• Clinical science

Acute leukemia

Summary

Acute leukemia is a malignant neoplastic disease that arises from either the lymphoid cell line (acute lymphoblastic/lymphocytic/lymphoid leukemia, or ALL) or the myeloid cell line (acute myeloid/myelogenous/myelocytic leukemia, or AML). ALL is the most common childhood malignancy, whereas AML primarily affects adults. An underlying cause is rarely identifiable, but risk factors include prior chemotherapy and radiation therapy, as well as hereditary syndromes such as Down syndrome. AML is also associated with pre-existing hematologic disorders (e.g., myelodysplastic disorder, myeloproliferative disorders). Acute leukemias are characterized by the proliferation in the bone marrow of immature, nonfunctional white blood cells (“blasts”) that impair normal hematopoiesis and lead to pancytopenia manifesting with symptoms and signs of anemia (↓ RBCs), clotting disorders (↓ thrombocytes), and increased susceptibility to infection (↓ fully functional, mature WBCs). Leukemic cells also infiltrate extramedullary organs, resulting in hepatosplenomegaly and, less commonly, involvement of the skin, CNS, and/or scrotum. Patients with AML, in particular, may develop extremely high WBC counts, increasing the risk of leukostasis and DIC. The first diagnostic steps include a complete blood count and peripheral blood smear to determine the WBC count and the presence of blasts. Bone marrow biopsy or aspiration with subsequent cytogenetic analysis and immunophenotyping confirm the diagnosis. A chemotherapy regimen consisting of high-dose (induction) and low-dose (consolidation and maintenance) cycles is the mainstay of treatment. Additional measures, such as allogeneic stem cell transplantation, may be indicated in patients with poor prognostic factors (e.g., unfavorable cytogenetics) or if initial chemotherapy fails.

Epidemiology

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Acute lymphoblastic leukemia (ALL)

Acute myeloid leukemia (AML)

References:[9][10]

Classification

ALL [1]

  • French-American-British (FAB) historical classification of ALL
    • L1 ALL with small cells (20–30%)
    • L2 ALL with heterogeneous large cells (70%)
    • L3 ALL with large cells, i.e., Burkitt lymphoma (1–2%)
  • The current WHO Classification (2016) classifies ALL into subtypes of precursor lymphoblastic leukemia/lymphoma based on morphologic and genetic factors:
    • B lymphoblastic leukemia with recurrent genetic abnormalities
      • ALL with BCR-ABL
      • ALL with t(v;11q23)
      • ALL with t(1;19)(q23;p13.3)
      • ALL with t(12;21)(p13;q22)
      • Hyperdiploid > 50
      • Hypodiploid
      • t(5;14)(q31;q32)
    • B lymphoblastic leukemia, not otherwise specified
    • Precursor T lymphoblastic leukemia/lymphoma
  • Immunophenotype classification of ALL: based on the origin (B cell or T cell) and maturity of the leukemic cells

AML

  • The French-American-British (FAB) classification distinguishes between eight subtypes of AML, according to the histopathological appearance of the cells.
FAB classification for AML
M0 Acute myeloblastic leukemia without maturation
M1 Acute myeloblastic leukemia with minimal granulocyte maturation
M2 Acute myeloblastic leukemia with granulocyte maturation
M3 Acute promyelocytic leukemia (APL)
M4 Acute myelomonocytic leukemia
M5 Acute monocytic leukemia
M6 Acute erythroid leukemia
M7 Acute megakaryoblastic leukemia
  • The WHO classification is based on various factors (e.g., presence of genetic abnormalities or associations to prior chemotherapy/radiation).
    • AML with recurrent genetic abnormalities (e.g., translocations)
    • AML with myelodysplasia-related changes
    • Therapy-related AML
    • AML not otherwise specified
    • Myeloid sarcoma
    • Myeloid leukemia associated with Down syndrome

References:[8][12]

Pathophysiology

References:[13][8][14]

Clinical features

Clinical features are either related to bone marrow failure, infiltration of organs by leukemic cells, or a combination of both.

General features of acute leukemia
Clinical features of ALL Clinical features of AML
  • Leukemia cutis (or myeloid sarcoma): nodular skin lesions with a purple or gray-blue color
  • Gingival hyperplasia (AML subtype M4 and M5)
  • Signs of CNS involvement, e.g., headache, visual field changes (uncommon)


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

Fever in a patient with acute leukemia must always be treated as a sign of infection until proven otherwise!

References:[17][1][15][16]

Diagnostics

Approach

  • Initial tests: CBC; and peripheral blood smear; (determine WBC count and the presence of blasts)
  • Confirmatory test: bone marrow aspiration and biopsy (examine morphology, histochemistry, cytogenetics, and immunophenotyping)
  • Further tests: if organ involvement is suspected (e.g., imaging, CSF analysis)

Laboratory studies

  • Complete blood count
  • Peripheral blood smear: presence of blasts
    • AML: Some subtypes (especially M3, or APL) exhibit Auer rods; , which are pink-red, rod-shaped granular cytoplasmic inclusion bodies in malignant immature lymphocytes (blasts)
  • Additional laboratory studies
    • Coagulation studies: rule out DIC
    • Electrolytes and metabolic markers: ↑ PO42-, ↓ Ca2+, ↑ K+, ↑ LDH, and ↑ uric acid indicate increased cell lysis

Bone marrow aspiration and biopsy

Morphology, histochemistry, cytogenetics, and immunophenotyping in ALL and AML
ALL AML
Morphology [20][21]
  • Large blasts (1.5–3 times the size of RBC)
  • Blasts with large, irregular nuclei (high nuclear-to-cytoplasm ratio)
  • Inconspicuous nucleoli
  • Coarse granules
  • No Auer rods
  • Large blasts (2–4 times the size of RBC)
  • Blasts with round or kidney-shaped nuclei, comparatively more cytoplasm than in ALL
  • Prominent nucleoli
  • Fine granules
  • Auer rods (present in 50% of cases) [22]
Histochemistry Myeloperoxidase (found in peroxidase-positive granules)
  • Negative
  • Positive
Terminal deoxynucleotidyl transferase (TdT)
  • Positive
  • Negative
Periodic acid-Schiff (PAS)
  • Often positive
  • Negative
Cytogenetics [16][9]
  • Philadelphia translocation (∼ 20–30% of ALL in adults and only 2–3% of ALL in children)
  • t(12;21): most common specific abnormality in childhood B-ALL
  • Hyperdiploidy is common in pre-B-ALL (see prognosis below)
Immunophenotyping by flow cytometry
  • B-ALL is usually positive for CD10 (CALLA), CD19, and CD20
  • T-ALL is usually positive for CD2–CD8, especially CD3
  • The majority of subtypes are positive for CD13, 33, 34, 117, and HLA-DR.


Myelogenous leukemia is myeloperoxidase positive.

Further tests

References:[23][25][2][1][15][24][9][26][16][12]

Treatment

Approach

  • Aggressive chemotherapy is the mainstay of treatment.
  • Radiation and/or targeted therapy are considered depending on the type and stage of disease.
  • Allogeneic stem cell transplantation is indicated in patients with poor prognostic factors or who do not achieve remission with chemotherapy.
  • Supportive measures are vital to manage severely immunocompromised patients and prevent treatment-related complications.

Chemotherapy

Chemotherapy regimens are comprised of induction, followed by consolidation, and finally maintenance therapy. The choice of chemotherapeutic agents is based on the cytogenetics of the leukemic cells. [21]

  1. Induction therapy (goal: massive reduction of tumor cell count)
    • Duration: 4–6 weeks
    • High-dose chemotherapy regimens are effective but usually cause severe side effects.
  2. Re-induction therapy (goal: massive reduction of tumor cell count)
    • 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)
    • Begin after complete remission is achieved
    • Duration: several months
    • Medium doses
    • ALL regimen: variable drug regimens
  4. Maintenance therapy (goal: maintaining remission)
Common agents used in the initial treatment acute leukemia
ALL [27][28] AML
Standard regimen
Philadelphia translocation

85% of children with ALL achieve complete remission with chemotherapy! [21]

A t(15;17) translocation causes the retinoic acid receptor to change, preventing myeloblast differentiation from occuring under physiologic levels of retinoic acid. Thus, high doses of all-trans-retinoic acid (vitamin A) may induce remission by causing malignant cells to mature.

Preventive CNS treatment

  • Intrathecal chemotherapy
    • ALL: indicated for all children to prevent meningeal leukemia (even if no CNS involvement is detected)
    • AML: only indicated after diagnostic measures have confirmed CNS involvement
  • CNS radiotherapy
    • Not routinely used because of associated risk of secondary malignancies and endocrine (e.g., hypothyroidism, growth hormone deficiency) and neurocognitive (e.g., cognitive decline, neuroinflammation) side effects.
    • Reserved for patients who do not respond to intrathecal chemotherapy or who develop impingement of important CNS structures (e.g., cranial nerve, spinal cord).

References:[29][14][30][31][32][33]

Allogeneic stem cell transplantation

  • Indication: poor prognostic factors (e.g., unfavorable cytogenetics); or patients who do not achieve remission through chemotherapy

Supportive therapy [12][21]

  • Preventing infection is very important as patients are severely immunocompromised.
    • Surveillance: regular inspection of oropharynx, skin, and catheter sites; regular chest x-rays or CT to detect pulmonary infection
    • Advise patients to pay special attention to personal hygiene (e.g., daily bathing and tooth brushing, cleaning of minor wounds, maintaining a germ-free environment; i.e., avoiding crowds and contact with sick individuals, wearing a face mask outside if WBC counts are low)
    • Antibiotic prophylaxis in afebrile neutropenic patients is controversial
    • PCP prophylaxis with TMP-SMX in all neutropenic patients
    • Mucositis prophylaxis with local antimycotics
    • Herpes simplex prophylaxis with acyclovir
    • Updating immunizations
    • Colony-stimulating factor administration can be considered for febrile neutropenia
  • Managing treatment side effects
  • Uric acid stone prophylaxis: begin prior to chemotherapy to prevent hyperuricemia and urate induced nephropathy

References:[23][34][35][29][36][27][24][37]

Complications

Oncologic emergencies

Leukostasis

  • Description: ↑ blood viscosity caused by an excessive number of leukocytes (usually > 150,000/mm3 in patients with AML and > 400,000/mm3 in patients with ALL)
  • Pathophysiology: : very high number of immature leukocytes → increased viscosity of blood → increased risk of vessel obstruction → cerebral and pulmonary complications, DIC
  • Occurrence: more common in AML than ALL
  • Clinical features
  • Treatment
    • Cytoreduction: hydroxyurea with or without leukapheresis to rapidly reduce WBC count
    • Preventive measures for tumor lysis syndrome (see “Prophylaxis” below)

Tumor lysis syndrome (TLS) [38]

“PUKE calcium” for the electrolytes affected in tumor lysis syndrome: Phosphorus, Uric acid, and potassium (K+) are Elevated; Calcium is decreased.

References:[39][40]

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

Prognosis

5-year survival rate following treatment

  • ALL: generally better than with AML (varies from ∼ 20% in elderly patients to ∼ 80% in children and adolescents)
  • AML: ∼ 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
Disease features
  • WBC count > 50,000/mm3
  • CNS involvement at diagnosis
  • ↑ LDH
  • FAB M7 (acute megakaryocytic leukemia)
Cytogenetics
  • Various translocations, e.g., t(6;9)
  • Karyotype abnormalities (e.g., trisomy 8, monosomy 5 or 7)
  • FLT3 gene mutation
  • Complex pattern of aberrations (i.e., > 3 aberrations)
Immunotyping

Favorable prognostic factors

ALL AML
  • < 50,000/mm3
  • No CNS involvement
  • t(12;21)
  • Hyperploidy

The most common specific abnormality in childhood B-ALL is the t(12;21) translocation, which is associated with a favorable outcome.

References:[41][42][43][21][44][45]