Leukemia

Introduction to Leukemia

Leukemia is a heterogeneous group of diseases characterized by infiltration of the blood, bone marrow and other tissues by neoplastic cells of the haematopoietic system

Two main types of Leukemia

  1. Myeloid leukaemia
  2. Lymphoid leukaemia

Each of the types is further divided into acute and chronic
Acute leukaemias are defined pathologically as blast cell leukaemias or malignancies of immature haematopoietic cells.
The bone marrow shows>30% blast cells
Two main groups of acute leukaemias

  1. Acute myeloid leukaemia (AML)
  2. Acute lymphoblastic leukaemia (ALL)

Childhood leukaemias: patients aged <15 years
Adult leukaemias: patients aged >15 years
Leukaemias in adults aged > 60 years: an important group because their responses to current treatment protocols both for ALL and AML are inferior. These patients are not usually considered for more radical treatment approaches such as autologous or allogeneic bone marrow transplantation.
80% of adult cases are AML

Epidemiology & predisposing conditions

Acute lymphoblastic leukaemia (ALL) and Acute myeloid leukaemia (AML)

  • More common in industrialized than rural areas.
  • Environmental agents implicated in the induction of certain types of leukaemia:
    • Ionising radiation: X-rays and other ionizing rays
  • Chemical carcinogens
    • Benzene and other petroleum derivatives
    • Alkylating agents
  • Host susceptibility e.g. genetic disorders:
    • Bloom’s syndrome
    • Fanconi’s anaemia (AML) Ataxia telangiectasia (ALL)
    • Oncogenic viruses:
    • Down’s syndrome
    • Blast transformation in pre-existing myeloproliferative disorders:
    • Aplastic anaemia (ALL)
    • Oncogenic viruses:
    • HTLV-1 (Human T-cell Lymphotropic virus 1): implicated in adult T cell leukaemia /lymphoma

Clinical features of Leukemia

  • General symptoms of anaemia
  • Bleeding
  • Infections.
  • Anorexia
  • Weight loss
  • Lymphadenopathy (not common in AML except in the monocytic variant)
  • Skin: Macules, papules, vesicles, pyoderma gangrenosum, neutrophilic dermatitis, leukaemic cutis, granulocytic sarcoma

Differential diagnoses

  • Septicaemia
  • Miliary tuberculosis.
  • Malignant histiocytosis

Complications of Leukemia

  • Worsening ill-health

Investigations

  • Full blood count with ESR, reticulocyte count, Coomb’s test
  • Bone marrow examination
  • Biochemical tests: serum electrolytes, urea, creatinine, uric acid, liver function tests
  • Prothrombin time, partial thromboplasnime human leucocyte antigen typing
  • HIV I and II
  • Cytochemical tests:
    • Peroxidase
    • Sudan Black B-Non-specific esterase reaction e.g. alpha napthyl acetate esterase
    • Bone marrow cultures.
    • Cytogenetic studies
  • Electron microscopy
  • Cell markers e.g. using a panel of antibodies combined with flow cytometric analysis or the alkaline phosphase-antialkaline
  • Abdominal ultrasound/CT scans phosphate (APAAP) technique to classify the blast cells into lymphoid or myeloid lineages

Immunological classification

  • Terminal deoxynucleotidyl transferase demonstration in nuclei of B and T lymphocytes

Treatment objectives

  • Induce remission to achieve complete remission
  • Maintain disease-free state

Non-drug treatment

  • Appropriate nutrition
  • Adequate hydration (at least 3 litres/24 hours)
  • Erythrocyte transfusion as required
  • Platelet concentrate transfusion as required
  • Maintain electrolyte balance

Drug treatment for Leukemia

Acute lymphoblastic leukaemia

Allopurinol 300 mg daily orally
DVP Regime

  • Daunorubicin 30 mg/m² intravenously on days 8, 15, 22 and 29
  • Vincristine 1.4mg/m² to a maximum of 2 mg intravenously on days 8, 15, 22 and 29
  • Prednisolone 60 mg orally once daily from day 1-28
  • L-asparaginase 1000 IU/rm intravenously on days 12, 15, 18, 21, 24, 27, 30 and 33

Or:

COAP Regime

  • Cyclophosphamide 650 mg/m² ‘mintravenously on days 1 and 8; 14 and 22
  • Vincristine 1.4mg/m² intravenously to a maximum of 2mg: days 1 and 8; 14 and 22 Cytosine Arabinoside 50 mg/m² subcutaneously 12 hourly for 12 days or bolus intravenous injection 100 mg/m² daily for 7 days
  • Prednisolone 40 mg/m² oral for 14 days
  • Drugs are given every 28 days for 3 courses

Nervous system prophylaxis

  • Methotrexate 12.5 mg/m² intrathecally twice weekly to a maximum of 15 mg i.e. 5 doses over 3 weeks.

Consolidation:

  • To be given on day 29

COAP regime to be given once provided WBC count is = 1x10s/L and platelet count is = 100x10VL

Maintenance:

  • 6-Mercaptopurine 75 mg/m² orally daily
  • Methotrexate 20 mg/m² orally weekly For 3 years if remission is maintained, otherwise reassessment

Pulse therapy (Intensification)

To be given every 3 months with Vincristine 1.4 mg/m² IV to a maximum of 2 mg weekly on days 1 and 8

Acute myeloblastic leukaemia

Either TAD or COAP as shown below:
TAD:

  • Cytarabine 100 mg/m² (continuous infusion) on days 12 and 2, and 100 mg/m² every 12 hours by intravenous infusion over 30 minutes on days 3-8
  • Thioguanine 100 mg/m² every 12 hours orally on days 3-9
  • Daunorubicin 60 mg/m² by intravenous infusion over one hour on days 3-5

Or:

COAP:

  • Cyclophosphamide 650 mg/m² intravenously on days 1 and 8
  • Vincristine 1.4 mg/m² intravenously to a maximum of 2 mg on days 1 and 8
  • Cytarabine 50 mg/m² subcutaneously every 12 hours for 7 days
  • Prednisolone 40 mg/m² orally for 14 days

Nervous system prophylaxis is not required
Assess for remission after 3 courses

Maintenance

  • COAP every 6 weeks for 2 years
  • Intrathecal treatment as for ALL if there is CNS disease of the monocytic type

Chronic Myeloid Leukaemia (CML)

Chronic Myeloid Leukaemia, also known as Chronic Myelogenous Leukaemia; Chronic Granulocytic Leukaemia (CGL) is a clonal disease that results from acquired genetic change in a pluri-potential haematopoietic stem cell.
Altered stem cell proliferation generates a population of differentiated cells, and a greatly expanded total myeloid mass

Classification

Majority of patients have relatively homogenous disease characterized by:

  • Splenomegaly
  • Leucocytosis
  • Presence of Philadelphia (Ph).
  • chromosone in all leukaemia cells.

Minority of patients has less typical disease (atypical CML)
These variants lack Ph chromosome.
Examples:

  • Chronic myelomonocytic leukaemia
  • Chronic neutrophilic leukeamia
  • Juvenile chronic myeloid leukaemia

Epidemiology, aetiology and natural history

  • Rare below the age of 20 years but occurs in all age groups
  • Increased risk of developing CML with exposure to high doses of irradiation
  • A biphasic or triphasic disease, usually diagnosed in the initial “chronic” or stable phase

Distinguishing features between phases of CGL

Chronic phase.

  • Untreated patient: <12% blast cells in blood or marrow
  • Treated patient: Normal or near-normal blood count without immature granulocytes in peripheral blood

Accelerated phase

  • Rising leucocyte count despite treatment
  • Rapid leucocyte doubling time
  • Immature granulocytes in blood
  • Blast cells >5% but <30°/o in marrow
  • Anaemia (Hb <10 g/dL) not attributable to treatment
  • Annuinition
  • Thrombocytosis (>1000×109/L)
  • Acquisition of specific new cytogenetic abnormalities
  • Increasing marrow fibrosis
  • Blastic transformation
  • More than 30% blasts

Or:

  • Blasts plus promyelocytes in blood or bone marrow

Clinical features

  • Asymptomatic
  • Abdominal swelling/pain
  • Lethargy
  • Shortness of breath on exertion.
  • Weight loss
  • Unexplained haemorrhage at various sites e.g. gums, intestinal/urinary tracts
  • Increased sweating
  • Visual disturbances
  • Gout
  • Priapism
  •  Splenomegaly
  • Anaemia
  • Haemorrhage
  • Fever
  • Lymphadenopathy (rare in chronic phase)

Complications

  • Blastic transformation
  • Death

Investigations

As above for acute leukaemia

plus:

  • Determination of Philadelphia chromosome
  • Lactic dehydrogenase
  • Serum calcium

Treatment objectives

  • Induce remission to achieve complete remission
  • Achieve absence of Philadelphia chromosome
  • Maintain disease-free state

Non-drug treatment

  • Appropriate nutrition
  • Adequate hydration
  • Electrolyte balance

Drug treatment

Hydroxycarbamide (hydroxyurea)

  • Adult: 20-30 mg/kg orally daily or 80 mg/kg every third day
  • Child: Not recommended

Interferon alpha

  • Adult: 9 million units subcutaneously or intravenously thrice weekly for 6-12 months Or:

Imatinib mesylate

  • 400 mg orally daily

To be used strictly under specialist supervision

Notable adverse drug reactions, caution

  • The above drugs (except the steroids) allc ause profound myelosuppression
  • Profound nausea, vomiting, diarrhoea and abdominal discomfort
  • Secondary malignancies Steroids: Cushing’s syndrome, hypertension, diabetes mellitus, immunosuppression, infections
  • Vincristine: neurotoxicity
  • Cylophosphamide: alopecia, haemorrhagic cystitis
  • Daunorubicin: myelosuppression, alopecia, cardiotoxicity
  • All are contraindicated in patients with history of hypersensitivity reactions to the respective medicines

Prevention

  • Avoid exposure to ionizing radiation
  • Early detection and treatment

Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia is a neoplastic proliferations of mature lymphocytes.
The diseases involve the blood bone marrow and other tissues Characterized by accumulation of small mature-looking CD5+ B lymphocytes in the blood, marrow and lymphoid tissues B-cell disorders are more common B-cell CLL is more common in males than females
Accounts for 60% of cases
Rarely diagnosed below the age of 40 years

Clinical features

  • Symptoms of anaemia
  • Asymptomatic (30% of cases)
  • Lymph node enlargement (painless)
  • Rare: pyrexia, sweating or weight loss
  • Severe chest infection/pneumonia
  • Splenomegaly (50% of cases)
  • Hepatomegaly (not frequent)

Differential diagnoses

  • Lowgrade non-Hodgkin’s lymphomas with frequent blood and bone marrow involvement (leukaemia / lymphoma syndromes)
  • Tuberculosis
  • Viral infections
  • Toxoplasmosis

Complications

  • Richter transformation.
  • Progression of disease

Investigations

Cell morphology:

  • Size
  • Nuclear: cytoplasmic (N: C) ratio
  • Regularity or irregularity of the nuclear outline
  • Characteristics of the cytoplasm (presence and length or absence of azurophil granules)
  • Degree of nuclear chromatin condensation and its pattern
  • Prominence, frequency and localization of the nucleolus

Investigations

As for anaemia and other leukaemias

Treatment objectives

  • Induce remission to achieve complete remission
  • Maintain disease-free state

Non-drug treatment

  • Appropriate nutrition
  • Adequate hydration
  • Maintenance of electrolyte balance
  • Bone marrow transplant
  • Red cell and platelet concentrate transfusion as required

Drug treatment

Chronic Lymphocytic Leukaemia

  • Allopurinol 100 mg orally every 8 hours
  • Chlorambucil 5 mg/ml orally on days 1 to 3
  • Prednisolone 75 mg orally on day 1; 50 mg orally on day 2 and 25 mg orally on day 3 Repeat every 2 weeks

Or:

  • Fludarabine 25-30 mg intravenously over 30 minutes on days 1-5 Repeat every 4 weeks

Or:

Combination chemotherapy

  • Cyclophosphamide 400 mg/m²
  • Vincristine 1.4 mg/m²
  • Prednisolone 100 mg orally days 1 – 5
  • Repeat every 3 weeks

Or:

  • Fludarabine 30 mg/m² intravenously over 30 minutes on days 1-3
  • Cyclophosphamide 250 – 300 mg/m² intravenously over 30 minutes on days 1-3
  • Repeat every 4 weeks

Supportive measures

  • Appropriate nutrition.
  • Adequate hydration

Notable adverse drug reactions, caution

Same as for other leukaemias

Prevention

  • Avoid chemicals on body (e.g. benzene)
  • Avoid ionizing radiation (X rays)
  • Early detection and treatment  disease