Acute Myelogenous Leukemia

1
Acute Myelogenous Leukemia

• Jim Czarnecki, D.O.
• The First in a Four-Part Series

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Introduction
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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.

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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.

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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.

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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.

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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.

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Race

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

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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.

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Age

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

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Clinical
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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.

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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.

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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.

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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.

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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.

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Gum Hypertrophy
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History

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

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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

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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.

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Leukemia Cutis
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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.

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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.

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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.

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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.

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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.

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Causes

• Prior exposure to chemotherapeutic agents for
  another malignancy.

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Differentials
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Differentials

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

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Differentials

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

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Workup
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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.

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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.

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Schistocytes
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Schistocytes
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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).

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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.

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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.

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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.

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Other Tests

• Electrocardiography should be performed prior to
  treatment.

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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.

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Histologic Findings

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

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Histologic Findings

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

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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
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Myeloid Maturation
MATURATION
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Acute Myelogenous Leukemia
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Acute Myelogenous Leukemia
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Acute Myelogenous Leukemia
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AML Auer Rods
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Treatment
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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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).

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Relapsed AML

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

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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.

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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.

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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.

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Follow-up
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Further Inpatient Care

• Patients require readmission for consolidation
  therapy or for the management of toxic effects of
  chemotherapy.

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Further Outpatient Care

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

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Deterrence / Prevention

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

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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.

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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.

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Patient Education

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

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Competency Exam
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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

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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

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Question Two

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

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Question Two

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

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Question Three

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

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Question Three

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

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End of Lecture

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