acute myeloid leukemia (aml) dr. ravi kant assistant professor department of general medicine
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Acute Myeloid Leukemia (AML)
Dr. Ravi Kant Assistant Professor
Department of General Medicine
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.
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.
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);
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 myelofibrosisMyeloid sarcoma
Myeloid proliferations related to Down syndrome
Transient abnormal myelopoiesis Myeloid leukemia associated with Down
syndromeBlastic plasmacytoid dendritic cell
neoplasmAcute 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, Mixed phenotype acute leukemia,
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
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.
Molecular Prognostic Markers in AMLMarker Marker Location Prognostic Impact
NPM1 mutation 5q35 Favorable
CEBPA mutation 19q13.1 Favorable
FLT3-ITD 13q12 Adverse
WT1 mutation 11p13 Adverse
KIT mutation 4q11-q12 Adverse
BAALC overexpression
8q22.3 Adverse
ERG overexpression 21q22.3 Adverse
MN1 overexpression 22q12.1 Adverse
EVI1 overexpression 3q26 Adverse
Clinical PresentationSymptomsPatients 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.
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.
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.
Hematologic FindingsThe 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.
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.
Management of Adult Patients with AMLHistory 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)
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 abscessesSkin infiltration or nodules (leukemia
infiltration, most common in monocytic leukemia)
Lymphadenopathy, splenomegaly, hepatomegaly
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.
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
THE END
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