Acute Lymphoblastic Leukemia

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)

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

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

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

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.