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, 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 (AML).
• 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 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
  • Bloom syndrome
  • 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/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:
  • T cells
  • B cells
  • Natural killer (NK) cells
• Myeloid stem cells eventually differentiate into platelets, 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)
  • EPO → differentiation to erythrocytes (RBCs)

Pathogenesis

• Genetic changes affect the expression and function 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 space, suppressing normal hematopoiesis → leukopenia, thrombocytopenia, and anemia
  • 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 (most common findings on presentation) can manifest as:
  • Abdominal pain
  • Abdominal distension
  • Anorexia
  • Weight loss
• Lymphadenopathy (nontender, firm, rubbery)
• Fever
• Bone pain:
  • Associated with 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

Diagnosis

Diagnostic findings

• CBC with differential: 
  • Anemia, 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 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

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-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 response.
  • Monitor chemotherapy side effects, which can include:
    • Bone marrow suppression 
    • Stomatitis (mouth sores)
    • Diarrhea
  • Improve symptoms and prevent infections:
    • RBC and platelet transfusions for anemia and thrombocytopenia
    • Granulocyte-colony stimulating factor for neutropenia
    • Only inactive vaccinations during chemotherapy
    • Trimethoprim-sulfamethoxazole prophylaxis for pneumocystis carinii pneumonia 
    • Herpes simplex prophylaxis with acyclovir
  • If with fever, especially accompanying 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

Differential Diagnosis

• AML: 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, and infection is related to anemia, thrombocytopenia, and lack of functional WBCs. Mass effects of malignant infiltration (in bone, liver, and spleen) are less common (than ALL). Peripheral blood smear and 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: 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, and 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.
• CLL: a hematologic malignancy characterized by the excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). Chronic lymphocytic leukemia usually presents in the elderly and has a median age of 70 years. Diagnosis is usually made when abnormal 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, HIV infection, TB) and other noninfectious conditions (autoimmune diseases, hypersensitivity) can result in aberrant lymphocytes. Elevated lymphocyte levels can persist for weeks to months. An underlying condition is usually revealed by history, examination, and laboratory workup.