NONNEOPLASTIC

DISORDERS OF WBC &

LEUKEMIAS

NONNEOPLASTIC DISORDERS OF

WHITE BLOOD CELLS

The number of leukocytes in the

peripheral circulating blood ranges from

4500 to 11 000/uL

The term leukopenia describes an

absolute decrease in WBC count

NEUTROPENIA

(AGRANULOCYTOSIS)

Neutropenia refers to a decrease in

neutrophils – less than 1500 cells/µL

(norm 1800 - 7700 cells/μL)

Agranulocytosis – a severe

neutropenia - is characterised by

count less than 200 cells /µL

ACQUIRED GRANULOCYTOPENIA

(↓)= NEUTROPENIA

Reduced or ineffective production

(neoplasms involving the bone marrow e.g.

acute leukemias, lymphomas, drugs, aplastic

anemia, chemotherapy, viral infections)

Excessive removal from the blood

(inflammation and infection)

Drugs (idiosyncratic)

DRUG-INDUCED

GRANULOCYTOPENIA (↓)

Cytotoxic drugs use in cancer therapy

Phenotiazin

Thiouracil

Chloramphenicol

Hydantoin derivates

Phenylbutazone

Most cases of neutropenia are drug related

The term idiosyncratic is used to describe drug reactions

that are different from the effects obtained in most

people and that cannot be explained in terms of allergy

Many idiosyncratic cases of drug-induced neutropenia

are thought to be caused by immunological mechanisms,

when the drug or its metabolites acting as antigens to

iniciate the production of antibodies react against the

neutrophils

NEUTROPENIA(↓)

CONGENITAL NEUTROPENIA (↓)

A group of hereditary hematologic disorders,

including:

Cyclic neutropenia (periodic neutropenia that

develops every 21 to 30 days and lasts about 3-6days=

impaired feedback regulation of granulocyte production and

release)

Kostmann’s syndrome (neutrophile count is

less than 200/uL but the total WBC may be within

normal limits. RBC and platelets are normally produced)

ACQUIRED GRANULOCYTOSIS (↑)

Bacterial infections

Malignancy (CML)

Excessive tissue trauma

NEOPLASTIC DISORDERS OF

HEMATOPOETIC AND LYMPHOID

ORIGIN

The leukemias, which arise from

hematopoetic precursors in the bone

marrow, can involve lymphocytes,

granulocytes and other blood cells.

Because blood cells circulate throughout

the body, these neoplasms are

disseminated from the onset

LEUKEMIA

Leukemia (from the Greek leukos-

white, and haima blood) is a type of

cancer of the blood or bone marrow

characterized by an abnormal increase

of immature WBC called “blasts„ or

mature WBC .

LEUKEMIAS

The leukemic cells spill out into the

blood and infiltrate the liver, spleen,

lymph nodes, and other tissues throughout

the body, causing enlargement of these

organs

Leukemias are more frequent in

adults than in children although

leukemias are the leading cause of death

in children between the ages of 1 and 14.

LEUKEMIA

Leukemia is clinically and

pathophysiologically subdivided into

acute and chronic forms.

ACUTE LEUKEMIA

Acute leukemia is characterized by

rapid increase of immature blood

cells and makes the bone marrow

unable to produce healthy blood cells

(most common in children)

CHRONIC LEUKEMIA

Chronic leukemia is distinguished by

the excessive build up of relatively

mature, but still abnormal WBCs,

Typically taking months or years to

progress. The cells are produced at a

much higher rate than normal

(most common in the elderly)

LEUKEMIAS

Additionally leukemias are subdivided

according to which kind of cell is

affected. This split divides leukemias

into:

• Lymphoblastic or lymphocytic leukemias

• Myeloid or myelogenous leukemias

LEUKEMIA

• The lymphocytic leukemias involve immature lymphocytes and their progenitors that originate in bone marrow but infiltrate the spleen, lymph nodes, CNS, and other tissues

• The myeloblastic leukemias, which involve the malignant transformation of pluripotent hematopoetic stem cell in bone marrow, interfere with the maturation of granulocytes, erythrocytes and thrombocytes.

LEUKEMIAS

Classification

Acute lymphocytic leukemia ( ALL)

Chronic lymphocytic leukemia (CLL)

Acute myeloblastic leukemia ( AML)

Chronic myeloblastic leukemia (CML)

LEUKEMIA- CAUSES

The causes of leukemia are largely unknown

The incidence of leukemia is higher among persons

who have been exposed to:

radiation

benzene

drugs (cyclophosphamide, procarbazin, chloramphenicol)

aggressive chemotherapy (leukemia as a second cancer)

There is also genetic predisposition to develop acute

leukemia incidence among a number of congenital

disorders ( Downe’s syndrome, Fankoni’s anemia)

Acute leukemias can occur within the same family

ACUTE LEUKEMIA

• ALLs are consist of a group of neoplasms

composed of immature precursor B or T

lymphocytes. Moste cases (85%) of ALL are of

pre-B-cell origin

• AMLs are an extremely heterogenous group

of disorders and compose of immature

myeloid cell precursor.

ACUTE LEUKEMIA

• ALL is the most common leukemia in childhood (80-85% of all leukemias)

• AML is chiefly an adult disease (median age 60-65 years ), however it is also seen in children

ALL

AML

ACUTE LEUKEMIAS

• Leukostasis is a condition in which the

circulating blast count is markedly elevated

(usually 100 000 cells/µL)

• Circulating leukemic blasts increase blood

velocity and predispose to development of

embolism of small vessels in the pulmonary

(progressive dyspnea) and cerebral (lethargy,

confusion and coma) circulation

LEUKEMIAS

SYMPTOMS

• Proliferating leukemic cells infiltrate bone marrow,

where they may constitute 60% to 100% of the cells

• The development of other blood cell lines in the

marrow is suppressed

• Anemia ( RBC), Haemorrhagic diathesis ( platelets)

and infections ( granulocytes 500 cells/µL).

• Weight loss, low-grade fever, night sweats (rapid

proliferation and hypermetabolism of lukemic cells)

ACUTE LEUKEMIAS

SYMPTOMS II

Nosebleeds and other type of hemorrhage,

easy bruising (decreased platelet count)

Anemia (weaknes, tachycardia, pallor)

Bone pain (bone marrow expansion by

leukemic cells)

Splenomegaly, hepatomegaly and lymph

node enlargement

Symptoms from CNS ( headache, nausea,

vomiting, seizures and coma - leukemic cells

can cross the blood-brain barrier)

CHRONIC LEUKEMIAS

• In contrast to acute leukemias, chronic

leukemias are malgnancies involving the

proliferation of well-differentiated

myeloid and lymphoid cells

• Two types of chronic leukemias: CLL and

CML

CLL & CML

frequency of morbidity

• CLL is mainly a disorder of old persons (above 50 years; men are affected twice as frequently as women)

• CML accounts for 15% of all leukemias in adults. It is predominantly a disorder of adults between the age of 30-50 years, but it can affect children as well

CLL

CLL is a lymphoproliferative disorder characterized by:

Lymphocytosis (95% of cases – transformation of mature B-

cells; B-cells are immunologically incompetent and don’t respond to antigen stimulation)

Lymphadenopathy (swollen/enlarged lymph nodes)

Splenomegaly (enlarge spleen)

CLL (BLOOD SMEAR)

•

CLL

Infections remain a major cause of morbidity and mortality because of:

• Immunologically incompetent B-cells

• Hypogammaglobulinemia (↓Ig)

Other immunological abnormalities include:

• Autoimmune hemolytic anemia (↓RBC)

• Immune-mediated thrombocytopenia (↓PLT)

CLL - SYMTOMS

Symptoms are related to the progresive infiltration of neoplastic lymphocytes in the

bone marrow and to secondary immunologic defects

Typical symptoms in CLL are: Fatigue

Enlargement of lymph nodes and spleen

Recurent or persistent infections

Pallor

Edema

Pain

CML

CML is a myeloproliferative disorder that results

from the malignant transformation of

pluripotent stem cell

CML is associated with the presence of the

Philadelphia chromosome (reciprocal translocation between

the long arm of chromosome 22 and the long arm of chromosome 9)

A new fusion gene on chromosome 22 resulting

in cell growth and proliferation.

Philadelphia chromosome

CML

• In 95% of persons with CML the Philadelfia

chromosome can be identified in granulocytic,

erythroid and megacariocytic precursors as

well as B cells, and some cases T cells

• Although CML originates in the pluripotent

stem cells, granulocyte precursors remain the

dominant leukemic cell type

CML( BLOOD SMEAR)

•

CML - symptoms gradually

exacerbated

Typical CML follows a triphasic course

1. Chronic phase (nonspecific symptoms such as

weakeness, weight loss; laboratory tests: leukocytosis with immature granulocyte cell type in the peripheral blood, anemia and eventually trompocytopenia; 4 years)

2. Short accelerated phase (enlargement of the spleen

and progresive symtoms like low-grade fever, night sweats, bone pain, weight loss, bleeding, easy bruising; 6-12 months)

3. Terminal blast crisis phase (splenomegaly can

increase significantly and symptoms become more pronounced, lab tests – blast counts 100 000/ l; median survival 3 months)