ACUTE MYELOID LEUKEMIA is a neoplastic disease characterized by infiltration of the blood, bone marrow, and proliferative, clonal undifferentiated cells of the hematopoietic system.

1. ACUTE MYELOID
LEUKEMIA

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3. dr.shumaylaaslam@gmail.com

4. ACUTE MYELOID LEUKEMIA (AML)
is a neoplastic disease characterized by
- infiltration of the blood,
- bone marrow, and
- proliferative, clonal undifferentiated
cells of the hematopoietic system.

5. Incidence
• ~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
• Hereditary
– 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

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.

10. CLASSIFICATION
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

11. • 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

12. • FAB subtype
– M0- Undifferentiated acute myeloblastic leukemia
– M1- Acute myeloblastic leukemia with minimal
maturation
– M2- Acute myeloblastic leukemia with maturation
– M3- Acute promyelocytic leukemia (APL)
– M4- Acute myelomonocytic leukemia
– M4 eos- Acute myelomonocytic leukemia with
eosinophilia
– M5- Acute monocytic leukemia
– M6- Acute erythroid leukemia
– M7- Acute megakaryoblastic leukemia

13. ACUTE LEUKEMIA
• Leukemia is defined as a group of malignant stem cell neoplasms
characterized by:
• Diffuse replacement of bone marrow with proliferating leukocyte precursors
(blast cells)
• Abnormal numbers and forms of immature white blood cells in circulation.
• In acute leukemia the immature, neoplastic leukemic ‘blast’ cells proliferate
and accumulate, but fail to mature. The blasts diffusely replace the normal
bone marrow and a variable number of these accumulate in the peripheral
blood.

14. ACUTE LEUKEMIA
• Acute leukemia should be diagnosed when the blast cells constitute more
than 20% of the nucleated cells in the marrow (normally blast cells are
less than 5%).
• In some patients there may be very few /no blasts in the peripheral blood
and is termed as aleukemic/subleukemic leukemia.
• Infiltration of the marrow by leukemic cells finally results in bone
marrow failure resulting in cytopenias. Most patients present with
consequences of cytopenias (anemia, neutropenia and thrombocytopenia)
particularly in the acute leukemias.

20. 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 are the presenting
symptom.

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22. • Physical Findings
– splenomegaly,
– hepatomegaly,
– lymphadenopathy,
– sternal tenderness,
– evidence of infection and hemorrhage are often
found at diagnosis.

23. • 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.

24. • 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.

25. • 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.

26. 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 agd
r
to one another.

27. PERIPHERAL SMEAR
• Total WBC Count: It is markedly raised ranging from 20 × 109/L to 100 ×
109/L. In few cases count may be normal or even reduced.
• Hemoglobin: It is decreased and ranges from 5 to 9 gm/dL.
• Peripheral smear RBCs: They show normocytic normochromic type of anemia.
• WBCs: Total WBC count is usually markedly increased. Leukemic blast cells
may replace normal myeloid series in the marrow and can cause neutropenia.

28. PERIPHERAL SMEAR
• Differential count: Shows more than 20% myeloid blasts. Several types of
myeloid blasts are identified and leukemias may show more than one type of blast
or blasts with hybrid features
• Morphology of myeloblasts
• Size: Myeloblasts are 3 to 5 times larger than the diameter of a small lymphocyte.
High N:C ratio
• Nucleus: Fine nuclear chromatin with 2-4 variably prominent nucleoli.
• Cytoplasm: More amount of cytoplasm than lymphoblasts. Often contains fine,
azurophilic, peroxidase-positive granules.

29. PERIPHERAL SMEAR
• Auer rods: They are distinctive azurophilic needle-like structures of
varying length and width.
• They represent an abnormal alignment and crystallization of
azurophilic granules and are peroxidase-positive.
• They are particularly numerous in AML-M3 (acute promyelocytic
leukemia). These hypergranular promyelocytes with many Auer rods
are known as faggot cells. Presence of Auer rods is definitive
evidence of myeloid differentiation

32. BONE MARROW
• Cellularity: Bone marrow is markedly hypercellular due to proliferation of
blasts which replace normal hematopoietic cells.
• Erythropoiesis: Markedly suppressed.
• Myelopoiesis: It shows suppression of myeloid maturation and myeloblasts
constitute more than 20% of marrow cells.
• Megakaryopoiesis: Megakaryocytes are gradually decreased. Megakaryocytes
usually show dysmegakaryopoiesis in the form of monolobate and hyperlobate
forms.

34. 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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36. BIOCHEMICAL FINDINGS
• Hyperuricemia (increased serum uric acid)
• Hyperkalemia (increased serum potassium)
• Hyperphosphatemia (increased serum phosphate)
• Hypocalcemia (decreased serum calcium) due to hyperphosphatemia.
• Serum lysozyme increased especially in monocytic subtypes (AML M4 and M5).
• Positive FDP and Decreased Fibrinogen
• In AML-M3, promyelocytes release tissue factor like substance which leads to
DIC, which shows the presence of FDP and reduced levels of fibrinogen in the
plasma.

37. • Immunophenotyping
• Since distinction between myeloblasts and lymphoblasts on
morphological features alone is difficult, the diagnosis of AML is
confirmed by using stains for myeloid specific antigens

38. CYTOGENETICS
• Cytogenetic analysis is very important in the WHO classification of AML
Particular chromosomal abnormalities correlate with certain clinical features.
• Balanced chromosomal translocations, particularly t(8;21), inv(16) and t(15;17)
are associated with AMLs arising de novo in young adults.
• AMLs which follow MDS or exposure to DNA-damaging agents (like
chemotherapy or radiation therapy) commonly have chromosomal abnormalities
like deletions or monosomies involving chromosomes 5 and 7 and are without
chromosomal translocations.
• AML in elderly is associated with deletions of chromosomes 5q and 7q.

39. Diagnosis
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

40. Treatment
• 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;

41. • 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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43. 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 well as febrile reactions.

44. 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
– Cytogeneticd
ar
classified as favorable or adverse

45. • 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)

46. PROGNOSIS
• It has a fulminant course and has worse prognosis than
ALL.
• Cytogenetic markers are major determinants of
prognosis.