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Todays Quranic verse

And hold fast, all together, by the rope which God (stretches out

for you), and be not divided among yourselves; and rememberwith gratitude God's favour on you; for ye were enemies and He

joined your hearts in love, so that by His Grace, ye became

brethren; and ye were on the brink of the pit of Fire, and He

saved you from it. Thus doth God make His Signs clear to you:

That ye may be guided. [003:103]

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Never deprive anyone of hope; it could be theNever deprive anyone of hope; it could be the

only thing a person owns.only thing a person owns.

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DISORDERSOF WHITEBLOOD CELLS

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White blood cell types (WBC differential)

Neutrophils (103/L) 1.4-6.5 (50-65%)

Band neutrophils (103/L) (3-6%)

Lymphocytes (103/L) 1.2-3.4 (25-40%)

Monocytes (103/L) 0.1-0.6 (3-7%)

Eosinophils (103/L) 0-0.5 (0-3%)

Basophils (103/L) 0-0.2 (0-1%)

White blood cell (WBC) count

Normal Count : 4.8-10.8 (103/L)

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Name the different cells.

Neutrophil (Band Cell)

Platelet

Eosinophil

Monocyte

Lymphocyte

MatureNeutrophil

Basophil

Red Blood Cell

(Mature Erythrocyte)

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BENIGN DISORDERSOF LEUKOCYTES

Leukocytosis

Condition characterized by abnormally increased number of WBC.

It may be generalized or involve only individual granulocytes oragranulocytes.

Leukopenia:Condition characterized by abnormally reduced number of WBC. It

may be generalized or involve only neutrophils or lymphocytes

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Neutrophilic

leukocytosis

Acute bacterial infections, especially those caused by pyogenic organisms; sterile

inflammation caused by, for example, tissue necrosis (myocardial infarction, burns)

Eosinophilic

leukocytosis

Allergic disorders such as asthma, hay fever, allergic skin diseases (e.g., pemphigus,

dermatitis herpetiformis); parasitic infestations; drug reactions; certain malignancies (e.g.,

Hodgkin disease and some non-Hodgkin lymphomas); collagen vascular disorders and

some vasculitides; atheroembolic disease (transient)

Basophilic

leukocytosis

Rare, often indicative of a myeloproliferative disease (e.g., chronic myelogenous leukemia)

Monocytosis Chronic infections (e.g., tuberculosis), bacterial endocarditis, rickettsiosis and malaria;collagen vascular diseases (e.g., systemic lupus erythematosus) and inflammatory bowel

diseases (e.g., ulcerative colitis)

Lymphocytosis Accompanies monocytosis in many disorders associated with chronic immunologic stimulation(e.g., tuberculosis, brucellosis); viral infections (e.g., hepatitis A, cytomegalovirus, Epstein-

Barr virus); Bordetella pertussis infection

LEUKOCYTOSIS

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Reduced or ineffective productionof neutrophils

Accelerated removal of neutrophils

from the circulating blood

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Leukemoid reaction

Leukemoid reaction is defined as a reactive leukocytosis in excess of 50000/L. It is usually seen in response to infection, inflammation, ortherapeutic agents such as growth factors and is less commonly caused

by malignancy. Milder elevations in leukocyte count are common both incarcinoma and Hodgkin lymphoma.

Cells are more mature than myelocytes in peripheral smear

Leukocytic alkaline phosphatase activity is high

Neutrophils contain toxic granules (Dohle bodies)

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LEUKEMIAS

Neoplastic Proliferations of White Cells

Lymphoid neoplasms Myeloid neoplasms

Histiocytoses

LymphomaChloroma

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Leukemia

Malignancy of hematopoietic cells

Starts in bone marrow, can spread to blood, nodes

Myeloid or lymphoid Acute or chronic

Lymphoma

Malignancy of hematopoietic cells

Starts in lymph nodes, can spread to blood, marrow

Lymphoid only

Hodgkin or non-Hodgkin

Hematologic Malignancies

Multiple myeloma

Histiocytosis

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HEMOPOIESISMYELOID/ LYMPHOID

STEM CELLS(CD34)

LYMPHOID

STEM CELLS

MYELOID

STEM CELLS

LYMPHOCYTES OTHER BLOOD CELLS

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HEMOPOIESISMYELOID/ LYMPHOID

STEM CELLS(CD34)

LYMPHOID

STEM CELLS

MYELOID

STEM CELLS

LYMPHOCYTESRBC

OTHER

WBC

PLATELET

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HEMOPOIESIS

MYELOID/ LYMPHOID

STEM CELLS

(CD34)

MYELOID

STEM CELLSPRO-

NORMOBLAST

EARLY

NORMOBLAST

INTERMEDIATE

NORMOBLAST

LATE

NORMOBLAST

RETICULOCYTE

RBC

MONOBLAST

PROMONO

CYTE

MONOCYTE

MYELOBLAST

PRO-MYELOCYTE

MYELOCYTE

META-MYELOCYTE

BAND or STAB

GRANULOCYTES

MEGAKARYO

CYTE

MEGAKARYO

BLAS

T

PLATELET

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HEMOPOIESIS

MYELOID/ LYMPHOID

STEM CELLS

(CD34)LYMPHOID

STEM CELLS

Pre-T

Thymocyte

Peripheral T Cells

T-

Helper

T-

Supp.

Pro-B

Pre-B

B- Virgin

B- Mature

LPC

PLASMA

CELL

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Myeloid maturationmyeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATIONMATURATION

Adapted and modified from U Va website

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LEUKEMIAS

Leukemias are usually diseases of

unknown etiology

Abnormal Uncontrolled

WidespreadWidespread

Proliferation

of

WBC Clonal

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Leukemia

Etiology and Pathophysiology

Associated with the development of leukemia

Chemical agents

Chemotherapeutic agents Viruses

Radiation

Immunologic deficiencies

Underlying hematologic disorders

Hereditary/genetic conditions

Idiopathic

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LEUKAEMIAMYELOID/ LYMPHOID

STEM CELLS(CD34)

LYMPHOID

STEM CELLS

MYELOID

STEM CELLS

LYMPHOCYTESGRANULOCYTES

ACUTE

CHRONIC

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Lymphoblasts

Lymphocytes Granulocytes

Myeloblasts

ALL AML

CMLCLL

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HEMOPOIESIS

MYELOID/ LYMPHOID

STEM CELLS

(CD34)LYMPHOID

STEM CELLS

Pre-T

Thymocyte

Peripheral T Cells

T-

Helper

T-

Supp.

Pro-B

Pre-B

B- Virgin

B- Mature

LPC

PLASMA

CELL

ALL

CLL

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Acute Leukemiameans

Maturation Arrest

SustainedSELF-RENEWALAT THE EXPENSE OF

DIFFERENTIATION

Differentiation

(Maturation)

Self-renewal

Maturation Arrest

Sustained

self-renewal

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Learn how to say No courteoulsy & promptlyLearn how to say No courteoulsy & promptly.

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LEUKEMIAS

TYPES

INCIDENCE

AGE

PRESENTATION

BONE

MARROW

Anemia

Neutropenia

Thrombocytopenia

CNS

BONESKIN

LYMPHATICS

etc

OTHERS

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Acute Leukemias(AML/ALL)

Block in differentiationblasts with prolonged generation time

Accumulation of blasts

(Result from a clonal expansion & Failure of maturation)

Suppress normal hematopoiesis

( in normal RBCs, WBCs and Platelets)

Aim of TX is to reduce the leukemic clone to allow reconstitution

with the progeny of remaining normal stem cells

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Acute Leukemias (AML/ALL)

Clinical features

Abrupt onset

Symptoms related to BM depression Fatigue from anemia, fever from infection, bleeding from thrombocytopenia

Bone pain and tenderness BM expansion with subperiosteal infiltration

Generalized adenopathy, hepatosplenomegaly (ALL>AML)

CNS manifestations (ALL>AML) Headache, vomiting, nerve palsies

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Acute Leukemias (AML/ALL)

Laboratory

Leukocytosis (>100,000) with blasts in circulation & BM (count may be 60% of the patients achieve complete remission with chemotherapy, but only 15% to30% remain free from disease for 5 years

>90% of children with ALL achieve complete remission, and 2/3 can be cured

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Blasts

Features Myeloblasts Lymphoblasts

Cytoplasm Mod/abundant Scant/Mod

Cyt. Granules Common Uncommon

Nucleus (chromatin) fine Coarse

Nucleoli Prominent Variable

Auer rods Present Absent

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Acute leukemia: bone marrow biopsy

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Acute lymphoblastic leukemia Acute myeloid leukemia

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AML

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Acute Leukemia

For diagnosis: >20% blasts in the bone marrow

Further characterized byWright stain (H & E stain)

Cytochemical stains (myeloperoxidase, NSE, PAS)

Flow cytometry & immunohistochemistry

Cytogenetics

Using a combination of CDs specifically recognizing B-cell, T-cell, and

myeloid antigens, it is possible to distinguish

AML from ALL in 95% to 99% of cases

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AML

ACUTE LEUKEMIAS

FAB CLASSIFICATION

M0

M1

M2

M3M4

M5

M6

M7L1

L2

L3

ALL

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M0 - acute myeloblastic leukemia, minimally differentiated 2-3%

M1 - acute myeloblastic leukemia without maturation 20%

M2 - acute myeloblastic leukemia with maturation 30% good prog. t(8:21)

M3 - acute promyelocytic leukemia 5-10% DIC, t(15,17), Responds to ATRA

M4 - acute myelomonocytic leukemia 20-30% better prognosis inv16/del16q

M5 - acute monocytic leukemia 10%, pediatric age-young adults, 11q23

M6 - acute erythroblastic leukemia 5%, older adults

M7 - acute megakaryoblastic leukemia Myelofibrosis

Acute Myeloid Leukemia

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Auer rods in AML (M3)

Hypergranular promyelocytes, many auer rods5-10% DIC, t(15,17), Responds to ATRA

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CD M1/M2 M3 M4/M5 M6 M7

CD11b - + ++ - -

CD13 + + ++ + +

CD14 - - ++ - -

CD15 + + ++ - -

CD33 ++ + ++ + +

CD34 ++ + + + +

Immunophenotyping of AML

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L1

FAB CLASSIFICATIONACUTE LYMPHOBLASTIC LEUKEMIAS

Lymphoblasts: Small & Monomorphic

L2

Lymphoblasts: Large & Heterogeneous

L3

Burkitt ALL

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Precursor B- and T- Cell Lymphoblastic

Leukemia/Lymphoma

Aggressive tumors of children/young adults

Composed of immature lymphocytes (lymphoblasts)

Lymphoblastic tumors are indistinguishable morphologically with similarsymptomatology

Pre-B: present as leukemias with extensive BM involvement (CD19+ andCD10+)

Pre-T: mediastinal masses involving the thymus progress rapidly to a leukemicphase or involve BM (CD1+, CD2+, CD5+, and CD7+)

Both pre-B/T lymphoblastic tumors have the clinical appearance ofALL at sometime during their course

Hyperploidy (>50 chromosomes), polyploidy, and t(12;21), t(9;22) and t(4;11) >90% of children with ALL achieve complete remission, and 2/3 can be cured

ALLs comprise 80% of childhood leukemia (peaks at age 4) and areusually pre-B phenotype

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Immunophenotyping of ALL

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M1

M5

L2 LYMPHOBLAST

MYELOBLAST

MONOBLAST

SPECIAL STAIN

S

*S

udan Black*Myeloperoxidase

*Specific Esterase

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Shed hate and rancour, they hurtShed hate and rancour, they hurt youyou more than they do others.more than they do others.

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Beware of who has nothing to lose.Beware of who has nothing to lose.

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Pallor

Purpura

Infection

Mucosal Bleeding

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Oral CandidiasisPneumonia

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Extensive Bruising

Gum Hypertrophy

Lymphadenopathy

Lymphadenopathy Leukemic Infiltrate

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Leukemic Infiltrate

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Lytic Skull Lesions

Mediastinal Involvement

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Chloroma

2% of AML have discrete tumors

Chloroma (Myeloblastoma)

Granulocytic Sarcoma

In the Orbit, Para-nasal sinuses, Brain, Spinal cord, Bone, Breast

Skin & Subcutaneous tissues

Called chloromas because of greenish color from MPO

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TreatmentChemotherapy & Bone marrow transplant

Prognosis for AML

Dismal

Some chromosomal abnormalities confer different prognosis

Prognosis for ALL

Immunophenotype (T is bad)

Age (1-10 good)

WBC (

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The Future

Clinical trials

New drug treatments

Vaccines

Immunotherapy

Leukemia type-specific therapy

Gene therapy Block encoding instructions of an oncogene

Target the oncoprotein

Blood and marrow stem cell transplantation

Bone marrow transplantation provides long-term, disease-free survivalamong patients in remission

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Chronic Myeloproliferative

DisordersClonal stem cell disorders characterized by proliferation of one or more

of the myeloid lineages (granulocytic, erythroid, megakaryocytic) in

bone marrow.

Characterized by:Normal maturation,

Insidious onset

Progression to myelofibrosis/transformation

Includes:

Chronic myelogenous leukemia (CML)Polycythemia vera (PV)

Myeloid metaplasia with myelofibrosis (MMF)

Essential thrombocythemia (ET)

Features common to all 4

Occur only in adults

Long clinical course

o WBC with left shift

Hypercellular marrow

Splenomegaly

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Chronic Myeloid

Leukemia

The First Disease

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The First Disease

The 1st disease for which the term leukemia was used (Virchow 1845; White Blood)

The 1st malignancy ~ with a recurring chromosomal abnormality (Philadelphia Chromosome)

The first disease in which the associated chromosomal abnormality was found to result from

the translocation of genetic material from one chromosome to another to form fusion gene

(BCR/ABL)

The first disease in which the fusion gene was recognized as giving rise to an abnormal fusion

protein fundamental in the pathogenesis of the disease.

The first disorder in which a therapeutic agent Glivec has been designed to specifically target

the molecular defect

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CML

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Chronic Myeloid Leukemia (Peripheral smear)

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Chronic

Phase

Accelerated

Phase

CML

Blast

Crisis

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PHASES (STAGING) OF CML

Three main stages, determined by percentage of blast cells in the blood

- Chronic Phase- Patient usually diagnosed

- Fewer than 10% of cells in blood and bone marrow are blast

- Prognosis: (with imatinib) 5yr: 70%, 10yr: 30-40%

- Accelerated Phase- 10-19% of cells in blood or bone marrow are blast, Basophilia 20%

- Blastic Phase, aka blast crisis- Fulminant symptoms of disease, multiple organ involvement

- 20-30% or more blasts in bone marrow and blood

- Prognosis: UNPROMISING, 2 months, may extend survival with newerdrugs or chemotherapy

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BCR

+

ABLFUSION

Normal chromosomes Chromosomes in CML

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Ph chromosomePh chromosome

BCRBCR--ABLABL (activatedactivated

tyrosine kinase)tyrosine kinase)

BCRBCR ABLABL

CMLCML

The Philadelphia (Ph) Chromosome Leads to

CML

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bcr

abl

Fusion abl/bcr (9)

Fusion bcr/abl (22)

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Practical Guidelines to Diagnose and Monitor CML

Test Guidelines

Routinecytogenetic analysis

At diagnosis and every year

I-FISH Pretreatment to have baseline percent of Ph-positive cells,then every 2-3 mo until Ph

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Treatment

Chemotherapy:

Tyrosine kinase inhibitor:

Interferon-E.

Stem cell transplant.

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Own up to your mistakes.Own up to your mistakes.

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Imatinib (Gleevec)

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Normal Bcr-Abl Signaling

The kinase domainactivates a substrateprotein, eg, PI3 kinase, byphosphorylation

This activated substrateinitiates a signalingcascade culminating incell proliferation andsurvival PP P

ADP P

P

PP P

ATP

SIGNALING

Bcr-Abl

Substrate

Effector

ADP = adenosine diphosphate; ATP = adenosine triphosphate;

P = phosphate.

Savage and Antman. NEngl J Med. 2002;346:683

Scheijen and Griffin. Oncogene. 2002;21:3314.

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Imatinib MesylateMechanism of Action

Imatinib mesylate occupies

the ATP binding pocket of

the Abl kinase domain

This prevents substrate

phosphorylation and

signaling

A lack of signaling inhibitsproliferation and survival

P

PP P

ATP

SIGNALING

Imatinibmesylate

Bcr-Abl

Savage and Antman. NEngl J Med. 2002;346:683.

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Impressive Results in CML ...

0

10

20

30

40

5060

70

80

90

100

Late chronic phase Accelerated phase Blast crisis

Hematologic response Major cytogentic response (MCR)

(n=532) (n=235) (n=260)

89%

68%

55%

23%29%

15%

< 10% of patients on IFN have MCR1

1 Kantarjian, 1998

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Chronic myelofibrosis

Panmyelosis then marrow fibrosis

Extramedullary hematopoiesis

Teardrop red cells

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Dont hesitate to lose a battle if it helps you win the war

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Chronic LymphoidLeukemia

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Chronic Lymphocytic Leukemia

(CLL)

Most common form of leukemia in North America and Northern Europe Essentially identical to small lymphocytic lymphoma (SLL)

M > F (2 : 1) Elderly (>60)

Mostly asymptomatic Hepatosplenomegaly may be present (in later stages) Symmetrical lymphadenopathy

Peripheral lymphocytosis (>200,000) B cells but CD5+ Increased susceptibility to bacterial infection (most frequent cause of death) May associated with autoimmune hemolytic anemia (AIHA) & Thrombocytopenia

Indolent but considered incurable (50% 5 year survival)

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Indolent clinical course

Median survival : 4-6 yrs

Occasional transformation to large non-Hodgkins lymphoma(Richters syndrome) --- 3 to 5 %

Chronic Lymphocytic Leukemia

(CLL)

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CLL:

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Chronic Lymphoid Leukemia (Peripheral smear)

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Chronic Lymphoid Leukemia (Bone marrow)

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Investigation:

CBC:

WBC:o.

Diff:lymphocytosis ,theabsolute lymphocyte countis>5x109/l and may be upto 300x109/l or.

Blood film:

70-99% of white cells mature lymphocyte.

Smudge or smear cells also present.Immunophenotyping:

Shows that the lymphocyte are B cells

(CD19) expressing one form of light chain

(O or P only) cells are also CD5 & CD23+ve.

Bone marrow aspiration:

Lymphocytic replacement of normal marrow.

Immunoglobulinelectrophoresis:

qof Ig, more marker with advance disease.

Cytogenetic :

The 4 most common abnormalities are; deletion of13q14,trisomy 12, deletion of11q23 & structural abnormality of 17p involving the p53 gene.

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RaiStaging

CLL

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Normal

Marrow

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CLL

Marrow

>40%LC

LC

>

15,000/uL

No

Palpable

L.N.

No

Palpable

Disease

Normal

Hb

Normal

Platelets

SURVIVAL

150

months

Stage 0

CLL

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CLL

Marrow

>40%LC

LC

>

15,000/uL

Palpable

L.N.

No

Palpable

Disease

Normal

Hb

Normal

Platelets

SURVIVAL

101

months

Stage I

CLL

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CLL

Marrow

>40%LC

LC

>

15,000/uL

Palpable

L.N.

Hepato-

Spleno-

megaly

Normal

Hb

Normal

Platelets

SURVIVAL

71

months

Stage II

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CLL

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CLL

Marrow

>40%LC

LC

>

15,000/uL

Palpable

L.N.

Hepato-

Spleno-

megaly

Anemia Thrombo-

cytopenia

SURVIVAL

19

months

Stage IV

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BinetStaging

CLL

CLL

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CLLGroup A

No anemia or thrombocytopenia,< three of five lymph node areas

Group B

No anemia or thrombocytopenia,Three or more lymph node areas

Group C

Anemia (Hb

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Chronic myeloid leukemia Chronic lymphocytic leukemia

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Acute leukemia

Sudden onset

Can occur in either adults or children

Rapidly fatal without treatment

Composed of immature cells (blasts)

Chronic leukemia

Slow onset

Occurs only in adults

Longer course

Composed of mature cells

Acute vs. chronic leukemia

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Do onto others as you wish others did onto you.

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Hairy Cell Leukemia

Uncommon variant of peripheral B-cell neoplasm

Clinically Middle age to elderly (younger than CLL)

splenic red pulp involvement

Histologically Lymphocyte with finger-like projections Phenotypically TRAP (Tartrate Resistant Acid Phosphatase)

CD19, CD20

H i C ll L k i

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Hairy Cell Leukemiaclinical

M > F (3-5 : 1)

Splenic red pulp involvementp red pulp lake

Bone marrow & liver involvement Tends to follow an indolent course

Pancytopenia - most prominent feature

- Granulocytopeniap recurrent bacterial infection

- Anemia p fatigue - Thrombocytopeniap bleeding

Good response to some chemotherapy regimen

l d l i S d

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Myelodysplastic Syndrome Group of Clonal stem cell disorders characterized by ineffective hematopoiesis,

hypercellular marrow with left-shift (increase of blasts, 5- 10%) may eventually transform into acutemyeloid leukemia or progress into marrow failure.

Types Primary or Idiopathic = > 50yrs, Gradual in onset, risk of AML

Rx ( RT orDrugs) related (t MDS) = after 2 -8 of RX, complication of Rx, Higher risk

of AML ( ) Pathogenesis

Unknown

FAB classification (based on % blasts and ringed sideroblasts)

1. Refractory anemia (RA)2. Refractory anemia with ringed sideroblasts (RARS)3. Refractory anemia with excess blasts (RAEB)4. Refractory anemia with excess blasts in transformation (RAEB-T)5. CMML (chronic myelomonocytic leukemia)

M l d l i S d

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Cytogenetic abnormalities Deletions (5q,7q,20q), Monosomy (5 & 7), Trisomy (8)

Morphology

Marrow = usually Hypercellular, Erythroid precursors - ring Sideroblasts, budding nucleated cells, Granulocytic Megaloblastoid, Pseudo Pelger Huet neutrophils( two

nuclear segments), Megakaryocytes- Pawn ball type( multinucleate)

Peripheral Blood = Cytopenias ( Pancytopenia)

Patients present with Refractory Anemias (not responding to hematenics even after6 months of Rx )

Myelodysplastic Syndrome

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Dont be afraid to say I dont know and Im sorryDont be afraid to say I dont know and Im sorry

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Normal neutrophil

(top left)

Neutrophil with

toxic granulation

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Dhle bodies

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Cytoplasmic vacuolization

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Left shift

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Leukoerythroblastotic reaction

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Mature neutrophilia

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117/121

Immature neutrophilia

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Mature lymphocytosis

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Reactive lymphocytosis

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Downey cells

IIIIII

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