Approach To The Highs And Lows Of White Cell Counts The What, Why - - PowerPoint PPT Presentation

Approach To The Highs And Lows Of White Cell Counts – The What, Why and How !

Dr Ng Chin Hin Consultant Haematologist National University Cancer Institute

11-MAR-2017

Approach to high WBC count

My approach

• Look at the differential count – especially the

manual differential count

• Check if other cell lines are affected.

– Low Hb or high Hb – Low Plt or high Plt

• History:

– Recent history of bleeding – Recent infection – Recent surgery – Recent chemotherapy, GCSF? – Any constitutional Sx? Fever, LOA/LOW, fatigue

• Physical examination – liver, spleen, LN

How Do We Approach High WBC ?

36 yrs old male, p/w with 4 days history of cough and

• fever. O/e: crackles were

heard over the right lung. Reactive neutrophilia – secondary to infection

Clues:

• Mainly neutrophilia
• Mild left shift
• May be a/w thrombocytosis
• Toxic changes reported in Neu

Monitor FBC weekly to two weekly. It should normalise over 2-4 weeks if the underlying infection is treated adequately.

Other causes of reactive neutrophilia

• Recovering from chemotherapy, especially after

administration of G-CSF

• Haemolysis
• Bleeding
• Chronic wound

58 yrs old female, presented with abdominal discomfort and progressive lethargy over the past 3 months. O/e: Pale, Splenomegaly (10 cm) Chronic Myeloid Leukemia

Clues:

• Marked neutrophilia with

prominent left shift – mainly myelocytes, not so much of metamyelocytes

• Basophilia
• Eosinophilia
• Thrombocytosis
• Splenomegaly !

Refer patient urgently to NUH via EMD

Diagnosis of CML

Demonstrating the presence of the t(9;22) or its gene product is absolutely essential in diagnosing a patient with CML Bcr-Abl

Bcr Abl

cDNA

Chronic / Accelerated / Blast Phase

Baccarani et al, Blood 2013

Treatment of CML

Tyrosine Kinase Inhibitor (TKi)

– 1st Generation: Glivec (Imatinib) – 2nd Generation: Tagsina (Nilotinib), Sprycel (Dasatinib), Bosulif

(Bosutinib), Iclusig (Ponatinib)

Quintas-Cardama et al. Mayo Clin Proc 2006; 81(7):973-988

71 yrs old female, p/w recurrent fever, night sweat, LOA/LOW.

• /e: moderate pallor,

splenomegaly (5cm)

Chronic Lymphoproliferative Disorders:

• Chronic Lymphocytic

Leukemia

• Splenic Marginal Zone

Lymphoma

• Mantle Cell Lymphoma
• Hairy Cell Leukemia
• Follicular Lymphoma

Clues:

• Marked Lymphocytosis
• May be associated with

anemia and thrombocytopenia

• Splenomegaly

Chronic Lymphocytic Leukemia

• Progressive accumulation of functionally incompetent

lymphocytes, which are monoclonal in origin.

• More common in the West – incidence: 4-6 per 100,000

per year. Asian incidence: 0.5-1.0 per 100,000 per year.

• Disease of the elderly. Median age: 70 yrs
• Presentation:

– Mostly asymptomatic. 25% of CLL found on routine FBC. – LN swelling: 50-90% – Splenomegaly: 25-55% – 10% with “B” Sx: Unintentional weigh loss >10% over 3 months,

fever, drenching night sweat, extreme fatigue

– Recurrent infection – Anaemia: related to disease load or secondary to autoimmune

haemolytic anaemia

Diagnosis of CLL

• Absolute lymphocytosis > 5x10-9/L
• Immunophenotyping:

– Expression of B cell associated antigens including CD19, CD20,

and CD23. Expression of CD20 is usually weak.

– Expression of CD5, a T cell associated antigen. – Low levels of surface membrane immunoglobulin (ie, SmIg

weak).

– Presence of Kappa or Lambda light chain restriction – needed to

confirm clonality.

• BMA or trephine biopsy – not needed for diagnosis
• FISH study – CLL panel – could identify good vs adverse

risk groups based on genetic abnormalities.

– Low risk: del13q14 – High risk: TP53 abnormalities

Staging

Median Survival: Stage 0 – 150 months Stage I – 101 months Stage II – 71 months Stages III and IV – 19 months

Treatment of CLL

• Treat only when symptomatic – symptomatic anaemia, “B” Sx, LN

enlargement with compression over vital organ, etc

• Chlorambucil – elderly
• Fludarabine/Cyclophosphamide/Ritux
• Bendamustine/Ritux
• Allogeneic stem cell transplant – very high risk patient – p53

abnormality

60 yrs old Malay gentleman, p/w sudden onset of left hypochondriac pain which was worsen on deep inspiration. O/e: Splenomegaly (6cm), and tender to palpation. Clues:

• Marked neutrophilia
• Marked monocytosis
• Splenomegaly

Chronic Myelomonocytic Leukemia

Presentation

• Median age: 65-75 yrs
• Mostly asymptomatic
• Splenomegaly with or without spenic infarct (pain)
• Hepatomegaly
• Lymphadenopathy
• Symptomatic anemia

Treatment

• Mainly supportive – blood transfusion,

hydroxyurea for cytoreduction

• Low intensity chemotherapy – azacytidine
• Curative: allogeneic stem cell transplant in

younger patients (<65 yrs old)

27 yrs old Indonesian lady, p/w recurrent fever and progressive

• lethargy. o/e: gum hypertrophy

Acute Monocytic Leukemia Clues:

• High WBC with increased

blast

• Gum hypertrophy
• Elevated LDH

20 yrs old boy, c/o chest tightness and persistent cough for past 2 weeks. He also noted easy bruising. Acute Lymphocytic Leukemia (T-ALL) Clues: Raised WBC with increased Blast, mediastinal mass, elevated LDH

Common presentation of Acute Leukemia

• Bleeding Sx: Easy bruising, epistaxis, gum

bleeding

• Recurrent or prolonged fever
• Easy fatigue
• Lymphadenopathy
• Splenomegaly / Hepatomegaly
• Mediastinal mass

Common lab findings

• LDH is almost always elevated – due to high turn over of

leukemic blasts

• Anemia and thrombocytopenia are common
• WBC is usually elevated, but can be within normal range
• r even leukopenia – so pay attention to the differential

count !

• DIC - acute promyelocytic leukemia.
• Tumorlysis – elevated UA, renal impairment,

hypocalcemia, hyperphosphatemia, hyperkalemia, elevated LDH – more common in acute lymphoblastic leukemia than acute myeloblastic leukemia

Acute Leukemia AML Non- APML APML ALL B-ALL T-ALL

Diagnosis of AML

• Bone marrow aspirate and trephine:

– Smear: morphological Dx (M0-M7) – Histology (trephine): immunohistochemistry – MPO, CD34,

CD117

– Cytogenetic (Karyotype): risk stratification and prognosis.

For examples: t(8;21), inv(16), t(15;17) are good risk, while monosomy 7, complex cytogenetics, t(6;9), inv(3) are very poor risk

– Molecular study: risk stratification and prognostic. For

examples: bialleilic CEBPA mutations, NPM1 mutation are good risk, while FLT3-ITD mutation, TP53, RUNX1 mutations are poor risk

– Flow cytometry (immunophenotyping): determine lineage,

describe baseline leukemia associated phenotypes for subsequent MRD monitoring

ELN 2017 Risk Stratification

Treatment of AML

• Induction  Consolidation
• Induction:

– Non-APML: Standard 3+7 (3 days of anthracycline

plus 7 days of continuous Cytarabine infusion)

– APML: ATRA/ATO with or without Anthracycline

• Consolidation:

– Favorable/Good risk: Chemotherapy alone (usually 3

cycles of high dose Ara-C)

– Intermediate risk: Mostly allogeneic SCT, those unfit

would be consolidated with chemotherapy (HIDAC)

– Adverse risk: Allogeneic SCT

Diagnosis of ALL

• Rarer than AML in adults
• NUH: AML (40-50 cases), ALL (12-15

cases)

• B-ALL vs T-ALL
• Bone marrow aspirate / trephine:

– Morphology – Cytogenetics – Molecular baseline MRD: IgvH and TCR

Risk Stratification of ALL

• High risk:

– Hypodiploidy – t(4;11) and other MLL rearrangement – t(9;22) – iAMP21 – IKZF1 deletion – TP53 mutation – Bcr-abl-like B-ALL – ETPALL – Complex cytogenetic – High WBC: B-ALL>30k, T-ALL>100k

• Standard risk: those without high risk

features

Treatment - ALL

• Age < 30 years: MASPORE Protocol

(Paediatric-inspired protocol)

• Age > 30 years: HyperCVAD Protocol
• Ph+ B-ALL: TKi + HyperCVAD
• CD20+ B-ALL: Rituximab + HyperCVAD
• Allogeneic SCT: high risk features, high

MRD

56 yrs old female, p/w abdominal discomfort and feeling easy fatigue. o/e: splenomegaly (12cm)

Clues:

• Leukoerythroblastic picture

in PBF (presence of immature granulocytes and nucleated red cells)

• Thrombocytosis –

dysplastic platelet (anisocytosis, giant platelets, agranular platelet)

• Tear-drop cells
• Splenomegaly (massive)

PRIMARY MYELOFIBROSIS

Common presentation of MF

• Abdominal discomfort – due to massive
• splenomegaly. If acutely painful – likely due to

splenic infarct

• Constitutional Sx : low grade temp, LOA, LOW,

excessive sweating, fatigue

Lab findings - MF

• Elevated WBC and platelet – common. Thrombocytosis

can be quite severe (>1000k)

• A/w Jak2 mutation (50%), CALR mutation (20-25%)
• LDH is often elevated
• Typical tear-drop cells and leukoerythroblastic picture on

PBF

• 1-2% blasts on PBF is common but if % increasing 

blast transformation

Diagnosis - MF

• PBF – leukoerythroblastic picture and tear-drop

cells

• BMA/Trephine – abnormal megakaryocytes,

increase reticulin staining on trephine

• Can be idiopathic (primary) or secondary – post

PV or ET myelofibrosis

Prognosis

• Using D-IPSS to risk stratify: Age >65, constitutional Sx,

WBC > 25k, Hb <10g, Peripheral blast ≥1%

Passamonti et al, Blood 2010

Treatment - MF

• Mainly supportive

– Blood product – Hydroxyurea – Thalidomide and steroid – Lenalidomide – Androgen (Fluoxymesterone) and steroid – Danazol – IFN – Jak2 inhibitor for splenomegaly and constitutional Sx – Splenic radiation – Splenectomy

• Allogeneic stem cell transplant is the only curative option

46 yrs old male, c/o chronic

• headache. o/e: mild

splenomegaly (3cm). Essential Thrombocytosis Clues:

• can be a/w high WBC

count – this is usually Jak2 mutation positive ET

Common presentation - ET

• Mostly asymptomatic – incidental
• Can present as stroke or AMI
• Usually no anemia – but if anemia present,

consider Primary Myelofibrosis

• Can sometime a/w bleeding manifestation –

usually in very severe thrombocytosis cases. Due to acquired vWD. Avoid Aspirin if Platelet count >1000k

Diagnosis - ET

• Persistent raised platelet count with no

secondary cause identified (normal CRP)

• Exclude CML, PMF, PV, MDS-t – all can present

with thrombocytosis

• Jak2 mutation – present in 50% of ET
• MPL mutation – present in 5% of ET
• CALR mutation – present in 20-25% of ET
• BMA/trephine may be needed if no mutation

detected.

Risk stratification – thrombosis & haemorrhage

Low risk: 2% of thrombosis in one year High risk: 24% in 2 yrs

Risk of Leukemic Transformation

• Low Hb < 12g for female, <13.5g for male
• Platelet count > 1000k

LT at 10 yrs:

1.

Low risk – 0.4%

2.

Intermediate risk – 4.8%

3.

High risk – 6.5%

Gangat et al, Leukemia 2007

Treatment - ET

• Based on risk group
• Low risk – Aspirin, no cytoreduction needed. Correct
• ther risk of thrombosis – quite smoking, cholestrol, DM

and Hypertension control

• Low risk but severe thrombocytosis (>1000k) – consider

cytoreduction to reduce risk of bleeding

• High risk – Aspirin and cytoreduction

– Hydrooxyurea – IFN – Anagrelide (risk of myelofirosis)

70 yrs old male, p/w acute left sided weakness and dysphasia. POLYCYTHEMIA VERA Clues:

• Polycythemia
• But microcytic hypochromic

RBC with iron deficiency

• Raised WBC and Plt
• Splenomegaly may or may

not present

Common presentation - PV

• Usually incidental
• Occ present with stroke or AMI at diagnosis
• Pruritus – usually following warm bath
• Erythromelalgia - burning pain in the feet or hands
• Thrombosis – arterial / venous
• Transient visual disturbance – amaurosis fugax,

scintillating scotomata, ophthalmic migraine

• GI Sx: epigastric distress, history of peptic ulcer disease,

and gastroduodenal erosions on upper endoscopy

Common Lab Findings - PV

• Hemoglobin >18.5 g/dL – 73%
• Total WBC >10,500/microL – 49%
• Platelet count >450,000/microL – 53%
• Platelet count >1 million/microL – 4%
• Elevated LDH – 50%
• Low EPO level – 81%
• Jak2 mut positive – 98%

Prognosis - PV

• Good ! Close to age-matched population.
• Death usually related to:

– Thrombotic event – Leukemic transformation – Myelofibrotic progression

Treatment - PV

• Mainly to reduce incident of thrombotic event
• Venesection:

–

preferred in younger patients

–

Aim to keep HCT < 0.45

–

Frequency: usually monthly to every two monthly

• Hydroxyurea:

–

Preferred in older patients and those with high platelet count

• Interferon:

–

Commonly used in young patients.

–

Very effective in lowering Hb, Plt as well as WBC.

–

The only treatment that actually have effect on Jak2 mutated clone. There are reported cases of prolonged remission after discontinuation.

–

Disadvantage: expensive, side effect

• Ruxolitinib:

– Intolerable to Hydroxyurea

Approach in interpreting low WBC count

My approach

• Check other cell lines – presence of anemia ? Or

Thrombocytopenia?

• Check for peripheral blasts - usually can be found in the

comment or formal PBF report

• Consider age group specific diagnosis – Aplastic anemia

in younger patient, MDS in older patients

• Look for palpable liver, spleen and lymph nodes
• Is the LDH elevated? Indicating high cell turn over or

haemolysis

• Recent viral infection?
• New medication over the past 1-2 months?

Approach to Low WBC count

Low WBC Thrombocytopenic? Anemic? Yes · MDS · Aplastic anemia · Acute leukemia · Post chemo · Drug: Myelosuppressive drug – HU, MTX, Valganciclovir · B12 deficiency Yes Anemic? No · Drug induced agranulocytosis · Viral infection · MDS No · MDS · B12 deficiency Yes Viral infection: Dengue No

45 yrs old male, was found to have low Hb (7.5g) and a palpable spleen. Referred to Haem clinic for further

• evaluation. Confirmed a diagnosis of

HbH disease, and found to have elevated ferritin 1500 (no history of blood transfusion). He was started on Deferiprone for iron chelation therapy.

4 weeks later …...

Hb 7.4 g WBC 1.2 (ANC 0.01, Lym 1.1, Mono 0.06) Plt 235 Deferiprone-induced agranulocytosis

Diagnosis

• Drug exposure – usually within the first 3 months
• f drug exposure
• Can still happen even after one month of drug

ceasation – due to immune mediated mechanism

• Isolated neutropenia with sparing of other cell

line

• BMA would demonstrate lack of granulocytic

precursors.

Medications associated with agranulocytosis

Treatment – drug-induced agranulocytosis

• Stop the offending drug
• Usually recover spontaneously over the

next 2 weeks

• GCSF can be considered in severe cases

(ie ANC <0.1) or if patient has on-going infection.

56 yrs old male, presented with progressive exertional dyspnoea with significant LOA/LOW (6 kg

• ver the past 3 months)

Megaloblastic anemia

Common presentation

• Progressive fatigue and symptomatic

anemia

• Significant loss of appetite and weight
• Can mimic cancer presentation

Common Lab Findings

• Low B12 – usually <100
• Anemia – usually severe (4-6g/L)

– High MCV >110 (but could be paradoxically lower 100-110

in severe deficiency)

– High RDW

• Thrombocytopenia – common and moderate (80-

100k)

• Leukopenia – common
• Anti-IF ab: positive in pernicious anemia
• LDH – invariably elevated (>700-1000). Due to

intramedullary haemolysis

• Elevated total bilirubin – mainly unconjugated. Due to

intramedullary haemolysis

• Can be mistaken for AIHA

Management

• IM B12 injection 1000mcg daily x 3 days, then

weekly x 3 weeks and then monthly.

• If presence of neurological deficit – IM B12

injection 1000mcg daily until resolution of symptom and then weekly x 3 weeks followed by monthly injection

• Folate supplement as well
• Avoid blood transfusion unless patient has high

CVS risk

72 yrs old male, presented with chest pain with progressive reduced effort tolerance over the past 6 months

Myelodysplastic Syndrome

Common presentation - MDS

• Incidental
• Symptomatic anemia
• Recurrent infection
• Bleeding - rare

Common Lab Findings

• FBC – pancytopenia, but can be anemia

alone or leukopenia alone

• PBF:

– RBC – anisopoikilocytosis – Neutrophils – dysplastic neutrophils, pelgeroid

form

– Platelet – dysplastic form

Diagnosis - MDS

• BMA – dysplastic maturation one or more

cell lines.

• Cytogenetics – from BM, could

demonstrate MDS-related chromosomal abnormalities, ie Trisomy 8

• Flow cytometry / immunophenotyping –

could often demonstrate aberrant expression in granulocytic and monocytic lineage, as well as erythroblast.

MDS Risk Stratification

Treatment - MDS

• Mainly supportive – blood transfusion, EPO
• Trial of IST – Cyclosporin
• Lenalidomide – MDS with 5q del
• Iron chelation – transfusion dependent MDS

with iron overload

• Azacitidine – high risk MDS. Improves survival

by 6-9 months

• Allogeneic SCT – is the only curative option, but

limited to younger and fit candidate.

26 yrs old female, presented with 4 days history of fever and bone

• pain. Previously well.

Viral Fever

28 yrs old male, presented with reduced effort tolerance progressively over the past 3 months. He noted history of fever and yellow discoloration of conjunctiva 5 months ago. Hb: 6.6 Platelet: 25 WBC 1.43 (ANC 0.3) PBF: normochromic normocytic anemia, thrombocytopenia and leukopenia with no immature white seen. Retic abs: 5

Aplastic Anemia

Common Presentation - AA

• Symptomatic anemia – reduced effort

tolerance, easy fatigue

• Recurrent infections – pneumonia, URTIs,

UTI

• Bleeding manifestation – easy bruising, GI

bleed, ICB

Diagnosis - AA

• Bone marrow aspirate and trephine
• Full blood count
• Reticulocyte count
• Screen for PNH clone – can be found in up to 65% of AA

Treatment - AA

• Immunosuppressive therapy:

– ATG, Cyclosporin, and Steroid – 40-60% response rate

• Allogeneic stem cell transplant – in young and severe AA
• Supportive care – blood products, ie. Red cells, platelet.

Should be used selectively to avoid alloimmunization.

• Growth factors:

– EPO is not effective in AA – GCSF can be considered in setting of infection. Not a standard

• therapy. Concern of clonal evolution and development of AML

– TPO has possible role in improving cytopenia (stimulate stem

cell compartment) but still under investigation.

Practical Advice

• Correlate Symptoms, signs, and FBC

would usually narrow down the DDx

• Pay attention to differential WBC – could

give you a lot of clues !

• Correlate the WBC with other cell lines –

Hb and Plt.

• If isolated high/low WBC and patient is

clinical well, you can afford to repeat another FBC in 1 week.

• Refer early if uncertain.

Thank You