• Clinical science

Acute leukemia

Summary

Acute leukemias are malignant neoplastic diseases that arise from either lymphoid (acute lymphoblastic/lymphocytic/lymphoid leukemia, or ALL) or myeloid (acute myeloid/myelogenous/myelocytic leukemia, or AML) cell lines. Acute leukemias are characterized by the proliferation of immature, non-functional cells in the bone marrow that are subsequently released into the bloodstream. ALL is the most common childhood malignancy, whereas AML mostly affects adults. Both diseases are associated with hereditary syndromes such as Down syndrome and previous exogenous bone marrow damage (e.g., caused by prior radiotherapy, chemotherapy, or exposure to benzene). The excessive proliferation of immature blasts in the bone marrow impairs all other cell lines, resulting in anemia, clotting disorders, and increased susceptibility to infections. Patients may also present with non-specific, flu-like symptoms or – in later stages – symptoms caused by leukemic organ infiltration (e.g., an enlarged scrotum). Diagnosis is usually confirmed by bone marrow aspirate, although a complete blood count and a peripheral blood smear are routinely performed as well. It is important to note that leukemias can present with a high, low, or even normal WBC count. Patients should be treated with a chemotherapy regimen consisting of high-dose (induction) and low-dose (consolidation and maintenance) cycles. Additional measures, such as allogeneic stem cell transplantation, may be indicated for patients with high-risk disease or if initial chemotherapy fails.

Epidemiology

References:[1][2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Acute lymphoblastic leukemia (ALL)

Acute myeloid leukemia (AML)

References:[1][2][3][4][5][6][7][8][9]

Classification

AML

The French-American-British (FAB) classification distinguishes between eight subtypes of AML, according to the histopathological appearance of the cells. The WHO classification is based on various factors (e.g., presence of genetic abnormalities or prior chemotherapy/radiation):

FAB classification for AML
M0 AML, minimally differentiated
M1 AML without maturation
M2 AML with granulocytic maturation
M3 Acute promyelocytic leukemia (APL)
M4 Acute myelomonocytic leukemia
M5 Acute monocytic leukemia
M6 Acute erythroid leukemias
M7 Acute megakaryoblastic leukemia

ALL

The WHO classification relies on cytogenetic criteria to determine the immunophenotype of the leukemic cells. This includes their origin (B or T cell) and maturity:

References:[2][10]

Pathophysiology

Two-hit hypothesis

The two-hit hypothesis assumes that leukemia is the result of two separate genetic mutations. The first causes clonal proliferation of a lymphoid or myeloid stem cell, while the second impairs its normal hematopoietic differentiation. As a result, the bone marrow is filled with numerous immature, non-functional cells that eventually impair normal hematopoiesis and cause the following abnormalities:

Following further proliferation, the leukemic cells eventually enter the bloodstream and infiltrate other organs (e.g., the liver or the spleen), leading to organ-specific symptoms.

References:[11]

Clinical features

Symptoms occurring in both AML and ALL

Symptoms more common in either AML or ALL

AML

  • Leukemia cutis (or myeloid sarcoma): nodular skin lesions with a purple or gray-blue color
  • Gingival hyperplasia (AML subtype M4 and M5)

Fever in AML patients is usually a sign of infection and requires immediate investigation!

ALL

Fever and lymphadenopathy are rare in AML, but can be common first signs in ALL!

References:[12][1][2][13]

Diagnostics

Laboratory tests

The diagnostic workup usually includes clinical examination, CBC, peripheral blood smear, and a bone marrow aspirate or biopsy.

  • Complete blood count
    • Leukocytes: The white blood cell count (WBC) may be elevated, normal, or low and is not a reliable diagnostic marker.
      • ALL: 50% may present with WBC count < 10,000/μL, 20% with WBC > 50,000/μL
      • AML: 25–40% may present with WBC count < 5000/μL, 20% with WBC > 100,000/μL
      • AML: Leukemic hiatus: A gap in the differentiation of white blood cells in which there is a high number of blast cells and mature leukocytes but no intermediate forms.
    • Thrombocytopenia
    • Anemia
  • Peripheral blood smear: presence of blasts
    • AML: Some subtypes (especially M3) exhibit Auer rods, which are pinkish-red, rod-shaped granular components within the cytoplasm.
  • Increased cell lysis: ↑ LDH; and ↑ uric acid
  • Bone marrow aspirate or biopsy: confirmatory diagnostic tests

Marker

 ALL AML
Myeloperoxidase (found in peroxidase-positive granules) negative positive
Terminal deoxynucleotidyl transferase (TdT) positive negative
CALLA positive negative
Periodic acid-Schiff (PAS) often positive negative
  • Immunophenotype
    • ALL
      • B-ALL is usually positive for CD10, 19, and 20
      • T-ALL is usually positive for CD2-5 and CD7 and 8
    • AML: The majority of subtypes are positive for CD13, 33, 34, 117, and HLA-DR.
  • Cerebrospinal fluid analysis: relevant for diagnosis and treatment of leukemic meningitis

Imaging

References:[14][1][2][13][15]

Treatment

Treatment involves aggressive chemotherapy and sometimes allogeneic transplantation. Depending on the type and stage of disease, additional measures such as radiation or targeted therapy may be considered.

Chemotherapy

Chemotherapy regimens are comprised of: induction → consolidation → maintenance therapy

  1. Induction therapy (goal: massive reduction of tumor cell count)
    • Duration: 4–6 weeks
    • Effective, but can cause severe side effects
  2. Re-induction therapy (goal: similar to induction therapy)
    • Only indicated in case of relapse or failure of primary induction therapy
    • Duration: 4–6 weeks
  3. Consolidation therapy (goal: destruction of remaining tumor cells)
    • Duration: several months
    • Medium doses
  4. Maintenance therapy (goal: maintaining remission)
    • Duration: up to 24 months
    • Low doses

Chemotherapeutic drugs

The choice of drugs depends on the type of leukemia:

Preventive CNS treatment

  • Intrathecal chemotherapy is indicated for all acute leukemia patients to prevent meningeal leukemia.
  • CNS radiotherapy is not routinely used because it increases the risk of secondary malignancies, as well as endocrine (e.g., hypothyroidism, growth hormone deficiency) and neurocognitive (e.g., cognitive decline, neuroinflammation) side-effects.

Supportive therapy

Supportive therapy is very important as patients are severely immunocompromised.

Allogeneic stem cell transplantation

References:[16][17][18][19][20][21][22][23]

Complications

Tumor lysis syndrome (TLS)

References:[24][25]

We list the most important complications. The selection is not exhaustive.

Prognosis

5-year survival rate

  • ALL: The 5-year survival rate of treated patients varies from 20% (elderly patients) to 80% (children and adolescents).
  • AML: The overall 5-year survival rate of treated patients is on average 30%, but it varies according to the patient's age. The survival time has increased more recently due to improvements in treatment.

Unfavorable prognostic factors

ALL AML
Age

  • < 1 year or > 10 years
  • > 60 years
Leukocyte count

  • > 50,000/mm3
Cytogenetics
  • Hypoploidy
  • Complex pattern of aberrations (> 3 aberrations)
  • t(9;22)
  • A variety of chromosomal changes
  • Complex pattern of aberrations (> 3 aberrations)
Immunotyping
  • Monosomy 7
Extent of disease
  • CNS involvement

Favorable prognostic factors

ALL AML
  • < 50,000/mm3
  • No CNS involvement
  • t(12;21)
  • High hyperploidy
  • t(8;21)
  • t(15;17)

References:[26][27][28]