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. In ALL/LBL, lymphoblasts replace the normal marrow, eventually entering the circulation and infiltrating other organs. The clinical presentation includes 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 infections, all of which are 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 the lack of functional WBCs. The onset of symptoms takes 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; thus, hepatosplenomegaly and 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 are seen. Diagnosis is by peripheral blood smear examination and 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 biopsy, which show the presence of lymphoblasts. Immunophenotyping, histochemistry, and genetic studies aid in the classification and guidance of treatment. Management is mainly by chemotherapy, which is administered in phases (induction, consolidation, and maintenance). Prognosis varies according to the age of onset and type of leukemia. The cure rate in children is 85%.

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Overview

Definition

Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the pathological proliferation of lymphoid precursor cells (primarily the B and T cell lineages)
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, with subsequent displacement of other blood cell precursors.

Classification

WHO system 2016 (supersedes the French-American-British classification):

  • B cell ALL/LBL (B-ALL/LBL) subclassified based on molecular and cytogenetic features:
    • B-ALL/LBL with recurrent genetic abnormalities:
      • t(12;21)(p13.2;q22.1): most common genetic lesion in childhood ALL/LBL
      • t(9;22); BCR-ABL1 fusion gene (Philadelphia chromosome)
      • t(v;11q23); KMT2A rearranged
      • t(12;21)(p13.2;q22.1); ETV6-RUNX1
      • Hyperdiploidy (> 50 chromosomes)
      • Hypodiploidy (< 46 chromosomes)
      • t(5;14)(q31.1;q32.3); IL3-IGH
      • t(1;19)(q23;p13.3); TCF3-PBX1
    • B-ALL/LBL, not otherwise specified
  • T cell ALL/LBL (T-ALL/LBL)

Epidemiology and Etiology

Epidemiology

  • Most common childhood cancer:
    • About 85% of cases manifest in childhood.
    • In children, it is 5 times more common than acute myeloid leukemia 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. Acute Myeloid Leukemia ( AML AML 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. Acute Myeloid Leukemia).
  • Affects more boys than girls
  • Peak incidence: 
    • 2–5 years of age
    • Again at > 65 years of age
  • In the US: incidence of 3.4 cases in children per 100,000 population
  • Worse prognosis in adults

Etiology

  • Risk factors: 
    • Ionizing radiation
    • Chemical exposure (benzene, prior chemotherapy)
    • Human T cell leukemia virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview I (HTLV-I), endemic in Japan and the Caribbean, leads to adult T cell leukemia/lymphoma.
  • Increased risk in the following conditions with genetic abnormalities:
    • 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
    • Bloom syndrome
    • Ataxia-telangiectasia Ataxia-telangiectasia Ataxia-telangiectasia, also known as Louis-Bar syndrome, is a neurocutaneous syndrome, which involves multiple systems but mainly affects the neurological system. Ataxia-telangiectasia is an autosomal recessive genetic disorder caused by a mutation in the ATM gene (ATM serine/threonine kinase or the ataxia-telangiectasia mutated gene). Ataxia-telangiectasia
    • Neurofibromatosis

Mnemonic

  • To recall the differentiation of ALL versus chronic leukemia, “remember your ABCs”:
    • Acute
    • Blasts predominate
    • Common in Children
    • Drastic course
    • Elderly (2nd peak incidence)
    • Few mature WBCs cause Fevers
  • For chronic, it is the opposite:
    • Mature cells predominate
    • Presents in middle-aged and older adults
    • Less debilitating course
    • Elevated WBCs and fewer instances of 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/infections

Pathophysiology

Hematopoiesis

Hematopoiesis starts 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 cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
    • B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells
    • Natural killer (NK) cells
  • Myeloid stem cells eventually 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:
In CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia, there is sustained proliferation of cells in the granulocytic line (myeloblasts → neutrophils, basophils, eosinophils). Both mature and maturing cells are seen; thus, there are cells that are only partially effective.
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

  • Genetic changes affect the expression and function of transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription factors in stem cell maturation.
  • The changes include:
    • Gene mutations affecting PAX5, ETV6
    • Polymorphic variants of ARID5B, CDKN2A, and IKZF1
  • Hematopoietic progenitor cells do not differentiate into functional cells, leading to defective maturation of the lymphocyte precursors: 
    • B lineage: 85%
    • T lineage: 10%–15%
    • NK lineage: < 1%
  • In acute leukemias, abnormal cells proliferate but do not differentiate into mature blood cells:
    • Leukemic cells occupy 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 space, suppressing 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 eventually enter the bloodstream, infiltrating other organs. 

Clinical Presentation

General clinical features

  • About 6% of patients are asymptomatic.
  • 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 (most common findings on presentation) can manifest as:
    • Abdominal 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
    • Abdominal distension
    • Anorexia
    • Weight loss
  • Lymphadenopathy (nontender, firm, rubbery)
  • Fever
  • 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:
    • Associated with 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 infiltration 
    • Children can present with a limp or difficulty in bearing weight.
  • Hematologic abnormalities:
    • Anemia:
      • Pallor
      • Tachycardia, fatigue
    • Thrombocytopenia:
      • Ecchymoses
      • Petechiae
    • WBC count may be normal, low, or high, but shows abnormal function and presents as:
      • Frequent or recurrent infections 
      • Fever
  • Less frequent: 
    • Headache from meningeal spread (< 5%)
    • Painless unilateral testicular enlargement (< 1%)
    • Mediastinal mass (associated with T-ALL/LBL): 
      • Can cause superior vena cava syndrome
      • Can lead to respiratory difficulty (from compression)

Acute lymphoblastic leukemia vs acute myeloid leukemia 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. Acute Myeloid Leukemia

Table: Acute lymphoblastic leukemia vs acute myeloid leukemia 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. Acute Myeloid Leukemia
Features Acute lymphoblastic leukemia Acute myeloid leukemia
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 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 (from depressed marrow function)
  • Abrupt onset (days to weeks)
  • CNS involvement
Clinical findings
  • 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
  • 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 (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: lymphoblasts
    • Scant basophilic cytoplasm (usually lacks granules)
    • Prominent nuclei
    • Inconspicuous/indistinct nucleoli
    • Condensed chromatin
  • Bone marrow examination: 
    • Hypercellular
    • Heavily packed lymphoblasts 
  • Cytochemistry:
    • PAS staining: often positive (some cells have PAS-positive granules)
    • Myeloperoxidase (MPO): negative 
    • Terminal deoxynucleotidyl transferase: positive
  • Immunophenotyping (using flow cytometry):
    • Characterizes antigens or markers on tumor cells:
      • B-ALL/LBL: Most are positive for CD10, CD19, CD20, CD24, cytoplasmic CD22, and CD-79a.
      • T-ALL/LBL: positive for CD3 (CD2–8 are seen); negative for B cell antigens
    • Aids in classification and determining treatment and prognosis
  • Genetic analysis:
    • Identifies mutations
    • Important in prognosis
Bone marrow smear from a patient with acute lymphoblastic leukemia

a: 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 smear from a patient with acute lymphoblastic leukemia (ALL), arrow pointing to lymphoblast
b: lymphoblast: large nucleus, scant cytoplasm

Image: “Segmentation of White Blood Cell From Acute Lymphoblastic Leukemia Images Using Dual-Threshold Method” by Li Y, Zhu R, Mi MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction L, Cao Y, Yao D. License: CC BY 4.0

Additional tests

  • Serum chemistry: may suggest tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome or other metabolic complications
  • Coagulation profile
  • Lumbar puncture:
    • To evaluate leukemic CNS involvement
    • All children must be evaluated prior to therapy, as CNS involvement affects management.
  • Imaging:
    • CT chest: evaluation of T-ALL/LBL (associated with mediastinal mass)
    • Echocardiogram or cardiac scan: pretreatment evaluation of cardiac function (as it can be adversely affected by chemotherapy)

Acute lymphoblastic leukemia vs acute myeloid leukemia 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. Acute Myeloid Leukemia

Table: Acute lymphoblastic leukemia vs acute myeloid leukemia 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. Acute Myeloid Leukemia
Features Acute lymphoblastic leukemia Acute myeloid leukemia
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 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 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
  • Terminal deoxynucleotidyl transferase: positive
  • PAS: negative
  • Sudan black B: positive
  • MPO: positive
  • Terminal deoxynucleotidyl transferase: negative
Immunophenotyping
  • B-ALL/LBL: CD10, CD19, CD20, CD24, cytoplasmic CD22 and CD-79a
  • T-ALL/LBL: CD2–8
CD13, CD33, CD117, HLA-DR
B-ALL/LBL: B cell acute lymphoblastic leukemia/lymphoma
T-ALL/LBL: T cell acute lymphoblastic leukemia/lymphoma
MPO: myeloperoxidase

Management

Treatment

Chemotherapy, which can span 2–3 years, is highly effective in young patients.

  • Induction therapy:
    • Initial chemotherapy is given:
      • To eradicate tumor cells (to < 5% blasts)
      • To achieve normal hematopoiesis 
    • Regimen:
      • Vincristine, corticosteroids, asparaginase 
      • With/without anthracycline (doxorubicin or daunorubicin)
    • Tyrosine kinase inhibitors (TKIs) are used in cases of t(9;22) translocation (Philadelphia chromosome). 
    • Adverse effects (from drug toxicity or rapid eradication of tumor cells) include:
      • Tumor lysis syndrome
      • Bleeding or thrombosis
      • Infection
      • Allergic reaction/anaphylaxis
      • Neuropathy (from vincristine)
      • Hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus-pituitary-adrenal gland suppression (from corticosteroids)
  • CNS prophylaxis:
    • Recommended in all children
    • Begins in the induction phase and administered throughout the treatment period
    • Protocols include:
      • Intrathecal chemotherapy 
      • With/without CNS radiotherapy (associated with cognitive impairment, decreased white matter volume, secondary brain tumors)
  • Consolidation
    • Further courses of chemotherapy to remove the remaining tumor cells
    • Goals:
      • To prevent regrowth
      • To decrease tumor burden
      • To reduce the risks from drug-resistant leukemic cells
    • Begins after complete remission is achieved
    • Regimens include:
      • Cytarabine
      • Methotrexate
      • Anthracyclines (e.g., daunorubicin)
      • Alkylating agents (e.g., cyclophosphamide)
      • Epipodophyllotoxins (e.g., etoposide)
  • Maintenance treatment: 
    • Less intensive treatment for 1–2 years
    • Regimen:
      • Daily oral 6-mercaptopurine (6-MP)
      • Weekly methotrexate 
      • Periodic vincristine, prednisone, intrathecal therapy
  • Allogeneic stem cell transplantation for high-risk ALL such as:
    • Patients with Philadelphia chromosome-positive ALL 
    • Patients with a poor initial response to induction therapy

Supportive therapy and monitoring

  • During treatment:
    • Monitor 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 response.
    • Monitor chemotherapy side effects, which can include:
      • Bone marrow suppression 
      • Stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis (mouth sores)
      • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Improve symptoms and prevent infections:
      • RBC 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 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
      • Only inactive vaccinations during chemotherapy
      • Trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim-sulfamethoxazole prophylaxis for pneumocystis carinii pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia 
      • Herpes simplex prophylaxis with acyclovir
    • If with 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, especially accompanying 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, broad-spectrum antibiotics are given.
    • Dietary modification (adjust for patients with mucositis, neutropenic diet)
  • Monitor for relapse:
    • Relapse rate: 10%–15% in children
    • Symptoms similar to those seen in the initial presentation
    • Areas of relapse:
      • Bone marrow
      • CNS
      • Testis

Prognosis

  • Children (< 15 years): cure rate > 85%
  • Prognosis declines with increasing age: cure rate of 30%–40% in adults ( ≥ 40 years)
  • Better prognosis is associated with:
    • Age < 30 years
    • Women
    • WBC count < 30,000/µL
    • No adverse cytogenetics
    • Translocation between chromosomes 12 and 21
    • Hyperdiploidy (leukemic cells with > 46 chromosomes)
    • Complete remission within 4 weeks
  • Worse prognosis is associated with:
    • Age > 60 years
    • Men
    • High WBC count (> 100,000/µL)
    • Adverse cytogenetics with translocations t(9;22) or Philadelphia chromosome
    • Hypodiploidy (leukemic cells with < 46 chromosomes)

Acute lymphoblastic leukemia versus acute myeloid leukemia 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. Acute Myeloid Leukemia

Table: Acute lymphoblastic leukemia versus acute myeloid leukemia 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. Acute Myeloid Leukemia
Management Acute lymphoblastic leukemia Acute myeloid leukemia
Induction
  • Vincristine, corticosteroids, asparaginase
  • With/without 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
  • Daily oral 6-mercaptopurine
  • Weekly methotrexate
  • Periodic vincristine, prednisone, intrathecal therapy
Nonmyelosuppressive chemotherapy and/or targeted agent
Additional treatment
  • Tyrosine kinase inhibitors (e.g., imatinib) given, if with t(9;22) translocation (Philadelphia chromosome)
  • CNS prophylaxis
Acute promyelocytic leukemia:
  • Medical emergency!
  • Give all-trans retinoic acid + arsenic trioxide.
Hematopoietic cell transplantation For patients with poor prognosis
Prognosis
  • Generally better prognosis in ages < 50 years
  • Associated 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(s) affect(s) prognosis.

Differential Diagnosis

  • AML AML 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. Acute Myeloid Leukemia: a hematologic neoplasm with malignant transformation and uncontrolled proliferation of myeloid precursors. Acute myeloid leukemia, seen predominantly in the elderly, is characterized by the accumulation of myeloblasts. The clinical presentation consisting of fatigue, pallor, 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 lack of functional WBCs. 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, and 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 less common (than ALL). Peripheral blood smear and 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 biopsy show myeloblasts and the presence of Auer rods. Treatment is mainly using chemotherapy. Prognosis varies according to the age of onset and type of leukemia.
  • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia: a malignant proliferation of the granulocytic cell line with a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22 resulting from reciprocal (9;22)(q34;q11) translocation. Patients have constitutional symptoms, sternal 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, 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. Elevated WBC count and increased numbers of immature cells in a peripheral smear are revealed after laboratory tests. In 10% of blast crisis, there is an increase in lymphoblasts like ALL/LBL. Philadelphia chromosome is demonstrated in the myeloid cells in CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia.
  • CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia: a hematologic malignancy characterized by the excess production of monoclonal B lymphocytes B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). Chronic lymphocytic leukemia Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia usually presents in the elderly and has a median age of 70 years. Diagnosis is usually made when abnormal lymphocytosis Lymphocytosis WBCs develop from stem cells in the bone marrow and are called leukocytes when circulating in the bloodstream. Lymphocytes are 1 of the 5 subclasses of WBCs. Lymphocytosis is an increase in the number or proportion of the lymphocyte subclass of WBCs, often as a result of an immune response to infection (known as reactive lymphocytosis). Lymphocytosis is seen in laboratory findings. Cytopenias can also be seen. Lymphocytes appear mature but are functionally incompetent; thus, recurrent infections are possible. 
  • Lymphocytosis: Infectious diseases (infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as "the kissing disease," is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis, HIV infection HIV infection Human immunodeficiency virus (HIV), a single-stranded RNA virus belonging to the Retroviridae family, is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus is a sexually transmitted or blood-borne infection that attacks CD4+ T lymphocyte cells, macrophages, and dendritic cells, leading to eventual immunodeficiency. HIV Infection and AIDS, TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis) and other noninfectious conditions (autoimmune diseases, hypersensitivity) can result in aberrant 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. Elevated lymphocyte levels can persist for weeks to months. An underlying condition is usually revealed by history, examination, and laboratory workup.

References

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