1. Acute Myeloid Leukemia (AML)
Dr. Ravi Kant
Assistant Professor
Department of General Medicine

2. Introduction
The myeloid leukemias are a heterogeneous group of diseases characterized by infiltration of the blood, bone marrow, and other tissues by neoplastic cells of the hematopoietic system.
Based on their untreated course, the myeloid leukemias have traditionally been designated acute or chronic.

3. Incidence
The incidence of acute myeloid leukemia (AML) is 3.5 per 100,000 people per year, and the age- adjusted incidence is higher in men than in women.
AML incidence increases with age.
Etiology
Heredity, radiation, chemical and other occupational exposures, and drugs have been implicated in the development of AML.

4. World Health Organization Classification
AML with recurrent genetic abnormalities
 AML with t(8;21)(q22;q22)
AML with inv(16)(pl3.1q22) or t(16;16)(p13.1;q22)
Acute promyelocytic leukemia with t(15;17)(q22;q12);
 AML with t(9;11)(p22;q23);
 AML with t(6;9)(p23;q34);
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2);
AML (megakaryoblastic) with t(1;22)(p13;q13);

5. AML with myelodysplasia-related changes
Therapy-related myeloid neoplasms
AML not otherwise specified
  AML with minimal differentiation
  AML without maturation
  AML with maturation
  Acute myelomonocytic leukemia
  Acute monoblastic and monocytic leukemia
  Acute erythroid leukemia
  Acute megakaryoblastic leukemia
  Acute basophilic leukemia
  Acute panmyelosis with myelofibrosis
Myeloid sarcoma

6. Myeloid proliferations related to Down syndrome
  Transient abnormal myelopoiesis
  Myeloid leukemia associated with Down syndrome
Blastic plasmacytoid dendritic cell neoplasm
Acute leukemia of ambiguous lineage
  Acute undifferentiated leukemia
  Mixed phenotype acute leukemia with t(9;22)(q34;q11,20)
  Mixed phenotype acute leukemia with t(v;11q23);
  Mixed phenotype acute leukemia,

7. French-American-British (FAB) Classification
  MO: Minimally differentiated leukemia
  Ml: Myeloblastic leukemia without maturation
  M2: Myeloblastic leukemia with maturation
  M3: Hypergranular promyelocytic leukemia
  M4: Myelomonocytic leukemia
 M4Eo: Variant: Increase in abnormal marrow eosinophils
  M5: Monocytic leukemia
  M6: Erythroleukemia (DiGuglielmo's disease)
  M7: Megakaryoblastic leukemia

8. A major difference between the WHO and FAB systems is the blast cutoff for a diagnosis of AML as opposed to myelodysplastic syndrome (MDS); it is 20% in the WHO classification and 30% in the FAB.

9. Molecular Prognostic Markers in AML
Marker Location
Prognostic Impact
NPM1 mutation 
5q35
Favorable
CEBPA mutation 
19q13.1
FLT3-ITD 
13q12
Adverse
WT1 mutation 
11p13
KIT mutation 
4q11-q12
BAALC overexpression 
8q22.3
ERG overexpression 
21q22.3
MN1 overexpression 
22q12.1
EVI1 overexpression 
3q26

10. Clinical Presentation
Symptoms
Patients with AML most often present with nonspecific symptoms that begin gradually or abruptly and are the consequence of anemia, leukocytosis, leukopenia or leukocyte dysfunction, or thrombocytopenia. Nearly half have had symptoms for 3 months before the leukemia was diagnosed.
Half mention fatigue as the first symptom, but most complain of fatigue or weakness at the time of diagnosis.

11. Anorexia and weight loss are common
Anorexia and weight loss are common. Fever with or without an identifiable infection is the initial symptom in 10% of patients.
Signs of abnormal hemostasis (bleeding, easy bruising) are noted first in 5% of patients.
On occasion, bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis is the presenting symptom.

12. Physical Findings
Fever, splenomegaly, hepatomegaly, lymphadenopathy, sternal tenderness, and evidence of infection and hemorrhage are often found at diagnosis.
Significant gastrointestinal bleeding, intrapulmonary hemorrhage, or intracranial hemorrhage occur 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.
Retinal hemorrhages are detected in 15% of patients.

13. Hematologic Findings
The anemia is usually 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.
The median presenting leukocyte count is about 15,000/L.

14. 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.

19. Management of Adult Patients with AML
History 
  Increasing fatigue or decreased exercise tolerance (anemia)
  Excess bleeding or bleeding from unusual sites (DIC, thrombocytopenia)
  Fevers or recurrent infections (granulocytopenia)
  Headache, vision changes, nonfocal neurologic abnormalities (CNS leukemia or bleed)
  Early satiety (splenomegaly)
  Family history of AML (Fanconi, Bloom, or Kostmann syndromes or ataxia-telangiectasia)

20. Physical Examination Performance status (prognostic factor)
Ecchymosis and oozing from IV sites (DIC, possible acute promyelocytic leukemia)
Fever and tachycardia (signs of infection)
Poor dentition, dental abscesses
Skin infiltration or nodules (leukemia infiltration, most common in monocytic leukemia)
Lymphadenopathy, splenomegaly, hepatomegaly

21. Laboratory and Radiologic Studies
 CBC with manual differential cell count
Chemistry tests (electrolytes, creatinine, BUN, calcium, phosphorus, uric acid, hepatic enzymes, bilirubin, LDH, amylase, lipase)
Clotting studies (prothrombin time, partial thromboplastin time, fibrinogen, D-dimer)
  Viral serologies (CMV, HSV-1, varicella-zoster)
 RBC type and screen
 HLA typing for potential allogeneic HSCT
Bone marrow aspirate and biopsy (morphology, cytogenetics, flow cytometry.

23. Treatment of Adults with AML
Class of Drugs
Examples of Agents in Class
Tyrosine kinase inhibitors
PKC412, MLN518, SU11248, CHIR-258, imatinib (STI571, Gleevec), dasatinib, AMN107
Demethylating agents
Decitabine, 5-azacytidine
Histone deacetylase inhibitors
Suberoylanilide hydroxamic acid (SAHA), MS275, LBH589, valproic acid
Heavy metals
Arsenic trioxide
Farnesyl transferase inhibitors
R115777, SCH66336
HSP-90 antagonists
17-allylaminogeldanamycin (17-AAG), DMAG, or derivatives
Cell cycle inhibitors
Flavopiridol, CYC202 (R-Roscovitine), SNS-032
Nucleoside analogues
Clofarabine, troxacitabine
Humanized antibodies
Anti-CD33 (SGN33), anti-KIR
Toxin-conjugated antibodies
Gemtuzumab ozogamicin
Proteasome inhibitors
Bortezomib
Aurora inhibitors
AZD1152, MLN-8237, AT9283
Immunomodulatory
Lenalidomide, IL-2, histamine dihydrochloride

24. THE END