ACUTE LEUKAEMIAS

PROF OLUSAYO, O ALAO

MBCHB, PGDM, MSc, MBA, FWACP

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Learning objectives

• Classify Leukaemias
• Define and classify Acute Leukaemias (AL)
• List risk factors for acute leukaemias (AL)
• Understanding of pathogenesis of AL
• Outline the clinical and lab features of acute leukaemia/Treatment
• How to Make diagnosis of leukaemia
• Prognostic factors

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Introduction

• Leukaemias are simply referred to as cancers of the WBCs
• They are a group of disorders characterized by the proliferation and accumulation of malignant white cells in the bone marrow and Peripheral blood.
• These malignant cells accumulate in the marrow causing a crowding out phenomena resulting in bone marrow failure and symptoms of cytopenias; anaemia, neutropenia, thrombocytopenia
• These abnormal cells may eventually spill into the peripheral blood and also infiltrate other organs (liver, spleen, lymph nodes, lungs, meninges, brain, spinal cord, skin, testes)
• The clinical features are usually due to marrow infiltration, failure of affected organs and hypermetabolic state.

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Introduction contd.

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Introduction contd.

• Leukaemias lead to the over-production of malignant WBCs

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Classification of leukaemia

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• Acute vs Chronic, Lymphoid vs Myeloid
• Acute-blastic

-Acute lymphoblastic leukaemias (ALL)

-Acute Myeloblastic (myeloid, myelogenous)leukaemias (AML)

• Chronic-cytic

-Chronic myeloid (myelocytic) leukaemias (CML)

-Chronic lymphocytic leukaemias (CLL)

• Secondary/de novo

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Acute Leukaemias

• These are haematological disorders characterised by arrest of cellular maturation, production and accumulation of immature cells resulting in the presence of over 20% blast cells (myeloblasts or lymphoblasts) in the bone marrow.
• Normal blast percentage in the BM is < 5% of nucleated cells
• Acute leukaemias can also be diagnosed with less than 20% blasts if specific leukaemia‐associated cytogenetic or molecular genetic abnormalities are present
• Genetic damage or mutation is believed to be involved
• Malignant transformation occurs in the HSC or early progenitors.

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Acute Leukaemias

• Acute leukaemias are of sudden onset, aggressive and progress rapidly
• They lead to death within weeks to months if not treated
• They are potentially curable especially in young patients
• Key features involved include; (i) an increased rate of cell proliferation (ii) reduced apoptosis and (iii) a block in cellular differentiation and maturation.
• These events cause crowding in the bone marrow of early haemopoietic cells known as blast cells.
• The dominant clinical feature are those of bone marrow failure and organ infiltration.

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Acute Leukaemias

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Classification of acute Leukaemias

• It is classified into;

i. Acute lymphoblastic leukaemia (ALL)

ii. Acute myeloblastic leukaemia (AML)

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Acute lymphoblastic leukaemia (ALL)

• Characterized by accumulation of more than 20% malignant lymphoblasts in the bone marrow
• This results from genetic mutation/damage involving a single immature cell/,frequently a lymphoblast, resulting in failure/arrest of maturation & differenciation, but keeping its ability for self-renewal: rapid proliferation that ensues results in a malignant clone. All these result in accumulation of the immature clones of lymphoid cells (lymphoblasts) in the bone marrow and peripheral circulation.
• These early malignant precursors replace the normal haematopoietic cells in the marrow.

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Epidemiology of ALL

• It is the most common leukaemia in children
• Peak incidence is 3-7 years
• It is the least common type of leukaemia in adults.
• Slightly commoner in males than females 1.3:1.0
• It is commoner in whites than blacks with ratio 2:1
• ALL accounts for about 3.8% of lymphoid malignancies

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Aetiology of ALL

• The Precise/Exact cause of ALL is currently unknown,but certain risk factors have been identified.
• There are both genetic and environmental risk factors
• Children with Downs syndrome have about 10 to 30 times risk of developing ALL compared to general population
• Family history: Non-identical twins and siblings of affected children have a 2 to 4-fold increased risk while an identical twin has a 20% probability of developing ALL if the other twin develops it.
• Ionizing radiation and chemical mutagens
• In utero exposure to diagnostic X-rays is associated with a slightly increased risk of ALL, proportional to the number of exposures.
• Infections both viral or bacterial
• Drugs including chemotherapeutic agents

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Aetiological risk factors

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Pathogenesis

• A process of leukaemia development is associated with dysregulation of cell growth and differentiation
• There may be a single gene mutation or series of genetic events within a cell that often occur in utero.
• Activation of a proto-oncogene to an oncogene
• Increased tyrosine kinase activity
• Inactivation of tumour suppressor gene pathway
• There is impaired cell differentiation, maturation and apoptosis
• These events result in the proliferation and establishment of the leukaemic clone in the marrow.
• The malignant cells (lymphoblasts) replace the normal marrow elements leading to cytopenias
• The lymphoblasts also infiltrate organs other than the marrow

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Malignant cell- Lymphoblast

• Large cells with large nuclei
• Very high N:C ratio
• Basophilic cytoplasm
• Absence cytoplasmic granules
• Presence of round or cleft nucleus
• Loose nuclear chromatin
• Nucleoli: few/infrequent, non-conspicuous

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Classification

• There are 2 classification systems for ALL
• French – American – British (FAB) classification based on morphology into 3 classes L1, L2 and L3.
• WHO classification.

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FAB Classification- L1

• Blasts are uniformly small
• Scanty to moderately basophilic cytoplasm
• Large nuclear-cytoplasmic ratio
• Regular nuclear shape though it may be indented or clefted
• Nucleoli are inconspicuous
• L1 is the most common type in childhood

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FAB Classification- L2

• Blasts are large and heterogenous
• Variable amount of cytoplasm
• Nucleus is irregular in outline with frequent indentations and folding.
• One or more prominent nucleoli

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FAB Classification- L3

• Large homogenous cells identical in appearance with Burkitt’s cells
• Cytoplasm- abundant and strongly basophilic often contains numerous vacuolation that often overlies the nucleus
• Multiple prominent nucleoli
• This subtype represents 1-2% of adult cases.

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Clinical features of ALL

• Clinical onset- acute and rapidly progressing
• Presenting symptoms- usually of short duration
• Common features are those bone marrow failure and organ infiltration

-Features of anaemia e.g. weakness, dizziness, exercise intolerance

-Features of neutropenia e.g. recurrent fever and infections

-Features of thrombocytopenia e.g. spontaneous bleeding

• Organ infiltration e.g. bone pains, lymphadenopathy, splenomegaly, hepatomegaly, orchidomegaly, CNS signs, SVC Syndrome
• Hypermetabolic symptoms e.g. weight loss, excessive night sweat
• Symptoms of hyperviscosity; esp in hyperleucocytosis

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Investigations

• FBC- Anaemia (normochromic, normocytic)

-Thrombocytopaenia

-Elevated WBC count ( may be normal or low!!!!)

• PBF-Typically will show the lymphoblasts [Absence of lymphoblast does not rule out ALL (Aleukaemic Leukaemia)]
• BMA ≥20% lymphoblasts is diagnostic of ALL
• Cytochemical tests- positive to Periodic acid-Schiff and Acid phosphatase but negative to Myelopreoxidase, sudan black and Non-specific esterase, TdT positive is hallmark of Lymphoblast, however negative for L3
• Lumbar puncture, SEUCr, LFT, CXR, CT chest, serum Uric acid, LDH, coagulation profile, blood culture, baseline Echo, ECG.

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Treatment of ALL

• ALL is haematological emergency
• Treatment is divided into 2;
• i. Supportive- Counselling, blood component support, control of infection, adequate hydration, Growth Factors eg G-CSF, Nutritional support, prevention and management of TLS, leucopheresis
• ii. Specific treatment with combination chemotherapy; divided into 4 stages: Induction of remission, Consolidation, CNS treatment and Maintenance. Treatment lasts for about 24- 36 months.
• Stem cell transplantation

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Treatment of ALL

• Induction of remission- Chemotherapy given with
• Aim to induce complete remission (CR) defined as

-Restore patient’s clinical status

-Achieve normal haemogram (ANC≥1 x 10⁹ cells/L, plt count ≥100,000 x 10⁹ cells/L, Hb≥10 g/dl )

-Marrow aspirate or biopsy; marrow blasts <5%

• Consolidation- aims to kill hidden cancer cells.

Higher doses of the above drugs can be given

• CNS directed treatment-either for prophylaxis or treatment
• Maintenance-for 2yrs in female and 3 years in males- oral drugs are used

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Treatment of ALL

• Various drug combinations are used. Best results are obtained using combination of 3 drugs rather than 1 or 2 drugs.
• In ALL treatment Dexamethasone is preferred to prednisolne because it has greater CNS penetration and better lymphoblastocidal effect,. However it has risk of infection. Higher doses of prednisolone produce similar effects as Dexamethasone.
• Pre-induction: Prednisolone, Vincristine, Cyclophosphamide and Methotrexate
• Induction of Remission: Daunorubicin, Vincristine and Methotrexate
• Consolidation: Cyclophosphamide, Daunorubicin, Vincristine, Methotrexate, Prednisolone
• Maintainance: 6- Mecaptopurine, Methotrexate, Prednisolone, Vincristine
• Patients with Ph/BCR-ABL positive ALL must be commenced on daily TKI (Imatinib) after first induction therapy. This continues indefinitely or 24 months after allogeneic SCT.

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Prognostic factors

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Acute myeloblastic leukaemia (AML)

• AML is a clonal disorder of haemopoietic stem cells characterized by characterized by accumulation of more than 20% malignant myeloblast in the bone marrow
• It typically arise from

-1 Maturation arrest with reduced capacity of haemopoietic progenitor cells to differentiate

-2 Clonal expansion and accumulation of abnormal myeloid precursor cells principally in the marrow

-3 Impaired production of normal blood cells.

• It occurs in all age groups, but commoner in adults
• There are two types (i) Primary- denovo (ii) Secondary- To other haematological disorders like MDS, CML, AA

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Epidemiology of AML

• Occurs at all age groups with peak incidence in the seventh decade
• The commonest form of acute leukaemia in the adults with median onset of 65 years
• Forms only the minor fraction of leukaemias in childhood
• However it is the most predominant form of leukaemia in neonates
• Higher in men than women
• In western world it accounts for about 25% of all leukaemias in adults
• World wide the incidence of AML is highest in the US, Australia and Western Europe
• A lower incidence is seen in persons of Asian descent.

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Aetiology

• Not known however there are some risk factors
• Family history (sibling or identical twin with AML)
• Environmental factors;   
• Radiation (Ionizing and non ionizing radiation)
• Solvents (Benzene)
• Chemotherapeutic agents
• Tobacco smoke

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Aetiology; Congenital factors

• Down syndrome.
• Bloom syndrome.
• Monosomy 7 syndrome
• Klinefelter syndrome
• Turner syndrome
• Neurofibromatosis
• Congential dysmorphic syndrome

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Other haematopoietic disorders

• Aplastic anaemia
• Fanconi anaemia
• Dyskeratosis congenita.
• Schwchman Diamond Syndrome
• Amegakaryocytic thrombocytopenia
• Blackfan Diamond Anaemia
• Kostmann Agranulocytosis
• Familial aplastic anaemia
• Familial platelet disorder.

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• CML
• Primary myelofibrosis
• Essential thrombocythemia
• Polycythemia vera
• Paroxysmal nocturnal hemoglobinuria

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Pathogenesis

• Leukaemia transformation results from altered cell proliferation, block in differentiation and maturation and impaired apoptosis through genetic dysregulations.
• AML results from a series of somatic mutations in either a HSCs or a more differentiated lineage-restricted precursor cell.
• An AML genome contains an average of 10 mutations within protein encoding genes
• Class 1: mutations that give rise to cell proliferation e g FLT3, c-kit, N/K-RAS, BCR-ABL, TEL-PDGFBR
• Class 2: mutations that interfere with terminal differentiation and apoptosis thereby providing survival advantage for the mutated cells; RUNX1-RUNX1T1, CBFB-MYH11, PML-RAR α
• There is dysregulation of cell growth rate, survival, differentiation and maturation of blood cell progenitors.
• Results in accumulation of blasts in BM

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Pathogenesis

• Abnormal cell proliferation
• FLT3 mutations
• Ras mutations
• Others: c-KIT mutations
• Block in differentiation
• CBF AML (t(8;21) and inv(16))
• PML-RARα (t(15;17))
• MLL translocations (11q23)
• Hox gene translocations
• C/EBPα mutations
• Suppression of apoptosis
• Bcl-2 over-expression
• Capacity for indefinite self-renewal

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Classification of AML

• FAB-classification:

1) Heavily depends on “Morphologic Findings”

2) Special staining (SBB, MPO, NSE, etc)

• WHO-classification:

1) Morphologic findings

2) Special staining

3) Immunophenotyping (in the form of flow cytometry/FC and immunohistochemistry/IHC).

4) Cytogenetics and molecular genetics studies frequently used.

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Classification of AML

• Classified by FAB scheme morphologically into M0-M7
• M0-Undifferentiated AML
• M1-AML without maturation
• M2-With granulocytic (minimal) maturation
• M3-Acute promyelocytic leukaemia
• M4-Acute myelomonocytic leukaemia
• M5-Monoblastic (M5a) or monocytic (M5b) leukaemia
• M6-Erythroleukaemia (acute erythroid leukaemia)
• M7-Megakaryoblastic leukaemia

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M1

M2

M3

M4

M5 with blasts.

M5 with fewer blast

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M6

M7

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Clinical features

• Similar to those of ALL
• DIC is characteristic of M3 variant
• Gum hypertrophy, skin involvement and CNS disease are characteristics of M4 and M5 variants

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Examination findings

• Fever
• Tachycardia/tachypnoea
• Ecchymosis and bleeding from IV sites, DIC
• Papilledema, retinal infiltrates, cranial nerve abnormalities (CNS leukemia)
• Poor dentition, dental abscesses, gum hypertrophy (leukemic infiltration)(M4/5)
• Skin infiltration, nodules, myeloid sarcomas or chloromas (leukemia infiltration)(M4/5)
• Lymphadenopathy, splenomegaly, hepatomegaly

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Examination findings

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Investigations

• Similar to those seen in ALL
• FBC
• Severe anaemia
• Severe thrombocytopaenia
• WBC is usually variable
• PBF
• Presence of blasts and blast equivalents in peripheral circulation

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Bone marrow

• Usually a hypercellular marrow
• Presence of myeloblasts (≥20%...WHO)-differentiated from lymphoblasts by their size (typically larger than lymphoblasts), presence of auer rods, cytochemical stains and immunophenotypic markers.
• The myeloblasts vary in the different subsets of AML
• Some myeloblast may possess auer rods, granular or agranular cytoplasm
• Nucleus may contain one or more nucleoli
• Some dysplastic features may be seen
• Suppression of other cell lines is typical

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Bone marrow;

• Marrow reticulin fibrosis is common but is usually slight to moderate except in megakaryoblastic leukemia in which intense fibrosis is the rule.
• Marrow biopsy may show increased blood vessel density (angiogenesis) in patients with AML compared to normal individuals.

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Coagulation profile

• Usually, PT and PTTK and TT are normal or near normal
• APL (AML-M3) variant is associated with DIC with prolonged clotting time, PT, APTT and TT
• APL is associated with hypofibrinogenemia and elaboration of thromboplastin- like substances into plasma

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Other Investigations

• LFT, Urinalysis, S/E/U/Cr, Ca2+, phosphate
• LDH, Uric acid may be increased
• Hypokalaemia due to urinary loss from proximal tubular dysfunction (if there is renal involvement in leukaemia)
• Hypercalcaemia from ectopic parathormone-like activity has been described.
• Hypophosphatemia as a result of phosphate uptake by leukaemic cells can occur.
• Cytogenetic studies

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Diagnosis

• As per recent WHO criteria, AML is defined as the presence of ≥20% blasts in BM at clinical presentation
• Patients with specific leukaemia- associated cytogenetic and molecular genetic abnormalities are considered to have AML regardless of blast percentage
• t(8;21), inversion (16), t(16;16) and t(15;17)

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Differential diagnosis

• Acute lymphoblastic leukaemia
• Blast crisis of Chronic Myeloid Leukemia
• Myelodysplastic syndrome (RAEB)
• Myeloid leukamoid reaction

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Treatment

• Both supportive and specific
• Supportive medical care; counseling and psychosocial support, blood product support, antibiotics, nutrition, proper nursing care, prevention and management of TLS
• Specific treatment; involve combination therapy (to induce remission and prevent further relapse) and Stem cell transplantation

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Treatment

• Specific is by chemotherapy with/without stem cell transplantation
• Treatment with chemotherapy is divided into two:
• Induction- with combination of Daunorubicin, Cytosine Arabinoside and Etoposide
• Aim of induction is as in ALL + Absence of auer rods and extramedullary disease
• Consolidation- with higher doses of same drugs
• AML-M3 has ATRA added to the treatment

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Stem cell transplantation

• HSCT; Allogeneic SCT is employed for younger patients (<45yrs) with an HLA-compatible donor.
• Risk of relapse is reduced from 45 to 20%.
• Cure rate for recipients of allogeneic SCT is around 60%.
• This results in an overall survival of 50 – 55% of those who receive this approach.

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Prognosis

• Age; <50 favourable; >60 unfavourable;
• Presenting leucocyte count; <25 X 10⁹/L favourable; >100 X 10⁹/L unfavourable.
• History of antecedent MDS or leukaemogenic therapy: unfavourable.
• Presence of specific cytogenetic abnormalities; favorable cytogenetic patterns t(8;21), t(15;17), inv16, or t(16;16)
• FAB subtype: M3, M4Eo favourable; M0, M5a, M5b, M6, M7 unfavourable.

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Conclusion

• Acute leukaemias are rapidly fatal haematological malignancies if left untreated
• Prior to advent of chemotherapy and other treatment modalities the median survival of patients was in weeks to months
• However the survival rate has significantly improved with advancement in treatment modalities
• Newer agents are becoming available to further improve survival rate of patients.

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