4. Acute myeloid leukemia (AML)
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is a neoplastic disease characterized
by
- infiltration of the blood,
- bone marrow, and
- proliferative, clonal undifferentiated
cells of the hematopoietic system.
5. Incidence
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• ~3.5 per 100,000 people per year
• higher in men than in women (4.5 vs 3.1)
• increases with age
• 1.7 in individuals age <65 years
• 15.9 in those age >65 years
• The median age at diagnosis is 67 years.
6. ETIOLOGY
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• Heredity
– aneuploidy (trisomy 21 noted in Down syndrome,
– Inherited diseases with defective DNA repair (Fanconi
anemia, Bloom syndrome, and ataxiatelangiectasia)
– Congenital neutropenia (Kostmann syndrome)
– Germline mutations of CCAAT/enhancer-binding protein
α (CEBPA), runt-related transcription factor 1 (RUNX1),
and tumor protein p53 (TP53)
7. • Radiation
– High-dose radiation
• atomic bombs ; nuclear reactor accidents,
• increases the risk of myeloid leukemias that peaks 5–7 years
after exposure.
– Therapeutic radiation alone seems to add little risk
• Chemical and Other Exposures
– Exposure to benzene
• plastic, rubber, and pharmaceutical industries, is associated
with an increased incidence of AML.
– Smoking and exposure to petroleum products
• paint, embalming fluids, ethylene oxide, herbicides, and
pesticides
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8. • Drugs
– Anticancer drugs are the leading cause of therapy-
associated AML.
– Alkylating agent-associated leukemias occur on average
4–6 years after exposure
– Topoisomerase II inhibitor–associated leukemias occur 1–
3 years after exposure
– Newer agents for treatment of other hematopoietic
malignancies and solid tumors are also under scrutiny for
increased risk of AML.
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9. CLASSIFICATION
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The current categorization of AML uses the World Health Organization
(WHO) classification
• AML with certain genetic abnormalities
– AML with a translocation between chromosomes 8 and 21
– AML with a translocation or inversion in chromosome 16
– AML with a translocation between chromosomes 9 and 11
– APL (M3) with a translocation between chromosomes 15
and 17
– AML with a translocation between chromosomes 6 and 9
– AML with a translocation or inversion in chromosome 3
– AML (megakaryoblastic) with a translocation between
chromosomes 1 and 22
10. • AML with myelodysplasia-related changes
• AML related to previous chemotherapy or radiation
• AML not otherwise specified
– AML with minimal differentiation (M0)
– AML without maturation (M1)
– AML with maturation (M2)
– Acute myelomonocytic leukemia (M4)
– Acute monocytic leukemia (M5)
– Acute erythroid leukemia (M6)
– Acute megakaryoblastic leukemia (M7)
– Acute basophilic leukemia
– Acute panmyelosis with fibrosis
• Myeloid sarcoma
• Myeloid proliferations related to Down syndrome
• Undifferentiated and biphenotypic acute leukemias
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14. CLINICAL PRESENTATION
• SYMPTOMS
• Patients with AML often have several non-
specific (general) symptoms. These can include:
– Fatigue usually the first symptom
– Fever with or without an identifiable infection is the initial
symptom in approximately 10% of patients
– Night sweats
– Loss of appetite
– Weight loss
– Signs of abnormal hemostasis (bleeding, easy bruising)
are noted first in 5% of patients.
– On occasion, bone pain, lymphadenopathy, nonspecific
cough, headac
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16. • Physical Findings
– splenomegaly,
– hepatomegaly,
– lymphadenopathy,
– sternal tenderness,
– evidence of infection and hemorrhage are
often found at diagnosis.
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17. • Significant gastrointestinal bleeding,
intrapulmonary hemorrhage, or intracranial
hemorrhage occurs most often in APL.
• Bleeding associated with coagulopathy may
also occur in monocytic AML and with
extreme degrees of leukocytosis or
thrombocytopenia in other morphologic
subtypes.
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18. • Retinal hemorrhages are detected in 15%
of patients.
• Infiltration of the gingivae, skin, soft
tissues, or meninges with leukemic
blasts at diagnosis is characteristic of
the monocytic subtypes and those with
11q23 chromosomal abnormalities.
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19. • Hematologic Findings
– Anemia is usually present at diagnosis and can be
severe.
• normocytic normochromic.
– Decreased erythropoiesis often results in a reduced
reticulocyte count, and red blood cell (RBC) survival
is decreased by accelerated destruction.
– Active blood loss also contributes to the anemia.
– leukocyte count is about 15,000/μL.
• Between 25 and 40% of patients have counts <5000/μL,
• 20% have counts >100,000/μL.
• Fewer than 5% have no detectable leukemic cells in the
blood.
– Platelet counts <100,000/μL are found at diagnosis
in ~75% of patients, and about 25% have counts
<25,000/μL.
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20. Morphology
• In AML, the cytoplasm often contains primary
(nonspecific) granules, and the nucleus shows fine,
lacy chromatin with one or more nucleoli
characteristic of immature cells. Abnormal rod-shaped
granules called Auer rods are not uniformly present,
but when they are, myeloid lineage is virtually certain.
• Poor neutrophil function may be noted functionally by
impaired phagocytosis and migration and mor-
phologically by abnormal lobulation and deficient
granulation.
• Both morphologic and functional platelet
abnormalities can be observed, including large and
bizarre shapes with abnormal granulation and inability
of platelets to ag
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24. Diagnosis
• 20% or more
leukemic blasts in the
bone marrow
• Immunohistochemical
staining for
myeloperoxidase is
the best method for
determining which
cells are committed to
the myeloid lineage
• Immunohistochemical diagnosis of acute myeloid
leukemia (AML). (A) Bone marrow aspirate shows
increased blasts from a patient with AML with
inv(16) (Wright-Giemsa stain, 350). (B) Bone
marrow biopsy from the same patient shows 100%
cellularity with sheets of blasts (hematoxylin-eosin
stain, 340)
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26. Diagnosis
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the diagnostic work-up for AML :
• Complete blood count (CBC) with manual differential and
routine chemistry profile (including liver function tests,
serum creatinine, lactate dehydrogenase [LDH], and uric
acid)
• Coagulation profile – Prothrombin time (PT), partial
thromboplastin time (PTT), fibrinogen)
• Bone marrow aspiration and biopsy, including classical
cytogenetics, immunophenotyping, and molecular testing
for c-KIT, FLT3-ITD, NPM1, and CEBPA
• HLA typing of patient and family
27. • Imaging studies, including dental survey and
computed tomography (CT) scan of the chest and
abdomen, or chest x-ray and abdominal
ultrasound
• Sperm preservation in men (if desired by patient)
• Pregnancy test in women
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28. Treatment
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newly diagnosed patient with AML is usually
divided into two phases,
– induction
– postremission management
• The initial goal is to induce Complete
remission
• based on the patient’s age
– <60 years - Intensifying therapy with traditional
chemotherapy agents such as cytarabine and anthracyclines
in younger patients appears to increase the cure rate of AML.
– >60 years - the benefit of intensive therapy is controversial;
29. • INDUCTION CHEMOTHERAPY
• The most commonly used CR induction
regimens (for patients other than those with
APL) consist of combination chemotherapy with
cytarabine and an anthracycline (e.g.,
daunorubicin, idarubicin, mitoxantrone).
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30. • <60 years-
– cytarabine is used either at standard dose
(100–200 mg/m2) administered as a
continuous intravenous infusion for 7 days
or higher dose (2 g/m2) administered
intravenously every 12 h for 6 days.
– anthracycline therapy generally consists
of daunorubicin (60–90 mg/m2) or
idarubicin (12 mg/m2) intravenously on
days 1, 2, and 3 (the 7 and 3 regimen).
– Other agents can be added (i.e., cladribine)
when 60 mg/m2 of daunorubicin is used.
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31. • ≥60 years- outcome is poor likely due to a
higher induction treatment–related mortality
rate and frequency of resistant disease,
especially in patients with prior hematologic
disorders (MDS) or who have received
chemotherapy treatment for another
malignancy
• older patients can be also treated with the 7
and 3 regimen with standard-dose cytarabine
and idarubicin (12 mg/m2), daunorubicin (45–90
mg/m2)*, or mitoxantrone (12 mg/ m2).
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32. • older patients may be considered for
single-agent therapies with clofarabine
or hypomethylating agents (i.e., 5-
azacitidine or decitabine)
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33. • Toxicity with high-dose cytarabine also
includes pulmonary toxicity and
significant and occasionally
irreversible cerebellar toxicity.
• This toxicity occurs more commonly in
patients with renal impairment and in
those older than age 60 years.
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34. • After one cycle of the 7 and 3 chemotherapy
induction regimen, if persistence of leukemia
is documented, the patient is usually re-
treated with the same agents (cytarabine and
the anthracycline) for 5 and 2 days,
respectively.
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36. POSTREMISSION THERAPY
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• without further therapy, virtually all patients
experience relapse.
• Thus, postremission therapy is designed to
eradicate residual leukemic cells to prevent
relapse and prolong survival.
• The type of postremission therapy in AML is
often based on age and cytogenetic and
molecular risk.
37. • In the postremission setting, high-dose
cytarabine for three to four cycles is more
effective than standard-dose cytarabine.
• For younger patients, most studies include
intensive chemotherapy and allogeneic or
autologous hematopoietic stem cell
transplantation (HSCT).
• Autologous HSCT preceded by one to two
cycles of high-dose cytarabine is also an
option for intensive consolidation therapy.
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38. Relapsed or Refractory disease
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• Response rates depend on duration of first remission
• Patients in complete remission (CR) longer than 2y have
a 60% chance of responding to front-line regimens
• Patients in CR 1-2y have a 40% chance of responding to
front-line regimens; clinical trials are preferred
• Patients in CR less than 1y are unlikely to respond to
front-line regimens and should be referred for clinical
trials
• The prognosis for patients beyond first salvage is very
poor
39. • Recommended chemotherapy regimens for
relapsed or refractory disease:
• Mitomycin, etoposide, and cytarabine (MEC) :
– Etoposide 80 mg/m 2 IV over 1h plus cytarabine 1
g/m 2 IV over 6h plus mitoxantrone 6 mg/m 2; all three
drugs should be given daily for 6d or
• CLAG-M (cladribine, cytarabine, mitoxantrone,
and filgrastim) :
– Cladribine 5 mg/m 2 IV over 2h daily for
5d plus cytarabine 2 mg/m 2 IV over 4h daily for 5d,
with each dose starting 2h after
cladribine plus mitoxantrone 10 mg/m 2 IV for
3d plus filgrastim 300 µg for 6d starting 24h prior to
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40. • FLAG-IDA (fludarabine, cytarabine,
idarubicin, and filgrastim) :
–Fludarabine 30 mg/m 2/day IV over
30min on days 1-5
–Cytarabine 2 g/m 2/day IV over 4h; 4h
after fludarabine on days 1-5
–Idarubicin 10 mg/m 2/day IV on days 1-3
–Filgrastim 5 µg/kg/day SC to begin on
day 6 until neutrophil recovery
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41. SUPPORTIVE CARE
• Patients with AML should be treated in centers expert
in providing supportive measures.
• Multilumen right atrial catheters should be inserted
as soon as patients with newly diagnosed AML have
been stabilized.
• Platelet transfusions should be given as needed to
main- tain a platelet count ≥10,000/μL.
• RBC transfusions should be administered to keep the
hemoglobin level >80 g/L (8 g/dL) in the absence of
active bleed- ing, DIC, or congestive heart failure,
which require higher hemoglobin levels.
• Blood products leukodepleted by filtration should be
used to avert od
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42. PROGNOSTIC FACTORS
• Favorable
– Translocation between chromosomes 8 and 21
– Inversion of chromosome 16 or a translocation
between chromosome 16 and itself
– Translocation between chromosomes 15 and 17
• Intermediate-I
– Mutated NPM1 and FLT3-ITD
– Wild-type NPM1 and FLT3-ITD
– Wild-type NPM1 without FLT3-ITD
• Intermediate-II
– t(9;11)(p22;q23); MLLT3-MLL
– Cytogeneticda
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43. • Adverse
– Deletion (loss) of part of chromosome 5 or 7 (no
specific AML type)
– Translocation or inversion of chromosome 3
– Translocation between chromosomes 6 and 9
– Translocation between chromosomes 9 and 22
– Abnormalities of chromosome 11 (at the spot
q23)
– Complex changes - those involving several
chromosomes (no specific AML type)
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