Acute leukaemia

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Acute leukaemia

• Dr. MO Kehinde
• Department of Medicine
• CMUL/ LUTH

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Acute Leukaemia

• These are a heterogeneous group of diseases
  characterized by infiltration of the blood, bone
  marrow and other tissues by neoplastic cells of
  the haematopoietic system.
• There are two main types
• myeloid leukaemia and
• lymphoid leukaemia .

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TABLE 1 The FAB classification of acute leukemia

• Lymphoblastic (ALL)
• L1 Small, monomorphic, high N C ratio (SCORES
  0 , 1 or 2 )
• L2 Large, heterogenous, nucleolated, low N C
  ratio (Scores - 1, -2 or - 3)
• L3 Burkitt cell type, basophilic, vacuolated

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Myeloid (AML)

• M0 Undiferentiated myeloblastic (requires cell
  markers )
• M1 Myeloblastic without maturation (requires
  cytochemistry peroxidase or SSB)
• M2 Myeloblastic with maturation
• M3 Hypergranular promyelocytic
• M3 variant Micro or hyper granular bilobed
  promyelocytes

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• M4 Myelomonocytic with both granulocytic and
  monocytic differentiation
• M5 Monoblastic (M5a requires cytochemistry
  ANAE or ANBE ) and promonocytic- monocytic(M5b)
• M6 Erythroleukaemia ,with gt 50
  erythroblasts and lt 30 blasts
• M7 Megakaryoblastic (requires cell markers )

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Diagnosis

• SBBSudan black B
• ANAE alpha naphthyl acetate esterase
• ANBEalpha naphthyl butyrate esterase
• A diagnosis of ALL now requires cell markers to
  demonstrate B. or T lineage commitment.

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Conditions predisposing to acute leukaemia

• Downs syndrome Transient
  
  
• Persistent (ALL
  or AML)
• Genetic or constitutional
• Blooms syndrome
• Fanconis anaemia (AML)
• Ataxia telangiectasia (ALL, lymphoma

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Conditions predisposing to acute leukaemia

• Acquired
• Myelodysplasia (AML)
• Chemotherapy radiotherapy ( MDS ? AML)
• Chronic myeloproliferative disorders (CML,
  PRV,myelofibrosis) (AML)
• Aplastic anaemia (ALL)
• Paroxysmal nocturmal haemoglobinuria (AML, rarely
  ALL)

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Abbreviation

• MDS myelodysplastic syndrome
• PRV polycythaemia rubra vera CMLchronic
  myeloid leukaemia

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Acute Leukaemias

• are defined pathologically as blast cell
  leukaemias or malignancies of immature
  haemopoietic cells.
• The bone cell marrow shows gt 30 blast cells and
  they are divided into two main groups Acute
  myeloid leukaemia (AML) and acute Lymphoblastic
  Leukaemia (ALL).

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Acute Leukaemia

• There are two main age groups Childhood (lt 15
  years ) and adult (gt 15 years).
• A third group is that of adults aged gt 60 years
  because of their response to current treatment
  protocols both for ALL and AML, is inferior and
  because the Patients are not usually included for
  the more radical approaches using autologous or
  allogeneic bone marrow transplantation (BMT).
• AML comprises about 80 of adult cases

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Epidemiology

• (ALL and AML
• Incidence (1) Age differences (as above)
• (2) Urban industrialized and rural areas
  (commoner in industrialized than rural)
• (3) Socio cultural factors Common CD 10 form
  of ALL ( c ALL) less frequent compared with T
  All in African countries and in poorer sections
  of the community in the USA (e.g Black or
  Spanish)

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Acute LeuKaemia

• (4) Environmental agents implicated in the
  induction of certain types of Leukaemia.
• a. Ionising radiation
• b. Chemical carcinogens especially
  alkylating agents used for treatment of other
• malignancies.
• (5) Host susceptibility e.g. genetic disorders
• (6) Blast transformation in pre existing
  myeloproliferative disorders
• (7) In Downs syndrome.

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Acute Leukaemia

• (8) Oncogenic viruses in causation of human acute
  Leukaemia
• HTLV -1 ( human T cell lymphoma virus -1
  directly implicated in adult Tcell leukaemia
  /Lymphoma.

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Acute Leukaemia

• Ionizing radiation
• X-rays and other ionizing rays can induce
  leukaemia (as observed in survivors
  of the atomic
  bomb explosions in Hiroshima and Nagasaki)
• Chemicals
• Two types of chemicals strongly suspected of
  being leukaemogenic are
• benzene and other petroleum derivatives
• alkylating agents

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Acute Leukaemia

• Chromosomes and oncogene abnormalities
• Cytogenetic abnormalities are found in AML and
  ALL.

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Clinical Features

• may include
• A General Symptoms of anaemia (Tiredness,
  weakness lassitude, lethargy, shortness of
  breath).
• Bleeding
• Infections
• Anorexia, weight loss
• Lymphadenopathy (very uncommon in AML
  except in monocytic variant of AML )

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Specific organ /system involvement

• Skin with nonspecific Lesions like macules or
  papules, vesicles , pyoderma gangrenosum,
• Neutrophilic dermatitis
• Leukaemic cutis
• Granulocytic sarcoma of the skin.

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Acute leukaemia

• Differential diagnosis
• Septicaemia
• Miliary tuberculosis
• malignant histiocytosis
• Complications
• Worsening Continuous ill health
• Death

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Relevant investigations

• Complete blood count, and ESR, reticulocyte
  count, combs test
• Bone marrow examination
• Biochemical tests such as serum electrolytes,
  urea, creatinine, uric acid
• Liver function tests.
• Prothrombin time, partial thromboplastic time
• Human Leucocyte antigen typing
• HIV I and II.

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Relevant investigations

• 1 Cytochemical tests such as
• (i) Peroxidase , Sudan black B
• (ii) Non specific esterase reaction such as
  alpha napthyl acetate esterace
• 2 Bone marrow cultures
• 3 Cytogenetic Findings
• 4 Electron microscopy

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Relevant investigations

• Cell Markers e.g. using a panel of antibodies
  combined with flow cytometric analysis or the
  alkaline phosphase antialkaline phosphate
  (APAAP) technique for the identification of
  specification antigens and / or enzymes on the
  membrane and / or in the cytoplasm or the
  nucleus which identify the blast cells to be of
  lymphoid or myeloid lineage
• 6 Abdominal scan or CT scan

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Relevant investigations

• 7 Immunological Classification
• Terminal deoxy nucleotidyl transferase
  demonstration in nucleus of B- and T lineage by
  means of a
• aN antibody using.

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Management

• (a) Treatment objectives
• . Induce remission to achieve complete remission
• . Maintenance of disease free patients
• (b) Non drug treatment
• - Appropriate Nutrition.
• - Adequate hydration (at least 3 liters/24
  hours)
• - Provision of
• (1) Erythrocytes transfusion as required
• (2) Platelets concentrate transfusion as
  required
• - Maintenance of electrolyte balance.

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Drug treatment

• For Acute lymphoblastic leukaemia
• Allopurinol 300mg daily p.o.
• To use DVP or COAP
• DVP i.e.
• Daunorubicin 30mg/ m2 iv d8,15,22,29
• Vincristine 1.4mg/ m2 to a maximum of 2mg iv
  d8,15,22, 29
• Prednisolone 60mg p.o.d 1-28
• L-asparaginase 1000IU/ m2 i.v. 12,15,18,21,24,27,3
  0,33.

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Drug treatment COAP

• Cyclophosphamide 650mg/m2 1V day 1 and
  day8 day14 day 22
• Vincristine I.V 1.4mg/m2 to max . of 2mg.day
  1 and day 8 day 14 and day 22
• Cytosine arabinoside S .C 50 mg/ m2 12 hourly x
  12 days or
• I/V bolus 100 mg/ m2 daily x 7 days
• Prednisolone 40mg/ m2 p.o. x 14/7
• Drugs are given every 28 days

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Drug treatment

• Number of courses 3
• Criteria for complete remission assess patient
  clinically and haematologically (including bone
  marrow and blood examination)
• Nervous system prophylaxis
• Methotrexate intrathecal 12.5mg /m2 to a max
  15mg. x 5 doses over 3 weeks
• i.e. twice weekly

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Drug treatment

• Consolidation This is to be given on day 29
• COAP once provided WBC 1x109/ L and Platelet
  count 100 x109/ L
• Maintenance to have bone marrow every 12 weeks
• 6 Mercaptopurine 75mg/ m2 daily p.o.
• Methotrexate 20mg/ m2 weekly p.o.

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Drug treatment

• Pulse therapy - (Intensification) To be given
  every 3 months with
• Vincristine 1.4 mg/ m2 to a maximum of 2mg
  weekly day1 and day8
• Maintenance therapy to continue for 3 years if
  remission is maintained
• otherwise re assessment.

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Acute Myeloblastic leukaemia

• a clonal disease that result from a acquired
  genetic change in a pluri potential haemopoietic
  stem cell . This altered stem cell proliferatial
  and generates a population of differented cells
  that gradually replaces normal haemopoiesis and
  leads to a greatly expanded total myeloid mass.

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• Use either TAD or COAP as shown below
• TAD
• Cytarabine 100mg/ m2 (cont inf) d12 and
• 100mg/ m2 b.i.d. i.v. (30 min inf) d3-8
• Thioguanine 100mg/ m2 b.i.d. p.o. every 12h
  3-9
• Daunorubicin 60mg/ m2 i.v.(1 h inf)
  d3-5

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AML

• Or COAP as shown below
• Cyclophosphamide 650mg/m2 1V day 1 and day8
• Vincristine I.V 1.4mg/m2 to max . of 2mg.day
  1 and day 8
• Cytosine arabinoside S .C 50 mg/ m2 12 hourly
  x 7 days
• Prednisolone 40mg/ m2 p.o. x 14/7
• 14 day cycle

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AML

• Nervous system prophylaxis is not required.
• Assess for remission after 3 courses.
• Maintenance
• Patient to have COAP every 6 weeks for 2 years.
• If there is CNS disease and it is monocytic give
  intrathecal treatment as for ALL.

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Thank you

• For
• Your
• Attention

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ACUTE MYELOID LEUKAEMIA

• Def.Introduction
• . Clonal malignant disease of the haemopoietic
  tissue
• characterized by
• . Proliferation of abnormal blast cells
• . Impaired production of normal blood cell
• . Leukaemia blast cells
• accumulate in the marrow. ?
• Suppress the proliferation differentiation of
  normal haemopoietic cells.

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Classification of AML ( FAB classification)

• M0 Undifferentiated myeloblastic
• MI Myeloblastci without maturation
• M2 Myeloblastic with maturations
• M2 BASO M2 with basophil blasts
• M3 Hypergranular pronyelocytic
• M3 Variant micro.or hypogranular
• bilobed progranular

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AML

• M4 .Myelomonocytic with both granulocytic and
  hypogranulocytic with both granulocytic and
  monocytic differentation
• M4 Eo M4 with bone marrow eosinoplilia
• M5 Monocytic monoblastic (m5a) and
• promonocytic monocytic (M5b)
• M6 Erythroleukaemia with gt 50
• erythroblasts
• M7 Megakaryoblastic

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EPIDEMIOLOGY

• Age incidence
• predominant form of leukaemia
• From middle age onward, the incidence increases
  progressively
• Sex incidence
• It is slightly more common in male M gt F

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PATHOPHYSIOLOGY

• arises following malignant transformation of a
  single haemopoietic progenitor followed by
  cellular replication and expansion of the
  transformed done.
• Defect in maturation beyond the myeloblast or
  promyelocyte level in AML.
• Proliferating leukaemia cell accumulate in BM ?

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PATHOPHYSIOLOGY

• Suppress normal haemopoiesis
• ?
• result in replacement of normal elements.
• ?
• anaemia, infections bleeding complications.
• - Primarily proliferate in BM

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PATHOPHYSIOLOGY

• circulate in the blood and infiltrate into other
• tissues such as
• Lymph nodes, skin, gum,
• . Liver viscera, CNS.
• . Spleen

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PATHOPHYSIOLOGY

• Growth. Advantages of Leukaemia cells
• Mechanisms ? unknown
• Postulates - GF production
• GF Receptors.
• . Factor Receptor coupling on normal versus
  Leukaemia cells may play a role
• . Transforming genes or cellular oncogene
  expressed in leukaemia cells code for GF
  receptors

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PATHOPHYSIOLOGY

• BM Failures due to
• Def. of normal stem cell differentiation
  proliferation maturation
• As a result of failure of production humoral or
  microenviromental stimulators
• Mechanism of Neoplastic Transformation
• - Poorly understood .

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• May involve a fundamental alteration of DNA
  conferring hereditable malignant xteristics to
  the transformed cell,
• In animal , Leukaemia can be induced by
  retroviruses which either carry a transforming
  gene (viral mcogene ) or integrate into specific
  sites in DNA causing activation of cellular
  proto- oncogenes (insertional mutagenesis)