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Acute leukemia

Last updated: August 2, 2021

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Acute leukemias are malignant neoplastic diseases that arise from either the lymphoid or myeloid cell line. Acute lymphocytic leukemia (ALL) is the most common childhood malignancy, whereas acute myeloid leukemia (AML) primarily affects adults. The underlying cause of acute leukemia is rarely identifiable, but risk factors include prior chemotherapy and radiation therapy, and hereditary syndromes such as Down syndrome. AML is also associated with preexisting hematologic disorders (e.g., myelodysplastic disorder, myeloproliferative disorders). Acute leukemias are characterized by the proliferation of immature, nonfunctional WBCs (blasts) in the bone marrow, which impairs normal hematopoiesis. This leads to pancytopenia, which manifests with symptoms and signs of anemia (decreased RBCs), clotting disorders (decreased platelets), and immunocompromise (decreased fully functional, mature WBCs). Patients with acute leukemia, especially those with AML, may develop extremely high WBC counts, increasing the risk of leukostasis and disseminated intravascular coagulation (DIC). Leukemic cells can also infiltrate extramedullary organs, resulting in hepatosplenomegaly, renal impairment, meningeal leukemia, and, less commonly, involvement of the skin and/or testicles. The first diagnostic steps include a complete blood count and peripheral blood smear to determine the patient's WBC count and assess for the presence of blasts. Bone marrow aspiration and biopsy are typically used to confirm the diagnosis, and subsequent cytogenetic analysis and immunophenotyping are used to identify subtypes and specific mutations. 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.

Epidemiological data refers to the US, unless otherwise specified.

Acute lymphoblastic leukemia (ALL)

Acute myeloid leukemia (AML)

References:[9][10]

ALL [1]

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-AML Acute myeloblastic leukemia without maturation
M1-AML Acute myeloblastic leukemia with minimal granulocyte maturation
M2-AML Acute myeloblastic leukemia with granulocyte maturation
M3-AML Acute promyelocytic leukemia (APL)
M4-AML Acute myelomonocytic leukemia
M5-AML Acute monocytic leukemia
M6-AML Acute erythroid leukemia
M7-AML Acute megakaryoblastic leukemia
  • The WHO classification is based on various factors (e.g., presence of genetic abnormalities or associations to prior chemotherapy/radiation).

References:[8][12]

References:[8][13][14]

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


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!

Remember metastasis for ALL by thinking of the following: ALL metaStaSizeS to the CNS and teSteS.

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

Approach

  • Initial evaluation
    • Suspect acute leukemia in patients with suggestive clinical or laboratory features.
    • Confirm the diagnosis with a morphological assessment.
  • Further diagnostic studies: Immunophenotype, cytogenetics, and molecular genetic testing should be obtained in order to identify the subtype of acute leukemia.

In order to choose the best treatment strategy, the morphological assessment, immunophenotype, and genetic studies should be as comprehensive as possible.

Initial studies [18][19][20]

Routine laboratory studies

Findings on initial laboratory studies are usually nonspecific but may help to identify potentially life-threatening acute complications.

The identification of DIC suggests APL, which is a medical emergency. Consult hematology and/or oncology immediately and transfer the patient to a critical care unit.

Confirmatory diagnostic tests [18][20][25]

Histopathological features should be assessed using bone marrow aspiration and biopsy. If unavailable, a peripheral blood smear may be sufficient.

Histopathological features of acute leukemia
ALL AML

Blasts (in bone marrow or peripheral blood) [18][26]

  • > 20% lymphoblasts
  • > 20% myeloblasts
  • Presence of recurrent genetic abnormalities, regardless of the blast percentage
    • AML: t(8;21), inv(16), or t(16;16)
    • APL: t(15;17)
Cell morphology [25]

Cell morphology can confirm the diagnosis of acute leukemia, but in most cases, it is necessary to complete immunophenotype and genetic studies before selecting a treatment.

Specialized studies

These studies are used to further characterize the cell line involved; some characteristics may be associated with a better response to certain therapies. These studies should be ordered in consultation with a specialist.

Immunophenotype and genetic studies [19][20][25][28]

Immunophenotype and genetic studies in acute leukemias
Findings in ALL Findings in AML
Immunophenotype [28] Immunohistochemistry
Flow cytometry
  • The majority of subtypes are positive for CD13, CD33, CD34, CD117, and HLA-DR
Genetic studies Cytogenetics (karyotype, FISH)
Molecular testing (PCR) [19]
  • BCR-ABL1 in confirmed or suspected B-ALL
  • Potential findings in childhood B-ALL include:
    • t(12;21)(p13.2;q22.1)
    • ETV6-RUNX1
  • FLT3-ITD: associated with a poor prognosis
  • PML-RARA in patients with APL

Myelogenous leukemias are myeloperoxidase positive.

Screening for extramedullary disease [18][19][31]

Consider the following studies to detect extramedullary disease based on the subtype of acute leukemia and clinical evaluation of the patient:

All patients with ALL should undergo screening for CNS infiltration.

Approach [25][32][33]

The treatment of acute leukemia is decided by a hematologist-oncologist specialist depending on the specific subtype and results of molecular testing.

Early and aggressive chemotherapy improves the prognosis, e.g., 80–90% of patients with ALL achieve complete remission with chemotherapy. [25]

Systemic chemotherapy [32][33]

Regimens vary depending on the subtype of leukemia, the age of the patient, and immunophenotype and genetic study results.

  • Induction therapy
    • High doses to induce a massive reduction of tumor cell count
    • Average duration for an adult with ALL: 4–8 weeks
    • Reinduction therapy may be required in case of relapse or failure of primary induction
  • Consolidation therapy
    • Medium doses to destroy any remaining tumor cells after induction
    • Average duration for an adult with ALL: 4–8 months
  • Maintenance therapy
    • Low doses to maintain remission
    • Average duration for an adult with ALL: 2–3 years
Common agents used in chemotherapy regimens for acute leukemia [18][20][25][32][33]
ALL
AML
APL

A chemotherapy regimen commonly used to treat ALL is hyper-CVAD: Cyclophosphamide, Vincristine, daunorubicin (or Adriamycin), and Dexamethasone.

If APL is suspected, start treatment early with a differentiation agent (e.g., ATRA) without waiting for immunotype or genetic confirmation. Treatment may be adjusted later depending on the results. [25]

In APL, the t(15;17) translocation and subsequent formation of the PML-RARA fusion gene can inhibit myeloblast differentiation under physiological levels of retinoic acid. High doses of ATRA (a vitamin A derivative) may induce myeloblast differentiation and promote remission.

Management of CNS infiltration [32][33][34]

Intrathecal prophylaxis should be initiated early, as prevention of CNS leukemia is usually effective. Patients with CNS infiltration are at higher risk of relapse than those without CNS infiltration.

Advanced therapies [25][31]

Management of complications [25]

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

5-year survival rate following treatment

  • ALL: The 5-year survival rate is generally higher compared to 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
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

To remember that translocation t(12;21) commonly manifests with pediatric B-ALL and usually has a favorable outcome, think: “Kids flip back to health!” (the number 12 is 21 flipped around).

References:[41][42][43][44][45][46]

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