Acute leukemias

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Acute leukemias

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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.

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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.

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Risk Factors

• Heredity
• Down syndrome
• Klinefelter syndrome
• congenital neutropenia
• Fanconi anemia
• neurofibromatosis

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Risk Factors

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

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Risk Factors

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

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Risk Factors

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

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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.

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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.

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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.

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Classification

• Morphologic

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Classification

• WHO classification

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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

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Clinical presentation

• Anemic syndrome
• Infection diseases
• Bleeding
• Anorexia and weight loss

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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 )

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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.

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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.

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Lab Studies
AML is defined by greater than 20 blasts in bone
marrow. Blasts in bone marrow Normal bone
marrow
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Lab Studies

• ?ytochemical investigation
• myeloperoxidase alpha-naphthyl butyrate
  esterase and chloroacetate esterase
  stains

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Lab Studies

• Flow cytometry

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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New agents
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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.

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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.

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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

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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)

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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

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Classification of ALL
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Etiology

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

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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)

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Lab Studies

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

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Lab Studies

• Bone marrow aspiration and biopsy

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Lab Studies
A negative peroxidase stain AML ALL
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Lab Studies

• Flow cytometry
• CD3 (T-lineage ALL)
• CD19 (B-lineage ALL)
• Cytogenetics
• t(229)
• t(411)
• t(28)
• t(814))

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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

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Lab Studies

• Blood cultures
• Imaging studies
• ECG
• Histologic findings

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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.

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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

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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).

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Supportive Care

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

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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.