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Acute leukemias

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Title: Acute leukemias


1
Acute leukemias
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2
Acute leukemias
  • are heterogeneous group of diseases characterized
    by infiltration of the blood, bone marrow, and
    other tissues by neoplastic cells (blasts) of the
    hematopoietic system.

3
Acute myeloid leukemia
  • The incidence of acute myeloid leukemia (AML) is
    about 3,6 per 100,000 people per year, and the
    age adjusted incidence is higher in men than in
    women (1,7-4,4 versus 1,4-3). AML incidence
    increases with age it is 1,7 in individuals lt65
    years and 16.2 in those.65 years. A significant
    increase in AML incidence has occurred over the
    past 10 years.

4
Risk Factors
  • Heredity
  • Down syndrome
  • Klinefelter syndrome
  • congenital neutropenia
  • Fanconi anemia
  • neurofibromatosis

5
Risk Factors
  • Radiation
  • Chemical and other exposures
  • benzene
  • smoking
  • petroleum products
  • paint
  • embalming fluids
  • ethylene oxide
  • herbicides and pesticides

6
Risk Factors
  • Drugs
  • alkylating agent
  • topoisomerase II inhibitor (etoposid)
  • chloramphenicol
  • phenylbutazone
  • chloroquine
  • methoxypsoralen

7
Risk Factors
  • Antecedent haematological disorders
  • myelodisplastic syndrome
  • aplastic anaemia
  • myelofibrosis
  • paroxismal nocturnal hemoglobinuria
  • polycithemia rubra vera
  • Familial syndromes

8
Pathophysiology
  • The underlying pathophysiology consists of a
    maturational arrest of bone marrow cells in the
    earliest stages of development. The mechanism of
    this arrest is under study, but in many cases, it
    involves the activation of abnormal genes through
    chromosomal translocations and other genetic
    abnormalities.

9
Pathophysiology
  • This developmental arrest results in 2 disease
    processes.
  • First, a marked decrease in the production of
    normal blood cells occurs, resulting in varying
    degrees of anemia, thrombocytopenia, and
    neutropenia. Second, the rapid proliferation of
    these cells, along with a reduction in their
    ability to undergo programmed cell death
    (apoptosis), results in their accumulation in
    various organs, most commonly the spleen and
    liver.

10
Diagnosis
  • The diagnosis of AML is established by the
    presence of more than 20 myeloblasts in blood
    and/or bone marrow according to the World Health
    Organization classification.

11
Classification
  • Morphologic

12
Classification
  • WHO classification

13
Classification
  • Cytochemical
  • Immunophenotypic
  • Chromosomal
  • AML with recurrent genetic abnormalities.
  • AML with t(821)(q22q22) has been associated
    with M2
  • AML with abnormal bone marrow eosinphils
    (inv(16)(p13q22) or t(1616)(p13,q22)
  • Acute promyelocytic leukemia with
    t(1517)(q22q12)
  • AML with 11q23 abnormalities has been associated
    with M5
  • Molecular

14
Clinical presentation
  • Anemic syndrome
  • Infection diseases
  • Bleeding
  • Anorexia and weight loss

15
Clinical presentation
  • Organ infiltration with leukemic cells
  • hepatosplenomegaly
  • lymphadenopathy
  • gum hypertrophy
  • leukemia cutis
  • infiltration of CNS (headache, papilledema,
    retinal infiltrates, nonfocal neurologic or
    cranial nerve abnormalities)
  • Leukostasis (respiratory distress and altered
    mental status, bone pain )

16
Lab Studies
  • 1. CBC count with differential demonstrates
    anemia and thrombocytopenia to varying degrees.
    Patients with AML can have high, normal, or low
    WBC counts.

17
Lab Studies
  • 2. Bone marrow aspiration
  • The disease then can be classified on the basis
    of cytochemical stains into any of 7 subtypes,
    M1-M7. Slides should be stained with
    myeloperoxidase (or Sudan black), terminal
    deoxynucleotidyl transferase (TdT) (unless
    performed by another method, such as flow
    cytometry), and double esterase to determine the
    French American British (FAB) type of the
    leukemia.

18
Lab Studies
AML is defined by greater than 20 blasts in bone
marrow. Blasts in bone marrow Normal bone
marrow
19
Lab Studies
  • ?ytochemical investigation
  • myeloperoxidase alpha-naphthyl butyrate
    esterase and chloroacetate esterase
    stains

20
Lab Studies
  • Flow cytometry

21
Lab Studies
  • Cytogenetic studies
  • Raise lactic dehydrogenase levels (LDL)
  • Raise uric acid
  • An elevated prothrombin time, a decreasing
    fibrinogen level, the presence of fibrin split
    products
  • Liver and renal function must be checked before
    initiating chemotherapy
  • Reduce potassium, calcium and magnesium (M4, M5)
  • If fever is present appropriate steps should be
    taken to identify and treat infection
  • Lumbar puncture for those with symptoms of CNS
    involvment

22
Clinical remission
  • The blood neutrophil count must be more then 1500
    in microl
  • The platelet count more then 100000 in microl.
  • Circulating blasts should be absent.
  • Bone marrow cellularity should be more then 20
    with trilineage maturation.
  • The bone marrow should contain less then 5
    blasts.
  • Extramedullary leukemia should not be present.

23
Prognostic factors
  • Age at diagnosis Chronic and intercurrent
    diseases impair tolerance to rigorous therapy.
  • Performance status.
  • Chromosome finding t(821), inv (16), or
    t(15,17) - good prognosis a coplex karyotype,
    inv (3) or (7) - a very poor prognosis.
  • Molecular markers.
  • A prolonged symptomatic interval (more than 1
    month before diagnosis of AML) with cytitopenias
    preceding diagnosis.

24
Prognostic factors
  • A history of an antecedent hemotologic disorder.
  • Other pretreatment clinical featueres that are
    associated with a lower rate and shorter survival
    time.
  • A high presenting leukocyte count.
  • The FAB classification diagnosis.
  • Several treatment factors including achievment
    of CR, rapidity with which the blast cells
    disappear from the blood after induction therapy.

25
Treatment
  • Induction chemotherapy
  • Cytarabine is a cell cycle S-phase specific
    antimetabolite that becomes phosphorylated
    intracellularly to an active triphosphate form
    that interferes with DNA synthesis.
  • Anthracyclines are DNA intercalaters. Their
    primary mode of action is thought to be
    inhibition of topoisomerase II, leading to DNA
    breaks.

26
Supportive Care
  • Growth factors
  • Multilumen right arterial catheters
  • Adequate and prompt blood bank support platelet
    transfusion, red blood cell transfusions
  • Prophylactic administration of antibiotics in the
    absence of fever is controversial
  • Oral nystatin or clotrimazole
  • Acyclovir prophylaxis
  • Early initiation of empirical broad-spectrum
    antibacterial and antifungal antibiotics has
    significantly reduced the number of patients
    dying of infectious complications.

27
Treatment of Promyelocitic Leukemia
  • Tretinoin is an oral drug that induces the
    differentiation of leukemic cells bearing the
    t(1517) it is not effective in other forms of
    AML. Trerinoin plus concurrent anthracyline
    chemotherapy appears to be the safest and most
    effective treatment for APL.

28
Postremission Consolidation Therapy
  • For younger patients, most studies include
    intensive chemotherapy and allogenic or
    autologous SCT. High-dose cytarabine is more
    effective than standard-dose cytarabine.
  • For older patients, exploration of attenuated
    intensive therapy that includes either
    chemotherapy or nonmyeloablative allogeneic SCT
    has been pursued. In addition, early introduction
    of new agents is often pursued.

29
New agents
30
Acute lymphoblastic leukemia
  • is a malignant (clonal) disease of the bone
    marrow in which early lymphoid precursors
    proliferate and replace the normal hematopoietic
    cells of the marrow.

31
Pathophysiology
  • The malignant cells of ALL are lymphoid precursor
    cells (ie, lymphoblasts) that are arrested in an
    early stage of development. This arrest is caused
    by an abnormal expression of genes, often as a
    result of chromosomal translocations. The
    lymphoblasts replace the normal marrow elements,
    resulting in a marked decrease in the production
    of normal blood cells. The lymphoblasts also
    proliferate in organs other than the marrow,
    particularly the liver, spleen, and lymph nodes.

32
FAB classification
  • L1 - lymphoid malignencies of small uniform
    blasts (e.g. typical childhood acute
    lymphoblastic leukemia) small cells with
    homogeneous chromatin, regular nuclear shape,
    small or absent nucleolus, and scanty cytoplasm
    subtype represents 25-30 of adult cases

33
FAB classification
  • L2 - lymphoid malignencies of uiniform cells with
    larger and more variable size cells large and
    heterogeneous cells, heterogeneous chromatin,
    irregular nuclear shape, and nucleolus often
    large subtype represents 70 of cases (most
    common)

34
FAB classification
  • L3 - lymphoid malignencies of uniform cells with
    basophilic and sometimes vacuolated cytoplasm
    (e.g. typical Burkitts lymphoma cells). Subtype
    represents 1-2 of adult cases

35
Classification of ALL
36
Etiology
  • Epstein-Barr virus
  • Higher socioeconimic subgroups
  • Trisomy 21 (Downs syndrome)
  • High-energy radiation
  • Industrial exposure
  • Exposure to agricultural chemicals
  • Smoking
  • Preexisting myeloproliferative disorder

37
Clinical Features
  • Bone pain
  • Hepatosplenomegaly, lymphadenopathy.
  • Rashes
  • Left upper quadrant fullness and early satiety
    due to splenomegaly.
  • Symptoms related to a large mediastinal mass,
    such as shortness of breath.
  • Symptoms of leukostasis (eg, respiratory
    distress, altered mental status)
  • Anemic syndrome
  • Increase risk of infection
  • Fever
  • Disseminated intravascular coagulation
    (hemorrhagic or thrombotic complications)

38
Lab Studies
  • A CBC count anemia,thrombocytopenia, a high,
    normal, or low WBC count, neutropenia, blasts

39
Lab Studies
  • Bone marrow aspiration and biopsy

40
Lab Studies
A negative peroxidase stain AML ALL
41
Lab Studies
  • Flow cytometry
  • CD3 (T-lineage ALL)
  • CD19 (B-lineage ALL)
  • Cytogenetics
  • t(229)
  • t(411)
  • t(28)
  • t(814))

42
Lab Studies
  • Coagulogramm
  • elevated prothrombin time
  • decreased fibrinogen levels
  • presence of fibrin split products
  • Chemistry profile
  • elevated lactic dehydrogenase level
  • elevated uric acid level
  • liver function tests
  • BUN/creatinine determinations

43
Lab Studies
  • Blood cultures
  • Imaging studies
  • ECG
  • Histologic findings

44
Prognosis
  • Genetic abnormalities
  • t(922) - poor outlook
  • t(411) - younger age, female predominance, high
    white cell counts, and L1 morphology
  • t(814) - older age, male predominance, frequent
    CNS involvement, and L3 morphology
  • Both are associated with a poor prognosis.

45
Medical Care
  • Induction therapy
  • 4-drug regimen of vincristine, prednisone,
    anthracycline, and cyclophosphamide or
    L-asparaginase or a 5-drug regimen of
    vincristine, prednisone, anthracycline,
    cyclophosphamide, and L-asparaginase given over
    the course of 4-6 weeks.
  • Consolidation therapy
  • a standard 4- to 5-drug induction usually
    include consolidation therapy with Ara-C in
    combination with an anthracycline or
    epipodophyllotoxin.
  • Maintenance
  • CNS prophylaxis

46
Supportive Care
  • Replacement of blood products packed red blood
    cells, platelets, fresh frozen plasma
  • Antibiotics a third-generation cephalosporin (or
    equivalent) with an aminoglycoside. Patients with
    persistent fever after 3-5 days of antibacterial
    antibiotics have amphotericin added to their
    regimen.
  • The use of prophylactic antibiotics in
    neutropenic patients who are not febrile is
    controversial. A commonly used regimen includes
    ciprofloxacin (500 mg orally twice daily,
    fluconazole (Diflucan) (200 mg orally daily), and
    acyclovir (200 mg orally 5 times/d).

47
Supportive Care
  • Growth factors
  • Allopurinol 300 mg 1-3 times/d
  • Central venous catheter

48
Prognosis
  • Good risk includes (1) no adverse cytogenetics,
    (2) age younger than 30 years, (3) WBC count of
    less than 30,000/mL, and (4) complete remission
    within 4 weeks.
  • Intermediate risk does not meet the criteria for
    either good risk or poor risk.
  • Poor risk includes (1) adverse cytogenetics
    (t922), (411), (2) age older than 60 years,
    (3) precursor B-cell WBCs with WBC count greater
    than 100,000/mL, or (4) failure to achieve
    complete remission within 4 weeks.
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