Pregnancy and CML While pregnancy in and of itself does not affect the course of CML, there is a risk for maternal disease progression if CML remains untreated for the duration of pregnancy. Unfortunately, treatment of CML during pregnancy is complicated due to the teratogenic nature of TKIs

1. Multidisciplinary Case
Chronic Myelogenous
Leukemia
in
Pregnancy
MUKESH SAH, MD
POST GRADUATE MEDICAL INTERN
GOODSAM MEDICAL INTERN
6 May 2020 1

2. General Data
BM
27y/o
Married
Manaoag
Housewife
Vocational course graduate
Unemployed
2

3. Chief Complaint
Watery vaginal discharge
3

4. History of Present Illness
2 years PTA
• increasing abdominal girth
and palpable abdominal mass
• Hematologist at (VDH),
peripheral blood smear and
whole abdominal ultrasound
revealed Chronic
Myelogenous Leukemia,
• started on Hydroxyurea
500mg tablet 3x a day and
Imatinib
4

5. History of Present Illness
8 mos PTA • Amenorrhea for 4 weeks
• Pregnancy test done at home
revealing positive
• Multivitamins OD and Aspirin
100mg tablet OD
5

6. History of Present Illness
11 days PTA
• Px was 1st admitted due to
Uterine contractions
• Diagnosis:PU 36 2/7wks
AOG, Cepahlic in Preterm
Labor, CML,
• Discharged as improved after
5 days.
• Hydroxyurea 500mg/tablet
TID as maintenance and
Isoxsuprine 10mg/tablet TID.
• OPD follow-up
6

7. History of Present Illness
Few hours PTA
• (+) Watery vaginal
discharge associated with
on and off hypogastric
pains
• Consulted at ER,
admitted
7

8. Past Medical History
(-) Hypertension
(-) DM
(+) Bronchial Asthma
(-) History of Trauma
(-) Use of Alcohol and Tobacco
(-) Previous Surgery
(-) Allergies
(+) Immunization- Tetanus toxoid
1 dose
No exposure to radiations
8

9. Family History
(+) Father side - Leukemia
(+) Sister – Colon Cancer
(-) Mother
9

10. OB History
Family Planning- None
PreNatal checkUp: 5x PMD
1x- OPD,R1MC
LMP: April 28, 2016
EDC: January 15, 2016
AOG: 37 6/7 weeks
G1P0
G1- Present Pregnancy
10

11. GYNE History
 Menarche-11y/o
 Interval- Regular
 Duration- 5 days
 Amount- 3 pads/day
 Symptoms-(+)Dysmenorrhea
 First coitus- 25y/o
 No. of Sexual Partner- 1
11

12. Physical Examination
Patient is conscious, coherent not in cardio respiratory
distress
BP:120/80mmHg CR:95bpm RR:22cpm T:36C
2
Skin: good turgor, (-)pallor (-) jaundice
HEENT : Pink palpebral conjunctiva, anecteric sclerae, no nasal discharge
Chest&Lungs: Symmetrical chest expansion, no retrations , clear breath
sounds
Adynamic precordium, normal rate regular rhythm, no murmur
12

13. Physical Examination
Globular, soft, normoactive bowel sound, Palpable spleen
3cm below the left costal margin with hypogastric tendeness
FH- 29cm FHT- 134bpm EFW- 2790gm
Utrine contractions moderate with a duration of 50-60sec and
interval of 5-6minutes
IE- Cervix 3-4cm dilated, 50% effaced, cephalic, station-1,
ruptured bag of water with show
13

14. Admitting Diagnosis
G1 P0
Pregnancy Uterine 37 6/7weeks AOG,
Cephalic in Beginning Labor
PROM (6hours)
Chronic Myelogenous Leukemia
14

15. Pertinent Findings
• G1P0
• Hypogastric pains
• Palpable spleen
• PROM
• CML
15

16. Plan
For Normal Spontaneous Vaginal Delivery
16

17. COURSE IN THE WARD
• Soft diet then NPO
• Venoclysed with D5LRS 1L x3ogtts/min
• Secured 2 units of Packed RBC
• CBC, Blood typing, Urinalysis, Peripheral blood
smear, APTT and Prothrombin time
• Ampicillin 2gm IV (-) ANST now then 1gram IV
every 6hours
• Gentamicin 240mg IV (-)ANST
17

18. January 18,2017
WBC: 122.74 X10 n 4-
10
Neu 92.8 %
Lym 2.6%
Mon 1.9%
Eos 0.7%
Bas 2.0%
RBC: 4.56x10 n:4-5.4
HGB: 124 n:120-160
HCT: 37.3% n:37-47
MCV: 81.7 fL n:805-100
MCH: 27.2 pg n:27-34
MCHC: 333g/L n:320-360
PLT: 118 n:150-450
Typing: O Positive
Complete Blood Count
18

19. January 9,2017
RBC: Normocytic,
Normochromic
WBC: Leukocytosis
Blast: 45%
Neutrophils: 38 %
Lymphocytes: 2%
Eosinophil: 2%
Platelet: Thrombocytosis
Impression: TO CONSIDER
LEUKEMIA, MYELOCYTIC SUGGESTS
HEMATOLOGY CONSULT
Peripheral Blood Smear
19

20. Number of fetus: Single
Presentation: Cephalic
Fetal heart Rate: 126 bpm
Amniotic Fluid: AFI: 9.6 cm
Grade II, Location: Posterior.
Biometry
BPD 98.5 cm AOG: 38w 4d
HC: 317.6 mm AOG: 33w 4d
AC: 325/2 mm AOG: 37w 5d
FL : 64.9 mm AOG: 33w 1d
EDD by ultrasound: July 2,2017
SEFW: 2722 grams
-INTRAUTERINE PREGNANCY 35 WEEKS AND 6 DAYS
-SINGLE LIVE FETUS CEPHALIC IN PRESENTATION
-SEFW: 2722 GRAMS
-BPS: 8/8
-NORMAL AMNIOTIC FLUID
BPS Ultrasound
(January 9, 2017)
20

21. Impression :
-Hepatosplenomegaly
-Hydronephrotic changes of both kidneys which may be
secondary to extrinsic compression of the distal ureters by
the gravid uterus.
Whole Abdominal Ultrasound
(January 10, 2017)
21

22. • Prothrombin time- 14.2secs n10-
14
• APTT - 30.5secs
n30-43
• Uric acid - 411.18 umol/L
n150-350
• HbsAg - Nonreactive
• Syphilis - Nonreactive
Other Labs
22

23. (1/18/2017)
Color Yellow Specific gravity 1.025
Trasparency Slightly Turbid Leucocyte +
Bilirubin Negative RBC 196
Urobilinogen Normal Pus Cells 46
Ketones Negative Epithelial Cells 5
Protein Negative Hyaline cast 1
Nitrites Negative Bacteria 5
Glucose Negative pH 6.5
Urinalysis
23

24. • Delivered via NSD(12hrs after Admission)
with repair of first degree laceration
• EINC done
• Continued on Ampicillin IV, Vitamin C tablet
OD, Mefenamic acid 500mg/cap TID and
Hydroxyurea 500mg/tab TID
1st Hospital day
24

25. • Minimal vaginal bleeding, afebrile, stable vital signs
• Patient was shifted to oral meds: Cephalexin
500mg/capsule TID, Ferrous sulfate tablet OD, Vitamin C
tablet OD, Mefenamic acid 500mg/cap TID and
Hydroxyurea 500mg/tab 2tablet TID
• Advised bottle feeding
Postpartum Day 1
25

26. • (+) Pallor with Minimal vaginal bleeding,
afebrile, stable vital signs, no dizziness, no
tachycardia
• BP 110/60mmHg
• Hemoglobin of 63g/L
• Transfused 3 units PRBC
• Continued oral medications
Postpartum Day 2
26

27. January 18,2017
WBC: 122.74 X10 n 4-10
Neu 92.8 %
Lym 2.6%
Mon 1.9%
Eos 0.7%
Bas 2.0%
RBC: 4.56x10 n:4-5.4
HGB: 124 n:120-160
HCT: 37.3% n:37-47
MCV: 81.7 fL n:805-100
MCH: 27.2 pg n:27-34
MCHC: 333g/L n:320-360
PLT: 118 n:150-
450
Complete Blood Count
January 21,2017
WBC: 79.9 X10 ^12/L
Neu 92.6 %
Lym 3.8%
Mon 2.0%
Eos 0.3%
Bas 1.3%
RBC: 2.4 x10^12/L HGB:
63
HCT: 0.19%
MCV: 79.7 fL
MCH: 26.7 pg MCHC:
335g/L
PLT: 968
27

28. • Scanty vaginal bleeding, afebrile, stable
vital signs, no pallor
• Patient was advised may go home if OK
with Pedia-Hema.
Postpartum Day 3
28

29. Complete Blood Count
January 21,2017
WBC: 79.9 X10 ^12/L
Neu 92.6 %
Lym 3.8%
Mon 2.0%
Eos 0.3%
Bas 1.3%
RBC: 2.4 x10^12/L
HGB: 63
HCT: 0.19%
MCV: 79.7 fL
MCH: 26.7 pg MCHC:
335g/L
PLT: 968
January 23,2017
WBC: 57.9 X10
Neu 93.0 %
Lym 3.0%
Mon 1.7%
Eos 0.6%
Bas 1.7%
RBC: 2.6 x10^12/L
HGB: 71
HCT: 21.0%
MCV: 79.8 fL
MCH: 27.6 pg
MCHC: 346g/L
PLT: 854
29

30. • No pallor, afebrile, stable vital signs
• Discharged IE: Cervix admits tip, uterus
enlarged to 3-4mos size, adnexae free with
scanty bleeding.
• Patient was advised may go home with oral
medications.
• OPD follow-up after 1 week.
Postpartum Day 4
30

31. Complete Blood Count
January 23,2017
WBC: 57.9 X10
Neu 93.0 %
Lym 3.0%
Mon 1.7%
Eos 0.6%
Bas 1.7%
RBC: 2.6 x10^12/L
HGB: 71
HCT: 21.0%
MCV: 79.8 fL
MCH: 27.6 pg
MCHC: 346g/L
PLT: 854
January 24,2017
WBC: 64.6 X10
Neu 91.6 %
Lym 2.8%
Mon 1.1%
Eos 0.4%
Bas 4.1%
RBC: 3.8 x10^12/L
HGB: 98
HCT: 29.0%
MCV: 75.2 fL
MCH: 25.6 pg
MCHC: 340g/L
PLT: 396
31

32. FINAL DIAGNOSIS:
G1P1(1001) Pregnancy uterine term cephalic
livebirth delivered vaginally to a baby boy BW
2600grams, BL50cm, AS 6/8, BS 37weeeks,
AGA
Chronic Myelogenous Leukemia
PROM (6 hours)
1st degree laceration with repair
32

33. Chronic Myelogenous Leukemia
In Pregnancy
Leukemia in pregnancy is rare condition
Annual incidence of 1-2/100,000 pregnacies
● CML results from a somatic mutation in a
pluripotential lymphohematopoietic cell
● Myeloproliferative disorder characterized by
increased granulocytic cell line, associated with
erythroid and platelet hyperplasia
● The disease usually envolves into an accelerated
phase that often terminates in acute phase
33

34. Chronic myelogenous leukemia (CML) - characterized
by
• Anemia
• Extreme blood granulocytosis and granulocytic
immaturity
• Basophilia
• Thrombocytosis
• Splenomegaly
• Characteristic genetic change - Reciprocal
translocation between chromosomes 9 and 22
(Philadelphia (Ph) chromosome) 4
DEFINITION
34

35. • 15 %of all cases of Leukemia
• Male predominance (1.4:1)
• Average age at presentation – 50 yrs
EPIDEMIOLOGY
35

36. 1. Environmental Leukemogens
• Very high doses of ionizing radiation
• Chemical leukemogens
• No concordance of the disease
between identical twins
• Several studies – no links with
smoking/diet/lifestyle
ETIOPATHOGENESIS
36

37. 2. The stem cell
Acquisition of the
BCR-ABL fusion
gene in a single
multipotential
hematopoietic
cell -CML stem
cell
37

38. • Majority of these cells would be in G0 phase of the
cell cycle
• These BCR-ABL stem cells favor differentiation over
self- renewal
• Ph chromosome is found on myeloid, monocytic,
erythroid, megakaryocytic, B-cells and sometimes T-
cell proof that CML derived from pluripotent stem
cell
38

39. 39

40. 3. BCR-ABL protein (Tyrosine Kinase)
• BCR (breakpoint cluster region) gene on
chromosome 22 fused to the ABL (Ableson leukemia
virus) gene on chromosome 9
• The fusion protein derived from the BCR-ABL gene
is a tyrosine kinase enzyme
40

41. BCR-ABL (Tyrosine Kinase)
Altered
adhesion
•No adhesion
to marrow
stroma
•Reduced
regulation by
marrow
factors
Mitogenic
activation
•Activation of
various
pathways
proliferation
Inhibition of
apoptosis
•Upregulation
of Bcl-2
•Uninhibited
proliferation
41

42. SYMPTOMS:
• Easy fatigability
• Loss of sense of well-being
• Decreased tolerance to exertion
• Anorexia
• Abdominal discomfort
• Early satiety
• Weight loss
• Excessive sweating
CLINICAL FEATURES
42

43. Uncommon symptoms
• Night sweats
• Heat intolerance
• Gouty arthitis
• Left upper-quadrant and left shoulder
pain
• Urticaria
• Hyperleukocytic Syndrome —dyspnea,
tachypnea, hypoxia, lethargy, slurred
speech
43

44. SIGNS
• Pallor
• Splenomegaly
• Sternal tenderness
• Rarely hepatomegaly, lymphadenopathy – Poor
prognostic indicators
44

45. A. Laboratory studies
Blood counts and blood smear
• Hemoglobin concentration is decreased
• Nucleated red cells in blood film
• The leukocyte count above 25,000/μl (even >
1,000,000/μl),
DIAGNOSIS
45

46. • Hypersegmented neutrophils
• The basophil and eosinophil counts are increased
(Absolute)
• The platelet count is normal or increased
• Blast cells ~ 3 % (<10% in the chronic phase)
46

47. 47

48. 48

49. Bone Marrow studies
• Mitotic figures are
increased
• Macrophages that mimic
Gaucher cells
• Macrophages - engorged
with lipids - yield ceroid
pigment - imparting a
granular and bluish cast - sea-
blue histiocytes
• Increased reticulin fibrosis
(Collagen type III)
• Angiogenesis
49

50. Cytogenetics
•
• Study of the number
and structure of chromosomes
• Samples from bone marrow
myeloid cells
• The presence of the
Philadelphia chromosome –
shortened chromosome 22*
• Cytogenetics cannot identify
complex translocations
50

51. • Molecular Probes
FISH (Fluorescence In
Situ Hybridization) •
Detect the BCR-ABL
fusion gene on
chromosome 22
• Qualitative
Diagnosis
51

52. PCR (Polymerase Chain Reaction)
• Most sensitive test to identify and measure
the BCR-ABL gene (Quantitative)
• Can be performed on blood/marrow cells
• Amplifies the BCR-ABL derived abnormal
mRNA
• One abnormal cell in one million cells can be
detected Diagnosis
52

53. COURSE OF THE DISEASE
Chronic Phase
• Most patients are asymptomatic
• Incidental leukocytosis/splenomegaly
•Bleeding and infectious complications are
uncommon in the chronic phase
53

54. COURSE OF THE DISEASE
Accelerated phase
• 10%–19% blasts in blood or bone marrow
• >20% basophils in blood or bone marrow
• Thrombocytosis, thrombocytopenia unrelated to therapy
• New clonal chromosome abnormalities
• Anemia progresses and cause fatigue, loss of sense of well-being
• Splenomegaly
• Ranges from 4-5 years before progressing Course of the disease
54

55. COURSE OF THE DISEASE
Blast Crisis
• 20% blasts in blood or bone marrow
• Extramedullary blastic infiltration (Chloroma)
• Resembles acute leukemia
• 2/3 transform to myeloid blastic phase and 1/3 to
lymphoid blastic phase
• Infection and bleeding common
• Abdominal pain, bone pain
• Survival is 6-12 months
55

56. Accelerated/Blast phase
Start chemotherapy immediately
• Late Trimester: offer early delivery,
if feasible
• First Trimester: offer termination
of pregnancy
56

57. Chronic Phase
Prepubertal patients
Start TKI’s
Postpubertal patients
Already under
TKI’s
Newly
Diagnosed
Unplanned
pregnancy
Planned
pregnancy
Counsel
about risk
and benefits
of TKIs
57

58. Unplanned Pregnancy
Counsel about the risk and
benefits of TKI’s on fertility and
pregnancy
• First Trimester:
Consider Leukapheresis, if feasible, for
hyperleukocytosis until the end of first trimester.
• Second/ Trimester :
Consider leukopheresis/ IFN @ or combination of
both , if needed
58

59. Planned Pregnancy
Only if patient is MMR/CMR for >= 2 years
• Stop TKI’s after counselling about risk and benefits
• Allow a few days of washout period before
conceiving
• Consider observation with regular disease
monitoring with blood counts and real time PCR
59

60. • CML Diagnosed During Pregnancy
a. Interferon-alpha(IFN-α)
-non-transplant treatment of choice for most
patients with CML before the advent of TKI
(imatinib)
TREATMENT
60

61. (i) selective toxicity against the leukemic clone
(ii) enhancement of ‘immune’ regulation
(iii) modulation of bone marrow micro-
environmental regulation of hematopoiesis
61

62. • B. Hydroxyurea
-inhibits DNA synthesis by decreasing the production
of deoxyribonucleotides by inhibition of the enzyme
ribonucleotide reductase
62

63. • Second and third trimester exposure to
hydroxyurea was associated with an increased risk
of pre-eclampsia.
• Hydroxyurea is known to be excreted in breast milk
and, therefore, should not be given to lactating
women.
63

64. C. Leukapheresis
-useful during the first trimester of pregnancy
64

65. d. Busulphan
-is an alkylating agent that does not alter the natural
course of the disease
- It is now rarely used in the management of CML in
chronic phase and should certainly be avoided in
pregnancy
65

66. e. Stem cell transplantation.
-remains an important treatment option for patients
with CML, particularly younger individuals who failed
treatment with imatinib
66

67. Unplanned pregnancy while on CML treatment
(imatinib)
-Continue imatinib and have the pregnancy closely
monitored
-Termination considered if significant abnormalities
in the fetus are identified
67

68. Planned pregnancy
A. Patient not on Imatinib.
-Sperm or oocyte cryopreservation in light of the
reported adverse outcomes in fertility and pregnancy
68

69. B. Patient already on Imatinib
-Due to the teratogenic effects of imatinib, it is
reasonable to discontinue the drug before planned
conception.
69

70. • Given that patients will not take imatinib for the
duration of the pregnancy, physicians may consider
suggesting that the period between stopping
imatinib and becoming pregnant should not exceed
6 months
70

71. • A patient with accelerated or blast phase CML
should be started on chemotherapy immediately.
• If the patient is in late trimester, early delivery
should be offered, if feasible, while termination
should be considered during the first trimester.
Evidence-based Management of CML in Pregnancy
71

72. • For a chronic phase CML, pre-pubertal patients
should be counseled about the risks and benefits of
TKIs, including effects in fertility, and started on
TKIs.
• All newly diagnosed post-pubertal patients should
be counseled about the effects of TKIs on fertility
and pregnancy and also offered sperm/oocyte
cryopreservation before starting on TKIs.
72

73. • If a patient is already under TKI therapy and is
pregnant, patients should be counseled on the risks
and benefits of stopping TKIs.
• TKIs can be stopped if the patient is in Complete
Molecular Remission for at least 2 years.
73

74. • If relapse occurs, leukapheresis can be considered
until the end of the first trimester and
leukapheresis/IFN-α or combination of both can be
considered in the second and third trimester of
pregnancy.
• For a woman who has been in CMR for at least 2
years, TKIs may be discontinued before planned
conception.
74

75. • The patient should also be educated on the risks
and benefits of stopping TKIs and a few days of
washout period should be allowed before
conceiving.
• The patient should be followed-up regularly with
blood counts and real time PCR.
75

76. • If the patient continues to be in CMR/CCyR, she
could be followed-up until after delivery and
started on TKIs.
• If there is loss of CMR then leukapheresis in the
first trimester and IFN-α, leukapheresis or both in
the second and third trimesters can be considered
76

77. • With the development of imatinib and various
other TKIs, today the concepts in the management
of CML in pregnancy are evolving.
• Male CML patients on imatinib treatment can
conceive normally with little or no adverse
outcome in pregnancy, the same is not true for
female patients.
Conclusion
77

78. • Treatment for every female patient should be
individualized based on the patient's wishes, her
molecular or hematological response to imatinib,
duration of remission she has achieved and the
availability of other alternative therapies.
78

79. • Counseling and a considered approach to disease
monitoring women wishing to conceive can still
become pregnant with minimal effects to fetus or
their disease status.
79

80. THANK YOU!
80