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, and infections, all of which are related to anemia, thrombocytopenia, and the lack of functional WBCs. The onset of symptoms takes days to weeks. Mass effects of malignant infiltration (in bone, liver, spleen) are common; thus, hepatosplenomegaly and lymphadenopathy are seen. Diagnosis is by peripheral blood smear examination and 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, 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)
Bone marrow hematopoiesis

Bone marrow hematopoiesis:
Proliferation and differentiation of the formed elements of blood:
In CML, 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 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

Table: Acute lymphoblastic leukemia vs acute myeloid leukemia
FeaturesAcute lymphoblastic leukemiaAcute myeloid leukemia
PopulationMore common in childrenMore common in adults
Common characteristics
  • Symptoms of anemia, thrombocytopenia, neutropenia (from depressed marrow function)
  • Abrupt onset (days to weeks)
  • CNS involvement
Clinical findings
  • Hepatomegaly and splenomegaly
  • Lymphadenopathy
  • Bone pain (more common)
  • Can affect testes
  • Can have mediastinal mass
  • Organomegaly (less frequent)
  • Lymphadenopathy (rare)
  • Leukemia cutis
  • Gingival hypertrophy
  • DIC

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
Bone marrow smear from a patient with acute lymphoblastic leukemia

a: 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 L, Cao Y, Yao D. License: CC BY 4.0

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

Table: Acute lymphoblastic leukemia vs acute myeloid leukemia
FeaturesAcute lymphoblastic leukemiaAcute myeloid leukemia
Laboratory findingsAnemia, thrombocytopenia, varying WBCs
Peripheral smear or 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-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

Table: Acute lymphoblastic leukemia versus acute myeloid leukemia
ManagementAcute lymphoblastic leukemiaAcute myeloid leukemia
Induction
  • Vincristine, corticosteroids, asparaginase
  • With/without anthracycline (doxorubicin or daunorubicin)
  • Cytarabine + daunorubicin or idarubicin
  • Additional targeted agent (based on mutation)
ConsolidationOptions:
  • 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 transplantationFor patients with poor prognosis
Prognosis
  • Generally better prognosis in ages < 50 years
  • Associated mutation(s) affect(s) prognosis.

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.

References

  1. Arber, D.A., et al. (2016). The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 127(20), 2391–2405. Retrieved April 26, 2021, from https://doi.org/10.1182/blood-2016-03-643544
  2. Blum, W., Bloomfield, C.D. (2018). Acute myeloid leukemia. In Jameson, J., et al. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192017732
  3. Gajendra, S. (2016). Flow cytometry in acute leukemia. Clin Oncol. 1(1166). https://www.clinicsinoncology.com/pdfs_folder/cio-v1-id1166.pdf
  4. Hoelzer, D. (2018). Acute lymphoid leukemia. In Jameson J., et al. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192017841
  5. Horton, T.M., Steuber, P., Aster, J.C. (2021). Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children. UpToDate. Retrieved April 27, 2021, from https://www.uptodate.com/contents/overview-of-the-clinical-presentation-and-diagnosis-of-acute-lymphoblastic-leukemia-lymphoma-in-children
  6. Kolitz, J.E. (2021). Overview of acute myeloid leukemia in adults. UpToDate. Retrieved June 8, 2021, from https://www.uptodate.com/contents/overview-of-acute-myeloid-leukemia-in-adults
  7. Larson, R. (2021). Initial treatment of acute promyelocytic leukemia in adults. UpToDate. Retrieved June 9, 2021, from https://www.uptodate.com/contents/initial-treatment-of-acute-promyelocytic-leukemia-in-adults
  8. Larson, R. (2021). Induction therapy for acute myeloid leukemia in medically-fit adults. UpToDate. Retrieved June 9, 2021, from https://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-medically-fit-adults
  9. Larson, R., Klepin, H. (2021). Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults. UpToDate. Retrieved June 9, 2021, from https://www.uptodate.com/contents/pretreatment-evaluation-and-prognosis-of-acute-myeloid-leukemia-in-older-adults
  10. Roberts, K.G. (2018). Genetics and prognosis of ALL in children vs adults. Hematology. American Society of Hematology. Education Program. 2018(1), 137–145. https://doi.org/10.1182/asheducation-2018.1.137
  11. Schiffer, C. (2021). Prognosis of acute myeloid leukemia. UpToDate. Retrieved June 9, 2021, from https://www.uptodate.com/contents/prognosis-of-acute-myeloid-leukemia
  12. Schiffer, C., Gurbuxani, S. (2021) Clinical manifestations, pathologic features and diagnosis of acute myeloid leukemia. UpToDate. Retrieved June 8, 2021, from https://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-acute-myeloid-leukemia
  13. Schiffer, C., Gurbuxani, S. (2021). Classification of acute myeloid leukemia. UpToDate. Retrieved June 8, 2021, from https://www.uptodate.com/contents/classification-of-acute-myeloid-leukemia
  14. Stock, W., Thirman, M. (2021). Pathogenesis of acute myeloid leukemia. UpToDate. Retrieved June 8, 2021, from https://www.uptodate.com/contents/pathogenesis-of-acute-myeloid-leukemia
  15. Thirman, M.J., et al. (1993). Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations. NEJM. 329(13), 909–914. https://doi.org/10.1056/NEJM199309233291302
  16. Zhang, Y., Le Beau, M., Aster, J. (2021). Classification, cytogenetics and molecular genetics of acute lymphoblastic leukemia/lymphoma. UpToDate. Retrieved June 8, 2021, from https://www.uptodate.com/contents/classification-cytogenetics-and-molecular-genetics-of-acute-lymphoblastic-leukemia-lymphoma

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