF medication 7 days after stopping TKI Restart TKI after oocyte collection Madabhavi I, Sarkar M, Modi M, Kadakol N. Pregnancy Outcomes in Chronic Myeloid Leukemia: A Single Center Experience. Journal of Global Oncology. 2019; Chowdhury T, Jereen I, Chowdhury T. Pregnancy with chronic myeloid leukemia: case report and literature review. 2020

51. Madabhavi I, Sarkar M, Modi M, Kadakol N. Pregnancy Outcomes in Chronic Myeloid Leukemia: A Single Center Experience. Journal of Global Oncology. 2019; Chowdhury T, Jereen I, Chowdhury T. Pregnancy with chronic myeloid leukemia: case report and literature review. 2020

52. SUMMARY Two women had been reported with pregnancy and CML have been reported in two women 35 years old and 38 years old . The first patient was a 35 years old woman who had had been treatment with imatinib for about 4 years and had achieved a BCR-ABL PCR value of <0.1% (major molecular response) after 1 year. During pregnancy, imatinib was discontinued until the patient gave birth. At 38-39 weeks of gestation, the condition of the fetus is sufficient to assess the criteria for birth so the process of induction of labor begins and the baby was born by normal delivery. The second patient was a 38 years old woman who had been started TKIs treatment with imatinib since 7 years. During pregnancy started from the fourth weeks of gestation, imatinib was discontinued. Treatment was resumed in the second trimester until now. At 38 weeks of gestation the patient had severe preeclampsia, so a caesarean section was decided. After giving birth the patient's condition worsened, the results of bone marrow aspiration showed a transformation from the chronic phase to the blast crisis phase with the morphology of acute myeloid leukemia (AML M2) and on January 1, 2021 the patient was reported to have died.

53. THANK YOU

54. Mammalian ovaries express c-kit, c- abl , and platelet-derived growth factor, which are inhibited by TKI, that are imperative in the growth and maturity of oocytes and follicles When CML is diagnosed in the first trimester, termination of pregnancy is considered harmless for the mother; however, TKIs are associated with fetal malformations if used in the second trimester. Platelet-derived growth factor A inhibition of imatinib resulted in teratogenicity in mice

55. Distinguishing congenital abnormalities have occurred after the administration of imatinib in early pregnancy. These include exomphalos, omphaloceles, pulmonary hypoplasia, duplex kidneys, renal agenesis, skeletal malformations (craniosynostosis, shoulder anomaly, and scoliosis), and spontaneous abortion.