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Dr Shamim KFellow, High Risk PregnancyHOSPITALHyderabad, INDIAwww.fernandezhospital.com

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CASE� Mrs. M 25 yrs

� Married for 4 yrs Non-consanguinous

� G3P2L2 Spontaneous conception

� LMP 21/04/2010EDD 28/01/2011

Now 33+ weeks

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Past obstetric history� 1. Em. LSCS

Indication – Presumed fetal compromise, female baby, alive and healthy (2005)

� 2. Elective LSCS Indication – Breech with prev. LSCS, Female baby ,

alive and healthy (2007)

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Present history� Uneventful till 20 weeks of gestation

� Complaining of blurring of vision in both eyes (Diagnosed as Central serous retinopathy) at 20wks

� Swelling in neck and groin noted at 24wks

� Referred to Fernandez Hospital

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� No fever

�Wt loss 1kg (50 to 49 kg) in one month

� No dyspnoea/ coryza/ cough

� No petechiae/ bleeding gums or nose

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� Pallor +� PR -80/min BP-110/80� One lymph node (2×2 cm) submandibular region

Few small lymph nodes in supraclavicular region One lymph node (2×2 cm) in right femoral and (1×1 cm) in left femoral region each

• Rest of the examination unremarkable

On Examination

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Initial Impression� Physician opinion – lymphadenopathy with

bicytopenia after CBC report? Koch’s lympadenopathy? Lymphoma /lymphoproliferative disorder ? Viral lymphadenitis

� Investigation : DCT, Reticulocyte count, LFT� Advised : Repeat Ophthalmologist opinion; USG

Abdomen, LN biopsy for AFB culture and histopathology

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Investigation Baseline(Mid Sept)

29.09.2010 01.10.2010 12.10.2010

Hemoglobin(gm%) 10.6 7.6 7.4WBC (/cu mm) 9500

N 44 L477900N69 L22

Platelet (/cu mm) 74000 72000 87000Peripheral smear Normochromic

normocyticNormochromicnormocytic

LFT Total Bilirubin -1.3mg%; direct -0.5, Indirect- 0.8

Uric acid(mg/dl) 7.8Creatinine(mg/dl) 0.8 0.8TSH(mU/L) 2.63S FerritinVit B12

252.4 ng/ml1922 pg/ml

LDHDCT

709u/LNegative

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� USG whole abdomen (01/10/2010) –

Liver-13.7 cm, normal size with coarse echotexture; No IHBD.; CBD-2cm;PV -8mm.

Moderate splenomegaly,16.7cm, Normal echotexture

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� Repeated ophthalmologist opinion

� Rt side – resolving retinopathy ;6/18� Lt side – persisting retinopathy; 6/60

Advised to continue pregnancy from ophthalmologist’s point of view

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Biopsy� (13/10/2010) Cervical Lymph node - High grade

NHL; suggested immuno-histochemical marker for confirmation and typing� (23/10/2010)Immuno-histochemistry-

Lymphoblastic lymphoma/leukemia probably of B cell origin� (26/10/2010)Bone marrow biopsy- Acute

lymphoblastic leukemia (cellularity- increased with prominence of blasts);Blast 70%; Erythropoiesis and myelopoiesis suppressed;Megakaryocyte - slightly decreased

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� Due to financial constraints and further prognostication not going to alter the course of treatment in this patient molecular genetics not done� The patient’s family were counselled by the obstetric

medicine team supported by the medical oncologist about the need to initiate chemotherapy immediately, risks to the mother and the fetus, need for close monitoring.

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� Option of termination of pregnancy was considered in view of risk of neutropenic sepsis that could have grave consequences in pregnancy (an immunocompromised state), to the mother and the fetus; � However pregnancy was continued as the risk to the

mother was almost the same for termination due to � a)two previous LSCS in the mother� b)she being in the late second trimester with a

possibility to salvage the fetus after crossing the second trimester

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Chemotherapy Regime� Inj Dexamethasone -8 mg i.v D1-D7� Intrathecal MTX-12mg D1,D8,D15,D22� Inj Vincristine 2mg i.v D8,D15,D22,D29,D36� Inj Daunorubicin 30mg i.v D15,D22,D36 – not given

inview of risk of leukopenia and increased mortality with sepsis during pregnancy� Inj L asparaginase- 10000U i.m alternate day from D8

for 8 doses� T Prednisolone 20 mg TID

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Monitoring� Baseline CBC, LFT, serum creatinine

� CBC every 2-3 days

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� Serial Investigations showed bicytopenia improving with chemotherapy. � Later, at 34+wks gestation, there was mild worsening

of LFTs probably secondary to methotrexate� Fetal Monitoring was done with fortnightly AFI/

EBW( amniotic fluid index and estimated birth weight) and monthly fetal umbilical artery dopplerwhich were normal� Prophylactic Inj. Betamethasone 12 mg – 2 doses 24

hrs apart administered at 32 weeks of gestation

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Patient’s response to therapy� Nausea , Vomiting – treated symptomatically� Post dural puncture headache treated with analgesics

t� Numbness of finger tips secondary to peripheral

neuropathy with vincristine� Puffiness of face secondary to steroids�White discharge P/V- severe vulval candidiasis

treated with local antifungals� Appetite initially low for 2weeks later picked up�Weight gain – 4 kg (50 to 54kgs) in 2months

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� Induction course finished on 27/11/2010� CBC- Hb- 10.2 gm%, WBC-12000, Platelet-3lacs� Repeat BM biopsy –

Impression: Marrow in remissionInterim maintenance therapy:� Inj. Vincristine 2mg i.v single dose� Intrathecal methotrexate 12 mg for 3 consecutive

weeks� Tab mercaptopurine 100 mg orally O.D for 1 month

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Delivery plan� Elective LSCS at 34 completed weeks (17.12.2010)� May try to prolong till 36weeks if patient’s condition

is stable to improve the fetal outcomes

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� Epidemiology of leukemias in pregnancy� Their presenting features� Affect of leukemia in pregnancy and viceversa� Financial implications� Termination vs continuation of pregnancy� Fetal monitoring� Longterm prognosis of the patient

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Leukemias in pregnancy-epidemiology� Leukaemias are cancers of the haematopoietic system,

derived from transformed haematopoietic stem cells within the bone marrow.

� Leukemia during pregnancy : 1 in 75000-100000 pregnancies

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General population Pregnancy

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Incidence

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Definition of ALL� Acute lymphoblastic leukemia (ALL) is a malignant

proliferation of lymphoid cells blocked at an early stage of differentiation

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ALL immunophenotypic classification Subtype Typical Markers Childhood

(%)Adult (%)

B-cell precursor CD19+, CD22+, CD79a+, cIg±, sIg–, HLA-DR+

Pro-B CD10– 5 11Early pre-B CD10+ 63 52Pre-B CD10±, cIg+ 16 9

B cell CD19+, CD22+, CD79a+, cIg+, sIg+, sIgK+, or sIg+

3 4

T lineage CD7+, cCD3+T cell CD2+, CD1±, CD4±, CD8±, HLA-DR–,

TdT±10 18

Pre-T CD2–, CD1–, CD4–, CD8–, HLA-DR±, TdT+

1 6

Early T-cell precursor

CD1–, CD8–, CD5weak, CD13+, CD33+, CD11b+, CD117+, CD65+, HLA-DR+

2 ?

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Clinical presentations� Fever� Fatigue� Frequent infections� Swollen or tender lymph nodes, liver, or spleen� Pallor� Easy bleeding or bruising� Petechiae under the skin� Bone or joint pain

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Chemotherapy risks on pregnancyTherapy in early pregnancy(Inadvertently or deliberately)

Treatment during the second and third trimesters

� Spontaneous abortion

� Intrauterine death

�Malformations

� Early premature birth� Intrauterine death� Disturbances of

intrauterine growth and development� Chemotherapy

induced myelosupression in fetus

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Side Effects Associated with Antileukemic Therapy

Treatment Acute Complications Delayed Complications

Prednisolone Hyperglycemia, hypertension, changes in mood or behavior, acne, increased appetite, weight gain, peptic ulcer, hepatomegaly, myopathy

Avascular necrosis of bone, osteopenia, growth retardation

Vincristine Peripheral neuropathy, constipation, chemical cellulitis, seizures, hair loss

None

Daunorubicin Nausea and vomiting, hair loss, mucositis, marrow suppression, chemical cellulitis, increased skin pigmentation

Cardiomyopathy (with high cumulative dose)

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Treatment Acute Complications Delayed Complications

L-Asparaginase Nausea and vomiting, allergic reactions (manifested as rashes, bronchospasm, severe pain at intramuscular injection site), hyperglycemia, pancreatitis, liver dysfunction, thrombosis, encephalopathy

None

Mercaptopurine Nausea and vomiting, mucositis, marrow suppression, solar dermatitis, liver dysfunction: increased hematologic toxicity in persons lacking thiopurine methyltransferase

Osteoporosis (long-term use), acute myeloid leukemia in persons with thiopurinemethyltransferasedeficiency

Methotrexate Nausea and vomiting, liver dysfunction, marrow suppression, mucositis (resulting from high-dose treatment), solar dermatitis

Leukoencephalopathy, osteopenia (resulting from long-term use)

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� Patients with ALL often have decreased neutrophilcounts, regardless of whether their total white blood cell (WBC) count is low, normal, or elevated� As a result, they are at increased risk of infection� The prevalence and severity of infections are inversely

correlated with the absolute neutrophil count (ANC)� Infections are common when the ANC is < 500/µL,

and they are especially severe when it is < 100/µL � Infections are still the most common cause of death in

patients undergoing treatment for ALL 32

Management� Acute leukaemia requires immediate treatment,

irrespective of the gestational age

� Pregnancy does not alter the course of acute leukaemia, but the outcome is far worse when treatment is delayed

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Obstetric management1st trimester

� Termination of the pregnancy

� After the first trimester the decision to terminate the pregnancy needs to be discussed with the patient

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Second and third trimester� Counselling of couple � Continuation of pregnancy� Fetal monitoring

TIFFA scan 19-24 weeksSerial growth scan with DopplerNon-stress test

� In women between 24 and 34+5 gestational weeks, betamethasone advisable prior to leukemia treatment

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Delivery� Delivery at hematological remission; after a first

treatment course� Goal is to deliver after 34 weeks� Mode of delivery on obstetric indication� Delivery of the baby might be indicated before

starting leukaemia treatment if disease diagnosed 3rdtrimester( Cancer and Pregnancy Recent Results in Cancer Research

A. Surbone ・ F. Peccatori ・ N. Pavlidis (Eds.) Published by Springer 2008 )

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Supportive Care� Metabolic complication

� Hyperleukocytosis

� Infection Control

� Hematologic Support

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Anti-leukemic TherapyAims of modern ALL treatment regimens

� Rapid restoration of bone marrow function

� Adequate prophylactic treatment of the CNS

� Post-remission continuation therapies

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3 standard phases� Remission induction

� Intensification or consolidation

� Prolonged maintenance or continuation therapy

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Remission Induction� Goal: inducing a complete remission and restoring

normal hematopoiesis� The induction regimen typically includes a

glucocorticoid (prednisone, prednisolone, or dexamethasone), vincristine, and L-asparaginase for children or an anthracycline for adults.

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Intensification (Consolidation) Therapy� Administered shortly after remission induction� High doses of multiple agents not used during the

induction phase or re-administration of the induction regimen

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Continuation Therapy� 2 to 3 years regime - integral part of pediatric and

adult regimens� Combination of methotrexate administered weekly

and mercaptopurine administered daily

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Therapy of the CNS

� CNS is a common sanctuary for leukemic cells and requires presymptomatic therapy� Early intensification by intrathecal and systemic

chemotherapy� Triple intrathecal therapy with methotrexate,

cytarabine, and hydrocortisone

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Stem Cell Transplantation� Roles during first

remission controversial� Benefits high-risk

patients 1) Philadelphia-chromosome–positive ALL

2) poor initial response to induction therapy

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� Improved outcome in adults with the t(4;11), but not that of children or infants

� Allogeneic transplantation not superior to chemotherapy in adults with standard-risk ALL

� The indications in first remission should be re-evaluated as chemotherapy and transplantation continue to improve

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Treatment outcome by age cohort

Complete remission

Disease free survivalat 3 years

Survival at 3 years

<30y 30-59y 60+y

90%

0%

50%

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Prognosis in this patient� In this patient because the bone marrow biopsy at the

end of induction phase shows favourable response even though it was a modified regime tailored to the financial needs and pregnant state of the patient, and the pt. was started on an interim maintenance phase withholding the intensification phase till post delivery, and there are no reported outcomes / prognosis for such treatment regime, we need to wait and see how the pt. is going to do in the longterm.