Acute leukemia

Acute leukemia is a malignant neoplastic disease that arises from either the lymphoid cell line (acute lymphoblastic/lymphocytic/lymphoid leukemia, ALL) or the myeloid cell line (acute myeloid/myelogenous/myelocytic leukemia, 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.

• Acute lymphoblastic leukemia ^[1]
  • Peak incidence: 2–5 years
  • Most common malignant disease in children
  • ∼ 80% of acute leukemias during childhood are lymphoblastic.
  • ♂ > ♀
• Acute myeloid leukemia ^[2]
  • Peak incidence: 65 years
  • 80% of acute leukemias during adulthood are myelogenous.

Epidemiological data refers to the US, unless otherwise specified.

Acute lymphoblastic leukemia (ALL)

• No identifiable cause or risk factors in most cases
• Prior bone marrow damage due to alkylating chemotherapy or ionizing radiation
• Adult T-cell leukemia/lymphoma is linked to infection with HTLV. ^[3][4][5]
• Genetic or chromosomal factors
  • Down syndrome: Risk of ALL is, like that of AML, 10–20 times higher in patients with Down syndrome compared to the general population. ^[6][7]
  • Neurofibromatosis type 1
  • Ataxia telangiectasia ^[1]

Acute myeloid leukemia (AML)

• No identifiable cause or risk factors in most cases
• Pre-existing hematopoietic disorder (most common identifiable cause) ^[8]
  • Myelodysplastic syndromes
  • Aplastic anemia
  • Myeloproliferative disorders (e.g., osteomyelofibrosis; , CML)
• Environmental factors ^[2]
  • Alkylating chemotherapy
  • Ionizing radiation
  • Benzene exposure
  • Tobacco
• Genetic or chromosomal factors
  • Down syndrome: The risk of AML is, like that of ALL, 10–20 times higher in patients with Down syndrome compared to the general population. ^[7]
  • Fanconi anemia

References:^[9][10]

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
  • B-cell ALL (∼ 80–85% of cases) ^[11]
    • Early (pro-B) ALL
    • Common ALL
    • Precursor B-ALL
    • Mature B-cell ALL (also known as Burkitt leukemia)
  • T-cell ALL (∼ 15–20% of cases)
    • Early (pro-T) ALL
    • Intermediate-T ALL
    • Mature T-cell ALL

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 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]

• Acquired somatic mutations (chromosomal translocations and other genetic abnormalities) in early hematopoietic precursors; → clonal proliferation of a lymphoid or myeloid stem cell line and arrest in cell differentiation and maturation in early stages of hematopoiesis; → rapid proliferation of abnormal and dysfunctional blasts (with impaired apoptosis pathways) → accumulation of leukemic white blood cells in the bone marrow → disrupted normal hematopoiesis → leukopenia (↑ risk of infections); , thrombocytopenia (↑ bleeding); , and anemia
• Immature blasts enter the bloodstream → infiltration of other organs (particularly the CNS, testes, liver, and skin)

References:^[8][13][14]

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

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 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
  • Leukocytes: The white blood cell count (WBC) may be elevated, normal, or low and is not a reliable diagnostic marker.
    • Leukemic hiatus in AML: 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
    • ↑ Myeloblasts
    • Some subtypes (especially M3, or APL) exhibit Auer rods
      • Pink-red, rod-shaped granular cytoplasmic inclusion bodies in malignant immature myeloblasts or promyelocytes
      • Auer rods are myeloperoxidase positive.
  • ALL: ↑ lymphoblasts
• Additional laboratory studies
  • Coagulation studies: rule out DIC
  • Electrolytes and metabolic markers: ↑ PO₄^3-, ↓ Ca²⁺, ↑ K⁺, ↑ LDH, and ↑ uric acid indicate increased cell lysis

Bone marrow aspiration and biopsy

• Confirmatory diagnostic tests
  • AML: > 20% myeloblasts in the bone marrow ^[18]
  • ALL: > 20% lymphoblasts in the bone marrow ^[19]

Myelogenous leukemia is myeloperoxidase positive.

Further tests

• Cerebrospinal fluid analysis: relevant for diagnosis and treatment of leukemic meningitis
• Chest x-ray: mediastinal mass in the case of thymic infiltration (occurs primarily in T-cell ALL) or mediastinal lymphadenopathy
• Abdominal ultrasound: organ enlargement (especially the liver and/or spleen)

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

Approach

• Aggressive chemotherapy is the mainstay of treatment; prognosis is good with 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)
   • Duration: up to 24 months
   • Low doses
   • ALL regimen: may include methotrexate, vincristine; , glucocorticoids

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 occurring 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 ^{[14][29][30][31][32][33]}

• Intrathecal chemotherapy: chemotherapeutic therapy administered directly into the subarachnoid space via spinal tap or a device placed under the scalp
  • 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).

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
    • If infection is suspected or neutropenia and fever are present: IV broad-spectrum antibiotics (see neutropenic fever)
  • 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
  • Antiemetics (e.g., ondansetron)
  • Enteral and parenteral nutritional support
  • Transfusion for severe cytopenia
• Uric acid stone prophylaxis: begin prior to chemotherapy to prevent hyperuricemia and urate induced nephropathy
  • Hydration and fluid administration
  • Allopurinol and rasburicase (see tumor lysis syndrome below)

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

• Tumor lysis syndrome
• Leukostasis
• See also “Oncologic emergencies”.

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

Favorable prognostic factors

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:^{[21][38][39][40][41][42]}

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