Leukaemia

Learning Objectives  Define leukemia  Identify the etiology of leukemia  Discuss the definition, Pathophysiology, signs and symptoms, management of:  Acute lymphatic leukaemia (ALL)  Acute Myelogenous Leukaemia (AML)  Chronic lymphocytic Leukaemia (CLL)  Chronic Myelogenous Leukaemia (CML)  Lymphedema

Definition  Leukemia’s are a group of cancers of the blood or bone marrow and are characterized by an abnormal proliferation (production by multiplication) of blood cells, usually white blood cells (leukocytes).  Leukemia is a broad term covering a spectrum of diseases. Any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs and which is usually accompanied by anemia and thrombocytopenia

• Bone marrow (BM) is the source of all blood cells • BM produces immature undifferentiated cells called stem cells • Stem cells are pluripotent can have more than one potential outcome • Stem cells take a specific pathway depending on the body’s needs and the presence of specific chemicals that direct their growth

 Type of cancer with uncontrolled production of immature white blood cells (WBC) (blast cells) in the bone marrow  Overcrowding with immature, dysfunctional cells which interfere with production of mature cells including Red blood cells (RBC), platelets, and WBC’s  Leukaemia cells can also be found in reticulonendothelial tissues (spleen, liver, lymph nodes)  Leukaemia can be seen in different populations and different age ranged but commonly leukaemia stunning in the younger populations.  Fatal if untreated

 Eitology and genetic risk  The exact cause is frequently not known, but predisposing factors are known:  Host factors  Some individuals have an inherited increased predisposition to develop leukemia  There is an increased incidence in those with an inherited tendency for chromosome fragility or abnormality or those with increased numbers of chromosomes (such as Down’s syndrome).  Many of these diseases are characterized by chromosomal translocations.  There is an increased incidence in those with hereditary immunodeficiencies.  There is an increased incidence in those with chronic marrow dysfunction such as those with myeloproliferative diseases, myelodysplastic syndromes, aplastic anemia, or paroxsymal nocturnal hemoglobinuria.  Environmental factors:  Exposure to ionizing radiation (high levels of radiation)  Exposure to mutagenic chemicals and drugs  Viral infections

Signs and symptoms

Signs  Pallor  Hemorrhage from the gums, epistaxis, skin, fundus, GI tract, urinary tract  Hepato-splenomegaly  Enlarged lymph nodes  Gum (hypertrophy) or skin infiltration (M5)  Fever (sepsis, pneumonia, peri-rectal abscess)

Symptoms • Swollen lymph nodes that usually don’t hurt • Fatigue, malaise, dyspnea (anemia) • Bleeding eg after dental procedure Easy bruisability Severe epistaxis • Fever or night sweats • Bone Pain • Frequent infection • Feeling weak or tired • Weight loss for no reason

Classification  General classification - Clinically and pathologically, leukaemia is subdivided into a variety of large groups. The first division is between its acute and chronic forms

number of immature blood cells. Crowding due to such cells makes the bone marrow unable to produce healthy blood cells. Immediate treatment is required in acute leukaemia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukaemia are the most common forms of leukaemia in children. - Chronic leukaemia is characterized by the excessive buildup of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal, resulting in many abnormal white blood cells. Whereas acute leukaemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy. Chronic leukaemia mostly occurs in older people, but can theoretically occur in any age group. Additionally, the diseases are subdivided according to which kind of blood cell is affected. This split divides leukemia’s into lymphoblastic or lymphocytic leukemia and myeloid or myelogenous leukemia’s 

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In lymphoblastic or lymphocytic leukemia’s, the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes, which are infection-fighting immune system cells. Most lymphocytic leukemia’s involve a specific subtype of lymphocyte, the B cell. In myeloid or myelogenous leukemia’s the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells, some other types of white cells, and platelets.

 Leukaemia’s are classified into 2 major groups - Two major types (4 subtypes) of leukemia’s  Acute leukemia’s o Acute lymphoblastic leukemia (ALL) o Acute myelogenous leukemia (AML) (also "myeloid" or "nonlymphocytic")  Chronic leukemia’s o Chronic lymphocytic leukemia (CLL) o Chronic myeloid leukemia (CML)

What does chronic and acute leukaemia means?  Chronic in which the onset is insidious, the disease is usually less aggressive, and the cells involved are usually more mature cells  Acute in which the onset is usually rapid, the disease is very aggressive, and the cells involved are usually poorly differentiated with many blasts.  Both acute and chronic leukemia’s are further classified according to the prominent cell line involved in the expansion:  If the prominent cell line is of the myeloid series it is a myelocytic leukemia (sometimes also called granulocytic)  If the prominent cell line is of the lymphoid series it is a lymphocytic leukemia  Therefore, there are four basic types of leukemia  Acute myelocytic leukemia – AML- (includes myeloblastic, promyelocytic, monocytic, myelomonocytic, erythrocytic, and megakaryocytic)  Acute lymphocytic leukemia – ALL- (includes T cell, B cell, and Null cell)  Chronic myelocytic leukemia – CML - (includes myelocytic and myelomonocytic)  Chronic lymphocytic leukemia – CLL - (includes plasmocytic {multiple myeloma}, Hairy cell,

prolymphocytic, large granular cell lymphocytic, Sezary’s syndrome, and circulating lymphoma

Four major kinds of leukaemia Cell type Lymphoid cells

Myeloid or "nonlymphocytic"

Acute Acute lymphocytic leukaemia (ALL) Acute myelogenous leukaemia (AML or myeloblastic)

Chronic Chronic lymphocytic leukaemia (CLL) Chronic myelogenous leukaemia (CML)

Myelogenous leukaemia

Myeloid vs. Lymphoid • Any disease that arises from the myeloid elements (white cell, red cell, platelets) is a myeloid disease ….. AML, CML • Any disease that arises from the lymphoid elements is a lymphoid disease ….. ALL, CLL

 Incidence  Acute leukemia’s can occur in all age groups  ALL is more common in children  AML is more common in adults  Chronic leukemia’s are usually a disease of adults  CLL is extremely rare in children and unusual before the age of 40  CML has a peak age of 30-50

 Comparison of acute and chronic leukemia’s: Age Clinical onset Course (untreated) Leukemic cells Anemia Thrombocytopenia WBC count Lymphadenopathy Splenomegaly

Acute

Chronic

All ages Sudden 6 months or less Immature > 30% blasts Prominent Prominent Variable Mild

Usually adults Insidious 2-6 years More mature cells Mild Mild Increased Present; often prominent Present; often prominent

Mild

Acute leukemia  Is a result of:  Malignant transformation of a stem cell leading to unregulated proliferation and  Arrest in maturation at the primitive blast stage. Remember that a blast is the most immature cell that can be recognized as committed to a particular cell line.

 Clinical features  Leukemic proliferation, accumulation, and invasion of normal tissues, including the liver, spleen, lymph nodes, central nervous system, and skin, cause lesions ranging from rashes to tumors.  A humoral mediator from the leukemic cells may inhibit proliferation of normal cells.  Failure of the bone marrow and normal hematopoiesis may result in pancytopenia with death from hemorrhaging and infections.

 Lab evaluation  The lab diagnosis is based on two things  Finding a significant increase in the number of immature cells in the bone marrow including blasts, promyelocytes, promonocytes (>30% blasts is diagnostic)  Identification of the cell lineage of the leukemic cells

 Peripheral blood:  Anemia (normochromic, normocytic)  Decreased platelets  Variable WBC count  The degree of peripheral blood involvement determines classification:  Leukemic – increased WBCs due to blasts  Subleukemic – blasts without increased WBCs  A leukemic – decreased WBCs with no blasts  Classification of the immature cells involved may be done by:  Morphology – an experienced morphologist can look at the size of the blast, the amount of cytoplasm, the nuclear chromatin pattern, the presence of nucleoli and the presence of Auer rods (are a pink staining, splinter shaped inclusion due to a rod shaped alignment of primary granules found only in myeloproliferative processes) to identify the blast type:  AML – the myeloblast is a large blast with a moderate amount of cytoplasm, fine lacey chromatin, and prominent nucleoli. 10-40% of myeloblasts contain Auer rods.

Laboratory Tests

1. CBC

High

a. Anemia b. Thrombocytopenia c. WBC

Normal

Low

2. Blood-clotting times (PT/PTT): Reduced levels of fibrinogen and other clotting factors cause prolonged bleeding times (in risk bleeding) 3. Biochemical Studies 4. Peripheral Blood smear – blasts in almost all cases 5. Bone Marrow Examination (>20% blasts) 6. Flow cyometry (Surface immunophenotype of blast cells) 4. Cytogenetics (chromosomal analysis) 5. CSF analysis (all ALL patients, some AML) 6. Human leukocyte antigen (HLA) typing (for younger high risk patients)

Diagnostic methods of importance • Bone marrow aspirate & Romanowsky stain (morphology) Enumeration (list) of blasts, maturing cells, recognition of dysplasia • Cytochemistry Myeloperoxidase, Sudan Black B, esterases to determine involved lineages

• Immunophenotyping Defines blast cell lineage commitment as myeloid, lymphoid or biphenotypic • Cytogenetics & molecular studies (Fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) Detects clonal chromosomal abnormalities, including those of prognostic importance

Blood Film-Normal

Normal BM cells

AML

Myoblasts with Auer rods Auer rods