Chronic Myeloid Leukemia In Pregnancy Case presentation Dr. Quraish Karim Consultant Ob/Gyn

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.[2]
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. Journal of
Clinical Oncology; 2004; 34 (4): 215-217
n 
12-Koh L-P, Kanagalingam D: (2006). Pregnancies in patient with chronic myeloid
leukemia in the era of imatinib. International Journal of Hematology; 2006; 84: 459 – 462.
(s)
n 
13-baer MR, Ozer H et al:Br J Haematol. 1992 jun;81(2):167-9.
n 
14-cole S,kantarjian H,Clin Lymphoma Myeloma.2009 Aug:9(4):324-7
n 
15-Brave M ,Goodman V,Clin Cancer Res. 2008 Jan 15;14(2):352-9.
`