Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Clinical presentation consisting of fatigue, bleeding, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and infection is related to anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, and a lack of functional WBCs. The onset of symptoms takes days to weeks. Additional findings in AML may include gingival hypertrophy and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin infiltration (leukemia cutis). Diagnosis is via peripheral blood smear and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones-marrow biopsy examination (shows myeloblasts). The precursor cells contain Auer rods. Immunophenotyping, histochemistry, and genetic analysis all aid in identifying and guiding the treatment of AML. Management is chemotherapy administered in phases (induction, consolidation, and maintenance) based on subtypes. Prognosis varies according to the age of onset and type of leukemia.

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Overview

Definition

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the pathological proliferation of myeloid precursor cells in the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow and subsequent displacement of other blood cell precursors.

Classification

The World Health Organization (WHO) classification system is based on multiple factors, including morphology, genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics, and clinical features:

  • AML with recurrent genetic abnormalities
  • AML with myelodysplasia-related changes 
  • Therapy-related AML and myelodysplastic syndrome
  • AML not otherwise specified
  • Myeloid sarcoma
  • Myeloid proliferations related to Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down Syndrome

Epidemiology and Etiology

Epidemiology

  • AML is mostly seen in adults:
    • Mean age of onset: 65 years old
    • United States incidence rate: 20 cases per 100,000 in patients > 65 years of age
  • Seen in children, but less frequently (accounts for 10% of acute childhood leukemias) 
  • Accounts for 1% of adult cancer-related deaths in the United States
  • Slightly higher incidence in men and nonHispanic whites

Etiology

  • May be primary (new malignancy) or secondary (occurring after chemotherapy or radiation therapy for a different type of cancer)
  • Increased risk in the following conditions:
    • Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down Syndrome
    • Fanconi anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Bloom syndrome
  • Ionizing radiation
  • Chemical exposure (e.g., benzene, alkylating agents for another cancer)
  • Preleukemic hematopoietic disorders:
    • Myelodysplastic syndromes Myelodysplastic Syndromes Myelodysplastic syndromes (MDS) are a group of clonal neoplasms with maturation defects characterized by dysplasia, cytopenia, and immature bone marrow precursors. Myelodysplastic syndromes can be idiopathic, or secondary to various injurious exposures such as cytotoxic chemotherapy, ionizing radiation, or environmental toxins. Myelodysplastic Syndromes
    • Aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia
    • Myeloproliferative disorders

Pathophysiology

Hematopoiesis

Hematopoiesis begins with a hematopoietic stem cell, which is prompted to divide and differentiate with appropriate chemical stimuli (hemopoietic growth factors).

  • Lymphoid stem cells give rise to lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes:
    • T cell
    • B cell
    • Natural killer (NK) cells
  • Myeloid stem cells differentiate into platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets, erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes, granulocytes (neutrophils, basophils, eosinophils), and monocytes:
    • IL-3 stimulates the differentiation of multipotent hematopoietic stem cells into myeloid progenitor cells.
    • Granulocyte-macrophage colony-stimulating factor (GM-CSF) → differentiation from myeloid progenitors to granulocytes (neutrophils) and monocytes 
    • IL-5 → differentiation to eosinophils
    • Thrombopoietin (TPO) → differentiation to thrombocytes ( platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets)
    • EPO → differentiation to erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes (RBCs)
Bone marrow hematopoiesis

Bone-marrow hematopoiesis: proliferation and differentiation of the formed elements of blood.
CFU-GEMM: colony-forming unit–granulocyte, erythrocyte, monocyte, megakaryocyte
CFU-GM: colony-forming unit–granulocyte-macrophage
GM-CSF: granulocyte-macrophage colony-stimulating factor
M-CSF: macrophage colony-stimulating factor
G-CSF: granulocyte colony-stimulating factor
NK: natural killer
TPO: thrombopoietin

Image by Lecturio. License: CC BY-NC-SA 4.0

Pathogenesis

  • In AML, myeloid differentiation is impeded by mutations, which affect the development of precursor cells.
  • AML is associated with specific chromosomal alterations such as:
    • Translocation: t(8;21) disruption of the RUNX1 gene, which is required for normal hematopoiesis
    • Inversion: inv(16) disruption of the CBFB gene
    • Deletion: del(5q)
  • Abnormal cells proliferate but cannot differentiate into mature blood cells:
    • Monoclonal leukemic cells occupy the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones-marrow space and suppress normal hematopoiesis → leukopenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, and anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Dysfunctional and immature blasts enter the bloodstream and infiltrate other organs.

Clinical Presentation

General clinical features

  • Some patients are asymptomatic and present with only laboratory irregularities. 
  • Signs and symptoms related to hematologic abnormalities:
    • Anemia:
      • Fatigue, tachycardia
      • Pallor
    • Thrombocytopenia:
      • Bleeding
      • Petechiae
      • Ecchymoses
    • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia:
      • Fever
      • Recurrent infections
    • Leukostasis or hyperleukocytosis:
      • AML with neurologic manifestations and respiratory problems or myeloblasts > 50,000/μL, OR
      • AML and myeloblasts > 100,000/μL
  • Additional signs of AML:
    • Leukemia cutis (purple/gray-blue papular or nodular skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions) and myeloid sarcoma: represent leukemic skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin infiltration
    • Sweet syndrome: tender nodules and plaques
    • Gingival hypertrophy: infiltration seen in acute monocytic leukemia and acute myelomonocytic leukemia 
    • Bleeding or bruising: signs of DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation in acute promyelocytic leukemia
    • Visual field changes, papilledema, retinal infiltrates, and cranial nerve palsy: seen in AML seeding the CNS 
  • Organomegaly (hepatomegaly and splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly) seen in approximately 10% of patients
  • Lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy: rare

Acute lymphoblastic leukemia Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma, the most common forms of cancer affecting children, show the presence of increased lymphoblasts. Acute Lymphoblastic Leukemia (ALL) versus acute myeloid leukemia

Table: ALL versus AML
Features ALL AML
Population More common in children More common in adults
Common characteristics
  • Symptoms of anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, neutropenia (from depressed marrow function)
  • Abrupt onset (days to weeks)
  • CNS involvement
Clinical findings
  • Hepato- and splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
  • Lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
  • Bone pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain more common
  • Can affect testes
  • Can have mediastinal mass
  • Organomegaly less frequent
  • Lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy rare
  • Leukemia cutis
  • Gingival hypertrophy
  • DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation

Diagnosis

Diagnostic findings

  • CBC with differential:
    • Anemia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
    • Varying WBCs
  • Peripheral smear: 
    • Myeloblasts:
      • More voluminous cytoplasm
      • Large nuclei
      • Prominent nucleoli
      • Delicate/fine nuclear chromatin
      • Peroxidase-positive azurophilic granules 
    • Auer rods:
      • Pink/red, needle- or rod-like or granular structures in the cytoplasm
      • Seen in many AML forms especially in t(15;17)-acute promyelocytic leukemia
      • Rich in lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes/myeloperoxidase (MPO) 
    • Most myeloblasts are positive for MPO, which confirms myeloid lineage, but some AML are negative.
  • Bone-marrow examination: 
    • Usually hypercellular: > 20% myeloblasts (some forms are exceptional)
    • A dry tap indicates extensive fibrosis or hypercellular (packed) bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow.
  • Cytochemistry:
    • Sudan Black B: positive
    • MPO: positive 
    • TdT: negative
  • Immunophenotyping: common antigens include CD13, CD33, CD117, HLA-DR.
  • Genetic analysis: identifies mutations
Aml bone marrow findings of auer rods

Acute myeloid leukemia (AML): bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones-marrow findings of Auer rods (pink, needle-like structures in the cytoplasm) in a myeloblast

Image: “Auer Rods in Leukemic Blast” by Ed Uthman. License: CC BY 2.0

Acute lymphoblastic leukemia Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma, the most common forms of cancer affecting children, show the presence of increased lymphoblasts. Acute Lymphoblastic Leukemia versus acute myeloid leukemia

Table: ALL versus AML
Features ALL AML
Laboratory findings Anemia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, varying WBCs
Peripheral smear or bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones-marrow examination (morphology) Lymphoblasts:
  • Large nuclei
  • Condensed chromatin
  • Inconspicuous nucleoli
  • Scant basophilic cytoplasm
Myeloblasts:
  • Delicate nuclear chromatin
  • Prominent nucleoli (2–4)
  • More voluminous cytoplasm
  • Fine azurophilic-cytoplasmic granules
  • Auer rods
Cytochemistry
  • PAS: positive
  • MPO: negative
  • TdT: positive
  • PAS: negative
  • Sudan Black B: positive
  • MPO: positive
  • TdT: negative
Immunophenotyping
  • B-ALL/LBL: CD10, CD19, CD20, CD24, cytoplasmic CD22, and CD-79a
  • T-ALL/LBL: CD2–8
CD13, CD33, CD117, HLA-DR

Management

Treatment

Chemotherapy requires pretreatment evaluation, including patient goals and preferences, comorbidities, physical functioning, and prognostic factors related to AML type.

  • Intensive remission induction:
    • Goal: remission
    • Cytarabine + daunorubicin or idarubicin
    • Additional targeted agent depending on the specific mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (e.g., midostaurin for AML with FLT3 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations)
    • Associated with multiple adverse effects, which may require prolonged hospitalization: 
      • Bleeding
      • Infection
      • Cytopenias
      • Tumor-lysis syndromes
      • Electrolyte abnormalities
    • Frail patients may be given lower-intensity treatment.
  • Consolidation:
    • Goal: reduce risk of relapse
    • Additional courses of chemotherapy (high-dose cytarabine)
    • Hematopoietic cell transplant (HCT) for high-risk disease or poor prognosis
  • Maintenance:
    • Goal: maintain remission
    • Low-dose chemotherapy (non-myelosuppressive) and/or a targeted agent
  • Different treatment for acute promyelocytic leukemia (APL) (formerly known as M3):
    • APL is the most malignant form of AML (a medical emergency):
      • Without treatment, median survival is < 1 month.
      • Presents with bleeding ( DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation), and low WBCs and blasts
      • Distinguished by responsiveness to treatment with all-trans retinoic acid
      • Chromosomal translocation t(15;17) leads to a fusion protein, which functions as a receptor (retinoic acid receptor alpha (RARα))
    • Induction therapy includes all-trans retinoic acid + arsenic trioxide 
  • Allogeneic HCT: preferred for patients with a poor prognosis, especially < 60 years of age

Supportive therapy and monitoring

  • Monitor bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones-marrow response.
  • Monitor for chemotherapy side effects (e.g., vomiting) and treat accordingly.
  • Red-cell and platelet transfusions for anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
  • Granulocyte colony-stimulating factor (G-CSF) for neutropenia
  • Dietary modification (neutropenic diet)
  • American Society of Clinical Oncology recommends:
    • Prophylactic antibacterial and antifungal therapy 
    • Prophylactic antiviral therapy (for Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus core antibody and HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2)
  • Surveillance monitoring for:
    • Relapse: AML recurs after complete remission
    • Refractory AML: no full response with remission induction therapy

Prognosis

  • AML survival rate in children: approximately 65%–70% (lower than ALL)
  • AML survival rate in adults (5-year survival decreases as age increases):
    • 25–39 years old: 49%
    • 40–59 years old: 33%
    • 60–69 years old: 13%
    • 70–79 years old: 3%
    • > 80 years old: 0%
  • Better prognosis:
    • < 50 years old
    • Good functional capacity/performance status (Karnofsky score > 60%)
    • Multidrug resistance (MDR1)-negative phenotype
    • No prior hematologic disorder, radiation therapy, or chemotherapy
    • t(8;21), inv(16)/t(16;16), t(15;17)
    • NPM1 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations, CEBPA mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
  • Worse prognosis:
    • Age > 60 years old
    • Poor functional capacity/performance status (Karnofsky score < 60%)
    • MDR1-positive phenotype
    • Prior hematologic disorder or therapy-related AML
    • Complex karyotypic abnormalities (e.g., 3q26 aberrations, t(6;9), -5, -7) 
    • Certain mutations: FLT3 internal tandem duplication, IDH1, IDH2

Acute lymphoblastic leukemia Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma, the most common forms of cancer affecting children, show the presence of increased lymphoblasts. Acute Lymphoblastic Leukemia versus acute myeloid leukemia

Table: ALL versus AML
Management ALL AML
Induction
  • Vincristine, corticosteroids, asparaginase
  • ± Anthracycline (doxorubicin or daunorubicin)
  • Cytarabine + daunorubicin or idarubicin
  • Additional targeted agent (based on mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations)
Consolidation Options:
  • Cytarabine
  • Methotrexate
  • Anthracyclines
  • Alkylating agents
  • Epipodophyllotoxins
Additional chemotherapy (cytarabine)
Maintenance
  • Oral 6-MP daily
  • Methotrexate weekly
  • Periodic vincristine, prednisone, and intrathecal therapy
Non-myelosuppressive chemotherapy and/or a targeted agent
Additional treatment
  • TKI (e.g., imatinib) given for t(9;22) translocation (Philadelphia chromosome)
  • CNS preventive therapy
Acute promyelocytic leukemia:
  • Medical emergency!
  • Give ATRA + arsenic trioxide.
Hematopoietic cell transplantation For those with a poor prognosis
Prognosis
  • Better prognosis if < 50 years old
  • Prognosis affected by associated mutations

Differential Diagnosis

  • Acute lymphoblastic leukemia Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma, the most common forms of cancer affecting children, show the presence of increased lymphoblasts. Acute Lymphoblastic Leukemia: hematologic neoplasms characterized by uncontrolled proliferation of lymphocytic precursors. Acute lymphoblastic leukemia Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma, the most common forms of cancer affecting children, show the presence of increased lymphoblasts. Acute Lymphoblastic Leukemia is the most common childhood cancer. Normal marrow is replaced by malignant cells, followed by the circulation of immature WBCs. The clinical presentation consists of fatigue, bleeding, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and infection (related to anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, and lack of functional WBCs), occurring in days to weeks. Mass effects of malignant infiltration (in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen) are common. Diagnosis is by peripheral blood smear and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones-marrow biopsy showing lymphoblasts. In contrast, AML is the proliferation of myeloblasts. Treatment is mainly chemotherapy. Acute lymphoblastic leukemia Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma, the most common forms of cancer affecting children, show the presence of increased lymphoblasts. Acute Lymphoblastic Leukemia generally carries a better prognosis than AML.
  • Myelodysplastic syndrome (MDS): a group of clonal neoplasms with maturation defects, characterized by dysplasia, cytopenias, and immature bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones-marrow precursors. Patients present near 70 years of age with symptoms of anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, neutropenia, or thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia. The bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones-marrow evaluation shows cytopenia, dysplasia in 1 or more lineage, and blast cells in < 20% of marrow cellularity, which helps distinguish MDS. The increased cumulative risk of transformation to AML varies depending on the MDS subtype. Acute myeloid leukemia developing from MDS carries a poor prognosis.
  • Primary myelofibrosis Primary myelofibrosis Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by chronic myeloproliferation with nonclonal fibroblastic deposition, resulting in bone marrow fibrosis. The abnormality stems from genetic mutations of the hematopoietic stem cells (typically, JAK2 mutation). Primary symptoms are anemia and extramedullary hematopoiesis,. Primary Myelofibrosis: a neoplasm characterized by chronic myeloproliferation with nonclonal deposition of fibroblasts, resulting in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones-marrow fibrosis. The condition is associated with a genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (typically JAK2 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations). Clinical findings include severe fatigue, weight loss, and hepatosplenomegaly. Laboratory studies include cytopenia and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones-marrow studies with a dry tap (representing extensive fibrosis), and may be like AML. Primary myelofibrosis Primary myelofibrosis Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by chronic myeloproliferation with nonclonal fibroblastic deposition, resulting in bone marrow fibrosis. The abnormality stems from genetic mutations of the hematopoietic stem cells (typically, JAK2 mutation). Primary symptoms are anemia and extramedullary hematopoiesis,. Primary Myelofibrosis can transform to AML, which is often the cause of death.
  • Leukemoid reaction: a WBC count > 50,000/μL from causes other than leukemia. Neutrophilia and prominent left shift, usually in response to infection, are typical. Findings include toxic granulation in the neutrophils and (most importantly) the presence of an obvious cause for the neutrophilia. Cytogenetic or molecular testing also distinguishes AML. Management is supportive with treatment of the underlying etiology and leukapheresis if hyperviscosity is present.

References

  1. Arber, D.A., et al. (2016). The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 127(20), 2391–2405. Retrieved April 26, 2021, from https://doi.org/10.1182/blood-2016-03-643544
  2. Blum, W., Bloomfield, C.D. (2018). Acute myeloid leukemia. In Jameson, J., et al. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192017732
  3. Gajendra, S. (2016). Flow cytometry in Acute Leukemia. Clin Oncol. 1(1166). https://www.clinicsinoncology.com/pdfs_folder/cio-v1-id1166.pdf
  4. Hoelzer, D. (2018). Acute lymphoid leukemia. In Jameson J., et al. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192017841
  5. Horton, T.M., Steuber, P., Aster, J.C. (2021). Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children. UpToDate. Retrieved April 27, 2021, from https://www.uptodate.com/contents/overview-of-the-clinical-presentation-and-diagnosis-of-acute-lymphoblastic-leukemia-lymphoma-in-children
  6. Kolitz, J.E. (2021). Overview of acute myeloid leukemia in adults. UpToDate. Retrieved June 8, 2021, from https://www.uptodate.com/contents/overview-of-acute-myeloid-leukemia-in-adults
  7. Larson, R. (2021). Initial treatment of acute promyelocytic leukemia in adults. UpToDate. Retrieved June 9, 2021, from https://www.uptodate.com/contents/initial-treatment-of-acute-promyelocytic-leukemia-in-adults
  8. Larson, R. (2021). Induction therapy for acute myeloid leukemia in medically-fit adults. UpToDate. Retrieved June 9, 2021, from https://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-medically-fit-adults
  9. Larson, R., Klepin, H. (2021). Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults. UpToDate. Retrieved June 9, 2021, from https://www.uptodate.com/contents/pretreatment-evaluation-and-prognosis-of-acute-myeloid-leukemia-in-older-adults
  10. Roberts, K. G. (2018). Genetics and prognosis of ALL in children vs. adults. Hematology. American Society of Hematology. Education Program. 2018(1), 137–145. https://doi.org/10.1182/asheducation-2018.1.137
  11. Schiffer, C. (2021). Prognosis of acute myeloid leukemia. UpToDate. Retrieved June 9, 2021, from https://www.uptodate.com/contents/prognosis-of-acute-myeloid-leukemia

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