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Acute Myelogenous Leukemia

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Title: Acute Myelogenous Leukemia


1
Acute Myelogenous Leukemia
  • Jim Czarnecki, D.O.
  • The First in a Four-Part Series

2
Introduction
3
Background
  • A malignant disease of the bone marrow in which
    hematopoietic precursors are arrested in an early
    stage of development.
  • Most AML subtypes are distinguished from other
    related blood disorders by the presence of more
    than 30 blasts in the blood, bone marrow, or
    both.

4
Pathophysiology
  • Consists of a maturational arrest of bone marrow
    cells in the early stages of development.
  • The mechanism is currently under investigation
    and research, however it is known that it
    involves the activation of abnormal genes through
    chromosomal translocations and other genetic
    abnormalities.

5
Pathophysiology
  • The developmental arrest results in 2 disease
    processes
  • A marked decrease in the production of normal
    blood cells, resulting in varying degrees of
    anemia, thrombocytopenia, and neutropenia.
  • The rapid proliferation of these cells, along
    with a reduction in their ability to undergo
    programmed cell death. This results in their
    accumulation in various organs, most commonly the
    liver and spleen.

6
Frequency
  • US Estimates indicated that 10,100 new cases
    would be diagnosed in 1999 (latest stat data).
  • Internationally AML is more commonly diagnosed
    in developed countries.

7
Mortality / Morbidity
  • In 1999, approximately 6,900 people in the US
    died from AML.
  • With current chemotherapy regimens, approximately
    25-30 of adults younger than 60 years survive
    longer than 5 years and are considered cured.
  • Results in older patients are more disappointing,
    with fewer than 10 of patients surviving.

8
Race
  • AML is more common in whites than in other
    populations.

9
Sex
  • AML is more common in men than in women.
  • Some researchers have proposed that the increased
    prevalence of AML in men may be related to
    occupational exposures.

10
Age
  • Prevalence increases with age. The median age of
    onset is 65 years.
  • However, this disease affects all age groups.

11
Clinical
12
History
  • Patients present with symptoms resulting from
    bone marrow failure, organ infiltration with
    leukemic cells, or both. The time course is
    variable.
  • Some patients can present with acute symptoms
    over a few days to 1-2 weeks
  • Others have longer course, with fatigue or other
    symptoms lasting from weeks to months.

13
History
  • Symptoms of bone marrow failure are related to
    anemia, neutropenia, and thrombocytopenia.
  • The most common symptom is fatigue from the
    anemia.
  • Other symptoms from anemia include dyspnea upon
    exertion, dizziness, and in patient with coronary
    artery disease, anginal chest pain.
  • In fact, myocardial infarction may be the first
    presenting symptom of acute leukemia in the older
    patient.

14
History
  • Patients often have decreased neutrophil levels
    despite an increased total WBC count.
  • They present with fever, which may occur with or
    without specific documentation of an infection.
  • Patients often have a history of upper
    respiratory infection symptoms that have not
    improved despite appropriate oral antibiotic
    treatment.
  • Patients present with bleeding gums and multiple
    ecchymoses.

15
History
  • Potentially life-threatening sites of bleeding
    include the lungs, gastrointestinal tract, and
    the central nervous system.
  • Symptoms may be the results of organ infiltration
    with leukemic cells.
  • Most common sites include the spleen, liver, and
    gums.
  • Infiltration most commonly occurs in those
    patients with monocytic subtypes of AML.

16
History
  • Patients with splenomegaly note fullness in the
    left upper quadrant and early satiety.
  • Patients with gum infiltration often present to
    their dentist first. Gingivitis due to neuropenia
    can cause swollen gums, and thrombocytopenia can
    cause the gums to bleed.
  • Patients with elevated WBC counts (gt 100,000)
    can present with symptoms of leukostasis
    (respiratory and altered mental status). This is
    a medical emergency.

17
Gum Hypertrophy
18
History
  • Patients with a high leukemic cell burden may
    present with bone pain caused by increased
    pressure in the bone marrow.

19
Physical
  • Signs of anemia, include pallor and cardiac flow
    murmur, are frequently present.
  • Fever and other signs of infection can occur,
    including lung findings of pneumonia
  • Patients with thrombocytopenia usually
    demonstrate petechiae, particularly on the lower
    extremities

20
Physical
  • Signs relating to organ infiltration with
    leukemic cells include hepatosplenomegaly and, to
    a lesser degree, lymphadenopathy.
  • Patients may have skin rashes due to infiltration
    of the skin with leukemic cells (leukemia cutis).
  • Signs relating to leukostasis include respiratory
    distress and altered mental status.

21
Leukemia Cutis
22
Causes
  • Although several factors have been implicated in
    the causation of AML, most patients who present
    with de novo AML have no identifiable risk
    factor.

23
Causes
  • Antecedent hematologic disorders (AHD)
  • The most common is MDS a disease of the bone
    marrow of unknown etiology that occurs most often
    in older patients and manifests as progressive
    cytopenias that occur over months to years.
  • Patients with low-risk MDS do not generally
    develop AML.
  • Other AHDs that predispose patients to AML
    include aplastic anemia, myelofibrosis,
    paroxysmal nocturnal hemoglobinuria, and
    polycythemia vera.

24
Causes
  • Congenital disorders
  • Usually, these patients will develop AML during
    childhood although rarely, some may present in
    young adulthood.
  • Disorders include Bloom syndrome, Down syndrome,
    congenital neurtropenia, Fanconi anemia and
    neurofibromatosis.

25
Causes
  • Familial syndromes
  • Rare cases of familial erythroleukemia (a subtype
    of AML), have been described.
  • These families tend to present with a preleukemic
    picture or acute leukemia in the sixth or seventh
    decades.
  • Inheritance appears to be autosomal dominant with
    variable penetrance.

26
Causes
  • Environmental exposures
  • Several studies demonstrate a relationship
    between radiation exposure and leukemia.
  • Early radiologists (prior to appropriate
    shielding) were found to have an increased
    likelihood of developing anemia.
  • Patients receiving therapeutic irradiation for
    ankylosing spondylitis were at increased risk.
  • Exposure to benzene is associated with aplastic
    anemia andpancytopenia. These patients often
    develop AML.

27
Causes
  • Prior exposure to chemotherapeutic agents for
    another malignancy.

28
Differentials
29
Differentials
  • Acute Lymphoblastic Leukemia
  • Agnogenic Myeloid Metaplasia With Myelofibrosis
  • Agranulocytosis
  • Anemia
  • Aplastic Anemia
  • Bone Marrow Failure

30
Differentials
  • Chronic Myelogenous Leukemia
  • Lymphoma, B-Cell
  • Lymphoma, Lymphoblastic
  • Myelodysplastic Syndrome

31
Workup
32
Lab Studies
  • CBC count with differential demonstrates anemia.
    Patients with AML can have high, normal, or low
    WBC counts.
  • Prothrombin time/fibrinogen products
  • Most common is DIC
  • Acute promyelocytic leukemia (APL), also known as
    M3, is the most common subtype of AML associated
    with DIC.

33
Lab Studies
  • Peripheral blood smear
  • Review of peripheral blood smear confirms the
    findings of the CBC count.
  • Circulating blasts are usually seen.
  • Schistocytes are occasionally seen if DIC is
    present.

34
Schistocytes
35
Schistocytes
36
Lab Studies
  • Chemistry profile
  • Most patients will have an elevated lactic
    dehydrogenase level, and frequently, an elevated
    uric acid level.
  • Liver function tests and BUN/Creatinine level
    tests are necessary prior to the initiation of
    therapy.
  • Hypokalemia, hypocalcemia, hypomgnesemia may
    develop because of renal losses seen in acute
    monocytic leukemia (M5) and acute myelomonocytic
    leukemia (M4).

37
Lab Studies
  • Appropriate cultures should be obtained in
    patients with fever or signs of infection, even
    in the absence of fever.
  • Cytogenetic studies performed on bone marrow
    provide important prognostic information and are
    useful to confirm a diagnosis of APL.

38
Lab Studies
  • Bone marrow aspiration
  • This enables a blast count to be performed.
  • Also allows an evaluation of the degree of
    dysplasia in all cell lines and the number of
    platelet precursors present
  • The disease can then be classified into any of 7
    subtypes (M1 M7) based on cytochemical stains.

39
Imaging Studies
  • Chest radiographics help assess for pneumonia and
    signs of cardiac disease.
  • Multiple gated acquisition (MUGA) scan is needed
    once the diagnosis is confirmed because many of
    the chemotherapeutic agents used in the treatment
    of AML are cardiotoxic.

40
Other Tests
  • Electrocardiography should be performed prior to
    treatment.

41
Procedures
  • Bone marrow aspiration and biopsy are the
    definitive diagnostic tests.
  • Aspiration slides should be stained for
    morphology with either Wright or Giemsa stain.
  • Bone marrow samples should also be sent for
    cytogenetics testing and flow cytometry.

42
Histologic Findings
  • M0 Undifferentiated leukemia
  • M1 Myeloblastic without differentiation
  • M2 Myeloblastic with differentiation
  • M3 Promyelocytic
  • M4 Meylomonocytic
  • M4eo Myelomonocytic with eosinophilia

43
Histologic Findings
  • M5 Monoblastic leukemia
  • M5a Monoblastic without differentiation
  • M5b Monocytic with differentiation
  • M6 Erythroleukemia
  • M7 Megakaryoblastic leukemia

44
Hematopoiesis
PLURIPOTENT STEM CELL
COMMITTED PROGENITOR CELL
RECOGNIZABLE BONE MARROW PRECURSOR CELL
MATURE BLOOD CELL
MIXED PROGENITOR CELL
pronormoblast
red cell
myeloblast monoblast
neutrophil monocyte
eosinophil
myeloid progenitor cell
basophil
platelet
CFU-Meg
megakaryocyte
pluripotent stem cell
pre-T
lymphoblast
T-cell
pre-B
lymphoblast
B-cell
lymphoid progenitor cell
plasma cell
45
Myeloid Maturation
MATURATION
46
Acute Myelogenous Leukemia
47
Acute Myelogenous Leukemia
48
Acute Myelogenous Leukemia
49
AML Auer Rods
50
Treatment
51
Medical Care
  • Current standard chemotherapy regimens cure only
    a minority of patients.
  • As a result, all patients should be evaluated for
    entry into well-designed clinical trials.
  • If a clinical trial is not available, patients
    can be treated with standard therapy.

52
Induction Therapy
  • Does not treat acute promyelocytic leukemia
  • Most common approach is 3 and 7, which is 3
    days of a 15- to 30-minute infusion of an
    anthracycline (idarubicin or daunorubicin) or
    anthracenedione (mitoxantrone) combined with
    arabinosylcytosine (araC), 100 mg/m2 as a 24-hour
    infusion daily for 7 days.

53
Induction Therapy
  • Idarubicin is given at a dose of 12 mg/m2/d for 3
    days, daunorubicin at 45-60 mg/m2/d for 3 days,
    or mitoxantrone at 12 mg/m2/d for 3 days.
  • These regimens require adequate cardiac, hepatic,
    and renal function.
  • Using these regimens, approximately 50 of
    patients achieve remission with one course.
    Another 10-15 enter remission following a second
    course of therapy.

54
Consolidation Therapy
  • In order to define the best post-remission
    therapy for young patients, several large,
    randomized studies comparing allogeneic bone
    marrow transplant (BMT), autologous BMT, and
    chemotherapy without BMT have been performed.
  • Unfortunately, the results of the studies are
    conflicting.

55
Consolidation Therapy
  • The following recommendations can be followed
  • Patients with good-risk AML, and inversion of
    chromosome 16, have a good prognosis following
    consolidation with high-dose araC and should be
    offered such therapy. Transplantation should be
    reserved for patients who relapse.

56
Consolidation Therapy
  • Patients with high-risk cytogenetics findings
    are rarely cured with chemotherapy and should be
    offered transplantation in first remission
  • However these patients are also at high risk for
    relapse following transplantation.

57
Consolidation Therapy
  • The best approach for patients with
    intermediate-risk cytogenetics findings is
    controversial.
  • Some oncologists refer patients for
    transplantation in first remission, whereas
    others give consolidation chemotherapy with
    high-dose araC for 4 courses and reserve
    transplantation for patient who relapse.

58
Consolidation Therapy
  • For older patients
  • The best post-remission therapy for elderly
    patients has yet to be determined.
  • Most patients are ineligible for standard
    allogeneic BMT.
  • Some patients may be candidates for autologous
    BMT however, the effectiveness of autologous BMT
    in this patient population is unclear.

59
Consolidation Therapy
  • The most commonly used regimen is araC at 100
    mg/m2 daily for 5 days combined with 2 days of
    anthracycline, for 2 courses.
  • Newer approaches under investigation include
    monoclonal antibodies and allogeneic
    transplantaion following nonmyeloablative
    chemotherapy (minitransplants).

60
Relapsed AML
  • Patients with relapsed AML have an extremely poor
    prognosis.
  • Most patients should be referred for
    investigational therapies.

61
Supportive Care
  • Replacement of blood products
  • Patients with AML have a deficiency in the
    production of normal blood cells, therefore need
    replacement. All blood products should be
    irradiated to prevent graft-versus-host disease,
    which is almost invariably fatal.
  • PRBCs are given to patients with a hemoglobin
    level of less than 7-8 g/dL, or at a higher level
    if the patient has cardiovascular or respiratory
    compromise.

62
Supportive Care
  • Platelets should be transfused if the level is
    less than 10,000 to 20,000 cells/uL.
  • Fresh frozen plasma should be given to patients
    with a significantly prolonged prothrombin time,
    and cryoprecipitate should be given if the
    fibrinogen level is less than 100 g/dL.

63
Supportive Care
  • Antibiotics
  • Should be given to all febrile patients.
  • At minimum, should include broad-spectrum
    coverage, such as a third-generation
    cephalosporin, usually with an aminoglycoside.
  • For patients receiving antibiotics with
    persistant fever of no focus, should also receive
    amphotericin at a dose of 0.5 mg/kg.
  • Allopurinol at 300 mg should be given 1-3 times a
    day during induction therapy until clearance of
    blasts and resolution of hyperuricemia.

64
Follow-up
65
Further Inpatient Care
  • Patients require readmission for consolidation
    therapy or for the management of toxic effects of
    chemotherapy.

66
Further Outpatient Care
  • Patients should come to the office for monitoring
    of disease status and chemotherapy effects.

67
Deterrence / Prevention
  • While receiving chemotherapy, patients should
    avoid exposure to crowds and people with
    contagious illnesses, especially children with
    viral infections.

68
Complications
  • The most common complication is failure of the
    leukemia to respond to chemotherapy.
  • The prognosis for these patients is poor because
    they usually do not respond to other chemotherapy
    regimens.

69
Prognosis
  • Relies on several factors
  • Increasing age is an adverse factor because older
    patients more frequently have cormorbid medical
    conditions that compromise the ability to give
    full doses of chemotherapy.
  • Cytogenetic analysis of the bone marrow is one of
    the most important prognostic factors. Patients
    with t(821), t(1517) or inversion 16 have the
    best prognosis, with long-term survival rates of
    approximately 65.

70
Patient Education
  • Patients should be instructed to call immediately
    if they are febrile or have signs of bleeding.

71
Competency Exam
72
Question One
  • 1) Acute Myelogenous Leukemia (AML) is defined
    as
  • 5 blasts in bone marrow
  • 12 blasts in bone marrow
  • 25 blasts in bone marrow
  • 30 blasts in bone marrow
  • 75 blasts in bone marrow

73
Question One
  • 1) Acute Myelogenous Leukemia (AML) is defined
    as
  • 5 blasts in bone marrow
  • 12 blasts in bone marrow
  • 25 blasts in bone marrow
  • 30 blasts in bone marrow
  • 75 blasts in bone marrow

74
Question Two
  • 2) All of the following cytogenetic analysis
    indicators have the best prognosis, except
  • t(821)
  • t(1517)
  • Inversion 16
  • 11q23

75
Question Two
  • 2) All of the following cytogenetic analysis
    indicators have the best prognosis, except
  • t(821)
  • t(1517)
  • Inversion 16
  • 11q23

76
Question Three
  • 3) Acute promyelocytic leukemia can be treated
    with induction therapy, as well as combination
    therapy.
  • True
  • False

77
Question Three
  • 3) Acute promyelocytic leukemia can be treated
    with induction therapy, as well as combination
    therapy.
  • True
  • False

78
End of Lecture
  • Thank you for your attendance.
  • This lecture will be made available at the
    Internal Medicine Residency website
  • http//IM.official.ws
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