Leukemia Notes

WBC Disorders

Leukaemia

• Leukaemia is a group of malignant disorders affecting the blood and blood-forming tissues of the bone marrow, lymph system, and spleen.
• Definition: Leukaemias are clonal proliferations of malignant leukocytes that arise initially in the bone marrow before spreading to the peripheral blood, lymph nodes, and other organs.

Classification

• Leukaemias are classified by the type of blood cell giving rise to the clonal proliferation (lymphoid or myeloid) and the clinical course (acute or chronic).

Etiology

• Combination of predisposing factors including genetic and environmental influences.
• Chronic exposure to chemicals such as benzene.
• Radiation exposure.
• Cytotoxic therapy for breast, lung, and testicular cancer.

Common Leukaemia Categories

• The main 4 leukaemia categories include ALL (Acute Lymphoblastic Leukemia), AML (Acute Myeloid Leukemia), CLL (Chronic Lymphocytic Leukemia), and CML (Chronic Myeloid Leukemia).
• In general, males are more affected than females.
• Age variations: AML & CML - adult, ALL - children.

Symptoms of Leukaemia

• Patients present with:
  • Cytopenias - anaemia, fever, bleeding & bruising.
  • Enlargement of lymph nodes, liver and spleen.
• Depending on the type of leukaemia, can present with:
  • Bone pain
  • Overgrown gums
  • Neurological signs
  • Extramedullary tumors
  • Pathological fractures
  • Disseminated intravascular haemolysis

Classification of Leukaemia

• Leukaemias are broadly classified into acute & chronic.
• Further classification depends on the cell of origin as either myeloid or lymphoid.
  • Morphological appearance
  • Flow cytometry
  • Molecular analysis
  • Cytochemistry
• Although new WHO classifications have been developed, the FAB (French-American-British) system is still used in some laboratories to describe leukaemia:
  • L1-L3 (lymphoid) & M0-M7 (myeloid)
• Other less common types of leukaemia exist & are classified in their own right.
• Determines prognosis & treatment for patients.

Acute vs Chronic Leukaemia

FAB & WHO Classification of Acute Leukaemia

Acute Leukemia Essentials:

• Short course of symptoms
• Fatigue, fever, easy bruising, bleeding
• Cytopenias - or pancytopenia
• More than 20% blasts in bone marrow
• Blasts in peripheral blood in 90% cases

Acute Myeloid Leukaemia (AML)

• Malignant transformation of myeloid cells.
• Rare in childhood but increases with age.
• Leukemic blast cells are present as well as a range of immature myeloid cells.
• Numerous subtypes/classifications of AML exist & each is associated with different treatment regimens and prognosis for the patient.

Incidence

• 2.3 per 100,000 people per year
• Higher among men than women (2.9 vs 1.9)
• Most common leukemia in adults (80% of cases)
• Vast majority of patients are 65 years or older.

Etiology

• Genetic
• Radiation
• Toxic chemical exposure
• Medications (Alkylating-agents, Topoisomerase-II inhibitors, Chloramphenicol, Phenylbutazone, Chloroquine, and Methoxypsoralen)

Most Common Presenting Symptoms

• Fatigue (50%)
• Anorexia (30-40%)
• Weight loss (30-40%)
• Fever without evident cause (10%)
• Easy Bruising (5%)
• Bleeding (5%)

Symptoms

• Nonspecific
• Most related to anemia, leukocytosis, leukopenia, leukocyte dysfunction, or thrombocytopenia
• Symptoms usually present for 3 months or more before diagnosis is made

Other Common Symptoms

• Bone pain
• Lymphadenopathy
• Non-specific cough
• Headaches
• Excessive diaphoresis
• Symptoms secondary to mass lesions (granulocytic sarcoma or chloroma)

Physical Findings

• Fever
• Splenomegaly
• Sternal tenderness
• Multiple bruises
• Bleeding (gingiva most common)
• Unexplained infections
• GI bleed
• Pulmonary, intracranial, and retinal hemorrhage

Laboratory and Radiographic Work-up

• CBC with manual differential
• Uric Acid level
• Clotting studies (PT, PTT, D-dimer, fibrinogen)
• Bone marrow aspirate and biopsy
• Chest X-ray
• Echocardiogram

Hematological Findings

• Anemia (normochromic, normocytic)
• Leukocytosis (median = 15,000)
• Thrombocytopenia (< 100,000)

Morphology and Cytology

• > 20% myeloblasts in blood and/or bone marrow
• Auer Rods (cytoplasmic granules)
• Positive myeloperoxidase reaction in > 3% blasts

WHO - AML without maturation

• >90% cells are myeloblasts
• >3% of blasts stain for MPO (Myeloperoxidase stain)

WHO - AML with granulocytic maturation

• 30 - 40%
• 30% - 90% are myeloblasts
• 15% with t(8:21)

Acute Lymphoid Leukemia (ALL)

Etiology

• Uncertain, but several proposed linkages:
  • Genetic - Philadelphia chromosome
  • Viral infection (EBV, HIV)
  • Exposure to high energy radiation (T-cell ALL)
  • Toxic chemical exposure
  • Smoking

Common Symptoms

• Pallor
• Fatigue
• Shortness of breath
• Easy bruising
• Petechiae
• Weight loss / failure to thrive
• Bone and/or joint pain

Physical Findings

• Fever
• Splenomegaly and/or hepatomegaly
• Lymphadenopathy
• Multiple bruises
• Petechiae
• Unexplained infections

Laboratory and Radiographic Work-up

• CBC with manual differential
• Chemistry studies to check for organ dysfunction
• Bone marrow aspirate and biopsy
• Genetic/Immunological studies
• Lumbar puncture

Hematological Findings

• Anemia (normochromic, normocytic)
• WBC < 5,000 (or > 25,000)
• Leukocytosis (median = 15,000)
• Thrombocytopenia (< 50,000)

Acute Leukemia Treatment

• Two phases of treatment:
  • Induction
  • Post-remission
• Initial goal is to quickly induce complete remission.
• Combination chemotherapy
• Continued low-dose post-remission therapy must be used to ensure prolonged survival.
  • Otherwise recurrence rates can be as high as 90%.

After Induction Chemotherapy

• Bone marrow biopsy is obtained.
• If >5% of blasts with >20% cellularity, then retreatment is necessary.
• Stem cell transplant may be necessary if retreatment fails.

Post-remission Treatment

• Stem cell transplant
• CNS prophylaxis (for ALL)
• Radiation therapy (for ALL)
• Prolonged low-dose chemotherapy for 1-3 years

What is remission?

• The main aim of treatment for acute lymphoblastic leukaemia is to give a remission.
  • This means that the abnormal, immature white cells or blasts can no longer be detected in your blood or bone marrow, and normal bone marrow has developed again.
• However, once you are in remission, there may still be a very small number of abnormal lymphoblasts left.
  • To destroy these, your doctor may prescribe maintenance or continuation chemotherapy which may last for several years.
  • These drugs are mainly taken as tablets, and you will need to have regular check-ups to monitor their effect.
• Very specialised blood tests to find particular proteins present on the surface of the leukaemia cells can show if any leukaemia cells are still present in the body.
• For many people with acute lymphoblastic leukaemia, the remission lasts indefinitely, and the person is said to be cured.

Supportive Care

• Transfusions
  • Platelets >20,000
  • Hgb >8
• Empiric antibiotic treatment when fever present
• Allopurinol for increased uric acid levels

Chronic Myeloid Leukaemia (CML)

• Is a haematopoietic proliferative disorder associated with a specific gene defect and a very characteristic blood picture.
• There is a marked neutrophil leukocytosis with some circulation of immature neutrophils and increased basophils.
• The gene defect is due to translocation at t(9:22) aka Philadelphia chromosome

Chronic Leukemia Essentials:

• Most are asymptomatic at presentation
• Strikingly elevated WBC
• Marked left-shift
• Philadelphia chromosome
• Splenomegaly typical
• Lymphocytosis

Incidence

• 1.3 per 100,000 people per year
• Higher among men than women (1.7 vs 1.0)
• Vast majority of patients 40 years or older
• There is no clear etiology

Pathophysiology

• Philadelphia chromosome (9:22) in up to 95%
• BCR-ABL protein junction

Common Symptoms

• Note: approximately 70% of patients are asymptomatic at the time of diagnosis
• Lethargy
• Weight loss
• Increasing abdominal girth
• Easy bruising or bleeding
• Excessive diaphoresis

Physical Findings

• Fever
• Splenomegaly and hepatomegaly
• Bruising
• Bleeding (gingivae most common)

Laboratory and Radiographic Work-up

• CBC with manual differential
• Serum Vitamin B12 and B12 binding capacity
• Leukocyte alkaline phosphatase (decreased)
• Uric acid level
• Chromosomal testing - Philadelphia chromosome
• Bone marrow biopsy

Hematological Findings

• Anemia (normochromic, normocytic)
• Leukocytosis (median = 20,000)
• Basophilia
• Thrombocytopenia (< 100,000)

Three Phases

• Chronic phase: 3-5 years. Current treatment is with alpha-interferon. Young patients should undergo BMT.
• Accelerated phase: New nonrandom cytogenic abnormalities in up to 80% of patients. Difficult to control. Development of myelofibrosis. Elevated leukocyte counts. Lasts several months before becoming blastic.
• Blast phase: > 30% blasts in blood or marrow. Treatment with chemotherapy similar to acute leukemia. Some patients go into remission with treatment, but it is short lived.

Chronic Lymphoid Leukemia (CLL)

Incidence

• 2 new cases per 100,000 people per year
• Comprises 30% of all cases of leukemia
• Most common lymphoid leukemia
• Almost exclusively due to B-cell clonal expansion
• More common in men
• Most common in individuals < 50 years

Etiology

• Uncertain, several proposed linkages:
  • Genetic
  • Viral infection (EBV, HIV) - Burkitt’s
  • Exposure to high energy radiation (T-cell ALL)
  • Toxic chemical exposure
  • Smoking

Common Symptoms

• Note: approximately 70% of patients are asymptomatic at the time of diagnosis
• Fever
• Pallor
• Fatigue
• Shortness of breath
• Easy bruising
• Gingival bleeding
• Weight loss
• Frequent infections

Physical Findings

• Fever
• Splenomegaly and/or hepatomegaly
• Lymphadenopathy
• Multiple bruises
• Bleeding gingivae
• Unexplained infections

Laboratory and Radiographic Work-up

• CBC with manual differential
• Peripheral smear
• Flow cytometry
• Chemistry studies to check for organ dysfunction
• Lymph node biopsy

Hematological Findings

• Increased number of lymphocytes on smear
  • smudge cells
• B-cells with CD 19 and CD 5 on flow cytometry
• Small lymphocitic lymphoma present in histology of nodal biopsy

Chronic Leukemia Treatment

• CML therapy is based on phase
  • Chronic: PO chemoprophylaxis
  • alpha-interferon with concominant BMT
  • Accelerated: within months progresses to blast phase
    • treatment same as for AML, with combination Chemotherapy
  • Blast: same as for AML, with combination chemotherapy
• CLL therapy is based on RAI stage
  • stage 0: Often followed without specific treatment
  • stage I and II: Treatment if symptomatic. Single agent treatment with fludarabine. Combination treatment with CVP or CHOP regimens
  • stage III and IV: Fludarabine, CVP, or CHOP regimens
  • Young patients with this disease are also candidates for bone marrow transplantation

Diagnostic Approach

FBE, film
WCC -low, normal, high
blasts
Platelets -low
Clinical history,
drug history
dysplastic
blast %
lineage
Cytochemistry
Bone marrow
lineage
cytogenetics
disease entity
immunophenotyping
lineage,
differentiation
Source. M. Pike Acute & Chronic Leukaemias

Flow Cytometry Immunophenotyping

• Evaluates individual cells in suspension for the presence or absence of specific antigen.
• This can be accomplished by conjugating monoclonal antibodies to a variety of fluorescence that can be detected directly by a flow cytometer.
• Immunophenotyping is critical to the initial diagnosis and classification of hematological malignancies since treatment strategies often depend on antigenic parameters.

Other information provided by immunophenotyping includes:

• Identification of cells from different lineages and determination on whether they are mature or immature
• Detection of abnormal cells through identification of antigen expression that differs significantly than normal
• Provides prognostic information not available by other techniques
• Provide sensitive means to monitor patients progress after chemo or BM transplantation