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