ACUTE LEUKEMIA

• Leukemia


  Derived from the ancient Greek words leukos (λEUкóç), meaning "white," and haima (alµa), meaning "blood"
• Acute leukemia


  Rapid, clonal proliferation in the bone marrow of lymphoid or myeloid progenitor cells known as lymphoblasts and myeloblasts
• When proliferation of blasts overwhelms the bone marrow, blasts are seen in the peripheral blood and the patient's symptoms reflect suppression of normal hematopoiesis
• For most cases of acute leukemia, the causes directly related to the development of the malignancy are unknown
• Exceptions that can induce genetic changes leading to a malignant phenotype

  • Certain toxins
  • Radiation
  • Exposure to organic solvents, such as benzene
• Rarely, leukemias can be seen in patients with known familial cancer predisposition syndromes
• Alkylating agents and other forms of chemotherapy used to treat various forms of cancer can induce deoxyribonucleic acid (DNA) damage in hematopoietic cells, leading to therapy-related leukemias
• Development of leukemia


  Stepwise progression of mutations or "multiple hits" involving mutations in genes that give cells a proliferative advantage, in addition to mutations that hinder differentiation
• Leukemic stem cells (LSCs)


  Transform normal hematopoietic stem cells or precursors into leukemic stem cells that initiate, proliferate, and sustain the leukemia
• French-American-British (FAB) classification


  Devised in the 1970s, based on morphologic examination along with cytochemical stains to distinguish lymphoblasts from myeloblasts
• Cytochemical stains continue to be a useful adjunct for differentiation of hematopoietic diseases, especially acute leukemias
• Techniques commonly used to diagnose hematopoietic malignancies include flow cytometry and genetic/molecular studies
• In 2001 the World Health Organization (WHO) published new classification schemes for nearly all of the tumors of hematopoietic and lymphoid tissues
• According to the WHO classification, a finding of at least 20% blasts in the bone marrow is required for diagnosis of the majority of acute leukemias, and testing must be performed to detect the presence or absence of genetic anomalies
• Acute lymphoblastic leukemia (ALL)


  Primarily a disease of childhood and adolescence, accounting for 25% of childhood cancers and up to 75% of childhood leukemia
• Acute lymphoblastic leukemia (ALL) in adults

  Rare, but risk increases with age, most adult patients are older than 50 years of age
• Patients with B cell ALL

  • Typically present with fatigue, fever, and mucocutaneous bleeding
  • Lymphadenopathy, splenomegaly, and hepatomegaly may be seen
  • Bone pain often results from intramedullary growth of leukemic cells
  • Eventual infiltration of malignant cells into the meninges, testes, or ovaries occurs frequently
• Patients with T cell ALL


  • May have a large mass in the mediastinum leading to compromise of regional anatomic structures
  • Similar to B-ALL, may present with anemia, thrombocytopenia, organomegaly, and bone pain, although the degree of leukopenia is often less severe
• WHO classification of B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities

  • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A (MLL) rearranged
  • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); TEL-AML1 (ETV6-RUNX1)
  • B-lymphoblastic leukemia/lymphoma with hyperdiploidy
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy
  • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.1);IGH/IL3
  • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1 (E2A-PBX1)
  • B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like
  • B-lymphoblastic leukemia/lymphoma with iAMP21
• Lymphoblasts


  Vary in size but fall into two morphologic types: small lymphoblasts (1.0 to 2.5 times the size of a normal lymphocyte) with scant blue cytoplasm and indistinct nucleoli, and larger lymphoblasts (two to three times the size of a lymphocyte) with prominent nucleoli and nuclear membrane irregularities
• Prognosis in ALL


  • Has improved dramatically over the past decades as a result of improvement in algorithms for treatment
  • Depends on age at the time of diagnosis, lymphoblast load (tumor burden), immunophenotype, and genetic abnormalities
  • Children rather than infants or teens do the best
  • Chromosomal translocations are the strongest predictor of adverse treatment outcomes for children and adults
  • Peripheral blood lymphoblast counts greater than 20 to 30 × 10^9/L, hepatosplenomegaly, and lymphadenopathy are associated with a worse outcome
• Immunophenotypic characteristics of acute lymphoblastic leukemia (ALL)

  • Early (pro/pre-pre) B-ALL: CD34, CD19, cytoplasmic CD22, TdT
  • Intermediate (common) B-ALL: CD34, CD19, CD10, cytoplasmic CD22, TdT
  • Pre-B-ALL: CD34, CD19, cytoplasmic CD22, cytoplasmic μ, TdT (variable)
  • T-ALL: CD2, CD3, CD4, CD5, CD7, CD8, TdT
• 1. ALL


  • Characterized by specific B cell antigens that are expressed at different stages of B cell development
  • B cells express CD19, CD20, CD22, CD24, C79a, CD10, cytoplasmic μ, and PAX-5 (B cell specific activator protein)
  • The degree of differentiation of B-lineage lymphoblasts often correlates with genetics and plays an important role in treatment decisions
• 1. ALL


  • The common T cell markers CD2, CD3, CD4, CD5, CD7, and CD8 are usually present
  • Most cases express TdT
  • A distinct subtype, ETP-ALL (early T cell precursor ALL), often shows expression of myeloid makers and is thought to be derived from T cell precursor cells that have the capacity for myeloid differentiation
• Cytogenetic abnormalities in B and T cell ALL


  • Majority of B and T cell ALL have cytogenetic abnormalities that affect normal B and T cell development and underlie the pathogenesis of these neoplasms
  • Majority of T-ALL have gain-of-function mutations involving the NOTCH1 gene, which alters the Notch receptor signaling pathway responsible for normal T cell development
  • B-lymphoblastic leukemia/lymphoma with the t(9;22)(q34;q11.2);BCR-ABL1 mutation (Philadelphia chromosome-positive ALL) has the worst prognosis among ALLs
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23);KMT2A(MLL)-rearranged is more common in very young infants and has a very poor prognosis
• Acute lymphoblastic leukemia (ALL)


  Neoplasms that produce changes affecting normal B and T cell development
• 1. ALL


  • Majority have gain-of-function mutations involving the NOTCH1 gene, which alters the Notch receptor signaling pathway responsible for normal T cell development
• 1. lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2);BCR-ABL1 mutation (Philadelphia chromosome-positive ALL)


  • Has the worst prognosis among ALLs, more common in adults than children
• 1. lymphoblastic leukemia/lymphoma with t(v;11q23);KMT2A(MLL)-rearranged


  • More common in very young infants, has a very poor prognosis
• 1. lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1);ETV6-RUNX1 translocation


  • Appears to derive from a B cell progenitor rather than the hematopoietic stem cell, has an excellent prognosis in children
• Hyperdiploidy in B-lymphoblastic leukemia/lymphoma

  • Common in childhood B-ALL, associated with a very favorable prognosis in children
• Hypodiploidy (less than 46 chromosomes)


  • Conveys a poor prognosis in both children and adults
• AML is the most common type of leukemia in adults, and the incidence increases with age
• Clinical presentation of AML

  • Decreased production of normal bone marrow elements, total white blood cell (WBC) count between 5 and 30 x 10^9/L, myeloblasts present in peripheral blood in 90% of patients, anemia, thrombocytopenia, and neutropenia
• Splenomegaly


  • Seen in half of AML patients, but lymph node enlargement is rare
• Cerebrospinal fluid involvement in AML

  • Rare and does not seem to be as ominous a sign as in ALL
• Laboratory abnormalities in AML

  • Hyperuricemia, hyperphosphatemia, hypocalcemia, hypokalemia
• Tumor lysis syndrome


  A group of metabolic complications that can occur in patients with malignancy, caused by the breakdown products of dying cancer cells
• Aggressive prophylactic measures to prevent or reduce the clinical manifestations of tumor lysis syndrome are critical
• 2017 WHO classification of myeloid leukemia and related precursor neoplasms

  • Acute myeloid leukemia with recurrent genetic abnormalities
  • Acute myeloid leukemia with myelodysplasia-related changes
  • Therapy-related myeloid neoplasms
  • Acute myeloid leukemia, not otherwise specified
  • Myeloid sarcoma
  • Myeloid proliferations associated with Down syndrome
  • Blastic plasmacytoid dendritic cell neoplasm
  • Acute leukemias of ambiguous lineage