Acute Myeloid Leukemia

Overview

Definition

Acute myeloid leukemia (AML) is a hematologic malignancy Malignancy Hemothorax characterized by the pathological proliferation of myeloid precursor cells in the bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis and subsequent displacement Displacement The process by which an emotional or behavioral response that is appropriate for one situation appears in another situation for which it is inappropriate. Defense Mechanisms 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 (Trisomy 21)

Epidemiology and Etiology

Epidemiology

• AML is mostly seen in adults:
  • Mean Mean Mean is the sum of all measurements in a data set divided by the number of measurements in that data set. Measures of Central Tendency and Dispersion age of onset: 65 years old
  • United States incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency rate: 20 cases per 100,000 in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship > 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 Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency in men and nonHispanic whites

Etiology

• May be primary (new malignancy Malignancy Hemothorax) or secondary (occurring after chemotherapy Chemotherapy Osteosarcoma or radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma 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 (Trisomy 21)
  • Fanconi anemia Fanconi anemia Congenital disorder affecting all bone marrow elements, resulting in anemia; leukopenia; and thrombopenia, and associated with cardiac, renal, and limb malformations as well as dermal pigmentary changes. Spontaneous chromosome breakage is a feature of this disease along with predisposition to leukemia. There are at least 7 complementation groups in Fanconi anemia: fanca, fancb, fancc, fancd1, fancd2, fance, fancf, fancg, and fancl. Aplastic Anemia
  • Bloom syndrome
• Ionizing radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
• 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 The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis

Hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and 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: Histology:
  • 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: Histology, 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: Histology, granulocytes Granulocytes Leukocytes with abundant granules in the cytoplasm. They are divided into three groups according to the staining properties of the granules: neutrophilic, eosinophilic, and basophilic. Mature granulocytes are the neutrophils; eosinophils; and basophils. White Myeloid Cells: Histology ( neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation, basophils Basophils Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. Innate Immunity: Phagocytes and Antigen Presentation, eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation), and monocytes Monocytes Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. Innate Immunity: Phagocytes and Antigen Presentation:
  • IL-3 stimulates the differentiation of multipotent hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis into myeloid progenitor cells.
  • Granulocyte-macrophage colony-stimulating factor ( GM-CSF GM-CSF An acidic glycoprotein of mw 23 kda with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. White Myeloid Cells: Histology) → differentiation from myeloid progenitors to granulocytes Granulocytes Leukocytes with abundant granules in the cytoplasm. They are divided into three groups according to the staining properties of the granules: neutrophilic, eosinophilic, and basophilic. Mature granulocytes are the neutrophils; eosinophils; and basophils. White Myeloid Cells: Histology ( neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation) and monocytes Monocytes Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. Innate Immunity: Phagocytes and Antigen Presentation 
  • IL-5 → differentiation to eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation
  • Thrombopoietin Thrombopoietin A humoral factor that stimulates the production of thrombocytes (blood platelets). Thrombopoietin stimulates the proliferation of bone marrow megakaryocytes and their release of blood platelets. The process is called thrombopoiesis. Platelets: Histology (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: Histology)
  • EPO EPO Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. Erythrocytes: Histology → 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: Histology ( RBCs RBCs 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: Histology)

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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, which is required for normal hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis
  • Inversion: inv(16) disruption of the CBFB gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
  • Deletion: del(5q)
• Abnormal cells proliferate but cannot differentiate into mature blood cells:
  • Monoclonal leukemic cells occupy the bone-marrow space and suppress normal hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and 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 and Types
  • Dysfunctional and immature blasts Blasts Injuries resulting when a person is struck by particles impelled with violent force from an explosion. Blast causes pulmonary contusion and hemorrhage, laceration of other thoracic and abdominal viscera, ruptured ear drums, and minor effects in the central nervous system. Blunt Chest Trauma enter the bloodstream and infiltrate other organs.

Clinical Presentation

General clinical features

• Some patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are asymptomatic and present with only laboratory irregularities. 
• Signs and symptoms related to hematologic abnormalities:
  • 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 Types:
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
    • Pallor
  • 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:
    • Bleeding
    • Petechiae Petechiae Primary Skin Lesions
    • 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 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
    • Recurrent infections Recurrent infections Common Variable Immunodeficiency (CVID)
  • 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. Skin: Structure and Functions 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. Skin: Structure and Functions infiltration
  • Sweet syndrome Sweet syndrome Condition characterized by large, rapidly extending, erythematous, tender plaques on the upper body usually accompanied by fever and dermal infiltration of neutrophilic leukocytes. It occurs mostly in middle-aged women, is often preceded by an upper respiratory infection, and clinically resembles erythema multiforme. Sweet syndrome is associated with leukemia. Hematopoietic Growth Factors: tender nodules and plaques
  • Gingival hypertrophy Hypertrophy General increase in bulk of a part or organ due to cell enlargement and accumulation of fluids and secretions, not due to tumor formation, nor to an increase in the number of cells (hyperplasia). Cellular Adaptation: 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 Visual Field The Visual Pathway and Related Disorders changes, papilledema Papilledema Swelling of the optic disk, usually in association with increased intracranial pressure, characterized by hyperemia, blurring of the disk margins, microhemorrhages, blind spot enlargement, and engorgement of retinal veins. Chronic papilledema may cause optic atrophy and visual loss. Idiopathic Intracranial Hypertension, retinal infiltrates, and cranial nerve palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies: seen in AML seeding Seeding The local implantation of tumor cells by contamination of instruments and surgical equipment during and after surgical resection, resulting in local growth of the cells and tumor formation. Grading, Staging, and Metastasis 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 Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
• 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

Diagnosis

Diagnostic findings

• CBC with differential:
  • 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 Types, 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 Chromatin The material of chromosomes. It is a complex of dna; histones; and nonhistone proteins found within the nucleus of a cell. DNA Types and Structure
    • Peroxidase-positive azurophilic granules Azurophilic granules Myeloperoxidase Deficiency 
  • 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 Dry Tap Hairy Cell Leukemia indicates extensive fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans or hypercellular (packed) bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis.
• Cytochemistry:
  • Sudan Black B: positive
  • MPO: positive 
  • TdT TdT Acute Lymphoblastic Leukemia: negative
• Immunophenotyping Immunophenotyping Process of classifying cells of the immune system based on structural and functional differences. The process is commonly used to analyze and sort T-lymphocytes into subsets based on CD antigens by the technique of flow cytometry. Non-Hodgkin Lymphomas: common antigens include CD13, CD33, CD117, HLA-DR.
• Genetic analysis: identifies mutations

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

Management

Treatment

Chemotherapy Chemotherapy Osteosarcoma requires pretreatment evaluation, including patient goals and preferences, comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus, physical functioning, and prognostic factors related to AML type.

• Intensive remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches induction:
  • Goal: remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches
  • Cytarabine Cytarabine A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the s phase of the cell cycle. It also has antiviral and immunosuppressant properties. Antimetabolite Chemotherapy + daunorubicin Daunorubicin A very toxic anthracycline aminoglycoside antineoplastic isolated from streptomyces peucetius and others, used in treatment of leukemia and other neoplasms. Antitumor Antibiotics or idarubicin Idarubicin An orally administered anthracycline antineoplastic. The compound has shown activity against breast neoplasms; lymphoma; and leukemia. Antitumor Antibiotics
  • 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 Prolonged Hospitalization Surgical Infections: 
    • Bleeding
    • Infection
    • Cytopenias Cytopenias IPEX Syndrome
    • Tumor-lysis syndromes
    • Electrolyte abnormalities
  • Frail patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may be given lower-intensity treatment.
• Consolidation Consolidation Pulmonary Function Tests:
  • Goal: reduce risk of relapse Relapse Relapsing Fever
  • Additional courses of chemotherapy Chemotherapy Osteosarcoma (high-dose cytarabine Cytarabine A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the s phase of the cell cycle. It also has antiviral and immunosuppressant properties. Antimetabolite Chemotherapy)
  • Hematopoietic cell transplant (HCT) for high-risk disease or poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
• Maintenance:
  • Goal: maintain remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches
  • Low-dose chemotherapy Chemotherapy Osteosarcoma (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 Blasts Injuries resulting when a person is struck by particles impelled with violent force from an explosion. Blast causes pulmonary contusion and hemorrhage, laceration of other thoracic and abdominal viscera, ruptured ear drums, and minor effects in the central nervous system. Blunt Chest Trauma
    • Distinguished by responsiveness to treatment with all-trans retinoic acid
    • Chromosomal translocation t(15;17) leads to a fusion protein Fusion protein Proteins that catalyze membrane fusion. Measles Virus, which functions as a receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (retinoic acid receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors alpha (RARα))
  • Induction therapy includes all-trans retinoic acid + arsenic Arsenic A shiny gray element with atomic symbol as, atomic number 33, and atomic weight 75. It occurs throughout the universe, mostly in the form of metallic arsenides. Most forms are toxic. According to the fourth annual report on carcinogens, arsenic and certain arsenic compounds have been listed as known carcinogens. Metal Poisoning (Lead, Arsenic, Iron) trioxide 
• Allogeneic HCT: preferred for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with a poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas, especially < 60 years of age

Supportive therapy and monitoring

• Monitor bone-marrow response.
• Monitor for chemotherapy Chemotherapy Osteosarcoma side effects (e.g., vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia) 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 Types 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 Granulocyte colony-stimulating factor A glycoprotein of mw 25 kda containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. White Myeloid Cells: Histology (G-CSF) for 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
• Dietary modification (neutropenic diet)
• American Society of Clinical Oncology recommends:
  • Prophylactic antibacterial Antibacterial Penicillins and antifungal Antifungal Azoles therapy 
  • Prophylactic antiviral Antiviral Antivirals for Hepatitis B therapy (for Hepatitis B core antibody Hepatitis B core antibody Hepatitis B Virus 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 and 2)
• Surveillance Surveillance Developmental Milestones and Normal Growth monitoring for:
  • Relapse Relapse Relapsing Fever: AML recurs after complete remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches
  • Refractory AML: no full response with remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches induction therapy

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• 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 Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas:
  • < 50 years old
  • Good functional capacity/performance status (Karnofsky score > 60%)
  • Multidrug resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing (MDR1)-negative phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics
  • No prior hematologic disorder, radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy, or chemotherapy Chemotherapy Osteosarcoma
  • 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 Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas:
  • Age > 60 years old
  • Poor functional capacity/performance status (Karnofsky score < 60%)
  • MDR1-positive phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics
  • 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

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

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 Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors 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 Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment of immature WBCs. The clinical presentation consists of fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, 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 and Types, 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 Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast 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. Bones: Structure and Types, 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: Anatomy, 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: Anatomy) are common. Diagnosis is by peripheral blood smear Peripheral Blood Smear Anemia: Overview and Types and bone-marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma showing lymphoblasts Lymphoblasts Lymphocytosis. In contrast, AML is the proliferation of myeloblasts. Treatment is mainly chemotherapy Chemotherapy Osteosarcoma. 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 Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas than AML.
• Myelodysplastic syndrome ( MDS MDS 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): a group of clonal neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors with maturation defects, characterized by dysplasia, cytopenias Cytopenias IPEX Syndrome, and immature bone-marrow precursors. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 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 and Types, 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, 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-marrow evaluation shows cytopenia, dysplasia in 1 or more lineage, and blast cells in < 20% of marrow cellularity, which helps distinguish MDS MDS 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. The increased cumulative risk of transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology to AML varies depending on the MDS MDS 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 subtype. Acute myeloid leukemia developing from MDS MDS 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 carries a poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas.
• 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 Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Sarcoidosis, resulting in bone-marrow fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans. 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 Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, and hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus. Laboratory studies include cytopenia and bone-marrow studies with a dry tap Dry Tap Hairy Cell Leukemia (representing extensive fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans), 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 Leukemoid reaction A peripheral blood picture resembling that of leukemia or indistinguishable from it on the basis of morphologic appearance alone. Shigella: a WBC count > 50,000/μL from causes other than leukemia. Neutrophilia and prominent left shift Left Shift Yersinia pestis/Plague, usually in response to infection, are typical. Findings include toxic granulation Granulation Wound Healing in the neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation 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 Hyperviscosity Hypercoagulable States is present.