Acute Lymphoblastic Leukemia

1/11/24, 10:26 PM Acute Lymphoblastic Leukemia - Lecturio
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%.
Last updated: October 24, 2022
CONTENTS
Overview
Epidemiology and Etiology
Pathophysiology
Clinical Presentation
Diagnosis
Management
Differential Diagnosis
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References
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:

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
Features Acute lymphoblastic Acute myeloid

leukemia leukemia
Population More common in More common in adults

children
Common Symptoms of anemia, thrombocytopenia,

characteristics neutropenia (from depressed marrow function)
Abrupt onset (days to weeks)
CNS involvement
Clinical findings Hepatomegaly and Organomegaly (less

splenomegaly frequent)
Lymphadenopathy Lymphadenopathy
Bone pain (more (rare)
common) Leukemia cutis
Can affect testes Gingival hypertrophy
Can have mediastinal DIC
mass
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
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
Features Acute lymphoblastic Acute myeloid

leukemia leukemia
Laboratory findings Anemia, thrombocytopenia, varying WBCs
Peripheral smear or Lymphoblasts: Myeloblasts:

bone marrow Large nuclei Delicate nuclear
examination Condensed chromatin
(morphology) chromatin Prominent
Inconspicuous nucleoli (2–4)
nucleoli More voluminous
Scant basophilic cytoplasm
cytoplasm Fine azurophilic
cytoplasmic
granules
Auer rods
Cytochemistry PAS: positive PAS: negative

MPO: negative Sudan black B:
Terminal positive
deoxynucleotidyl MPO: positive
transferase: Terminal
positive deoxynucleotidyl
transferase:
negative
Immunophenotyping B-ALL/LBL: CD10, CD13, CD33, CD117,

CD19, CD20, HLA-DR
CD24, cytoplasmic
CD22 and CD-79a
T-ALL/LBL: CD2–8
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
Management Acute lymphoblastic Acute myeloid

leukemia leukemia
Induction Vincristine, Cytarabine +

corticosteroids, daunorubicin or
asparaginase idarubicin
With/without Additional targeted
anthracycline agent (based on
(doxorubicin or mutation)
daunorubicin)
Consolidation Options: Additional

Cytarabine chemotherapy
Methotrexate (cytarabine)
Anthracyclines
Alkylating agents
Epipodophyllotoxins
Maintenance Daily oral 6- Nonmyelosuppressive

mercaptopurine chemotherapy and/or
Weekly methotrexate targeted agent
Periodic vincristine,
prednisone, intrathecal
therapy
Additional Tyrosine kinase Acute promyelocytic

treatment inhibitors (e.g., leukemia:
imatinib) given, if with Medical emergency!
t(9;22) translocation Give all-trans retinoic
(Philadelphia acid + arsenic
chromosome) trioxide.
CNS prophylaxis
Hematopoietic For patients with poor prognosis

cell
transplantation
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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1/11/24, 10:26 PM Acute Lymphoblastic Leukemia - Lecturio

Last updated: October 24, 2022

Epidemiology and Etiology

Lymphoid stem cells give rise to lymphocytes:

Bone marrow hematopoiesis:

Genetic changes affect the expression and function of transcription factors in

About 6% of patients are asymptomatic.

Acute lymphoblastic leukemia vs acute myeloid leukemia

Table: Acute lymphoblastic leukemia vs acute myeloid leukemia

Features Acute lymphoblastic Acute myeloid

Population More common in More common in adults

Common Symptoms of anemia, thrombocytopenia,

Clinical findings Hepatomegaly and Organomegaly (less

CBC with differential:

Serum chemistry: may suggest tumor lysis syndrome or other metabolic

Acute lymphoblastic leukemia vs acute myeloid leukemia

Table: Acute lymphoblastic leukemia vs acute myeloid leukemia

Features Acute lymphoblastic Acute myeloid

Laboratory findings Anemia, thrombocytopenia, varying WBCs

Peripheral smear or Lymphoblasts: Myeloblasts:

Cytochemistry PAS: positive PAS: negative

Immunophenotyping B-ALL/LBL: CD10, CD13, CD33, CD117,

B-ALL/LBL: B cell acute lymphoblastic leukemia/lymphoma

Supportive therapy and monitoring

Acute lymphoblastic leukemia versus acute myeloid

Table: Acute lymphoblastic leukemia versus acute myeloid leukemia

Management Acute lymphoblastic Acute myeloid

Induction Vincristine, Cytarabine +

Consolidation Options: Additional

Maintenance Daily oral 6- Nonmyelosuppressive

Additional Tyrosine kinase Acute promyelocytic

Hematopoietic For patients with poor prognosis

Prognosis Generally better prognosis in ages < 50 years

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