- Clinical science
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.
- Acute lymphoblastic leukemia 
- Acute myeloid leukemia 
Epidemiological data refers to the US, unless otherwise specified.
- 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 . 
Genetic or chromosomal factors
- Down syndrome 
- No identifiable cause or risk factors in most cases
- Pre-existing hematopoietic disorder (most common identifiable cause) 
- Environmental factors 
- Genetic or chromosomal factors
- French-American-British (FAB) historical classification of ALL
- The current WHO Classification (2016) classifies ALL into subtypes of precursor lymphoblastic leukemia/lymphoma based on morphologic and genetic factors:
- Immunophenotype classification of ALL: based on the origin (B cell or T cell) and maturity of the leukemic cells
- 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).
- 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 liver, spleen, lymph nodes, but also testes, skin, and mediastinum)
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|
- 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)
Complete blood count
- Leukocytes: The white blood cell count (WBC) may be elevated, normal, or low and is not a reliable diagnostic marker.
- Peripheral blood smear: presence of blasts
- Additional laboratory studies
- Confirmatory diagnostic tests
|Morphology, histochemistry, cytogenetics, and immunophenotyping in ALL and AML|
|Histochemistry||(found in peroxidase-positive granules)|| || |
|Terminal deoxynucleotidyl transferase (TdT)|| || |
|(PAS)|| || |
|Immunophenotyping by flow cytometry|| |
Myelogenous leukemia is myeloperoxidase positive.
- Cerebrospinal fluid analysis: relevant for diagnosis and treatment of
- 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)
- 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 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. 
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.
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
Consolidation therapy (goal: destruction of remaining tumor cells)
- Begin after complete remission is achieved
- Duration: several months
- Medium doses
- ALL regimen: variable drug regimens
- Maintenance therapy (goal: maintaining remission)
|Common agents used in the initial treatment acute leukemia|
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: chemotherapetic therapy administered directly into the subarachnoid space via spinal tap or a device placed under the scalp
- 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).
- Indication: poor prognostic factors (e.g., unfavorable cytogenetics); or patients who do not achieve remission through chemotherapy
Supportive therapy 
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
- Mediastinal or thymic infiltration (primarily in T-cell ALL) → , airway compromise
- Severe thrombocytopenia; or anemia
- 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
Tumor lysis syndrome (TLS) 
- Description: The rapid destruction of tumor cells leads to a massive release of intracellular components, which subsequently damage the kidneys and may cause potentially life-threatening renal failure.
- Etiology: mostly occurs after initiating cytotoxic treatment of ALL, AML, or NHL
- Pathophysiology: tumor cell lysis → release of intracellular components (e.g., K+, PO43-, nucleic acid) into the bloodstream
- Clinical features
- All patients
- Possibly in addition to hydration
- Treat electrolyte abnormalities
- Rasburicase, if not already given as prophylaxis
- Fluid administration with or without loop diuretics to aid renal excretion of uric acid crystals
- Renal replacement therapy may be necessary
“PUKE calcium” for the electrolytes affected in tumor lysis syndrome: Phosphorus, Uric acid, and potassium (K+) are Elevated; Calcium is decreased.
We list the most important complications. The selection is not exhaustive.
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
|Age|| || |
|Disease features|| || |
Favorable prognostic factors
The most common specific abnormality in childhood B-ALL is the t(12;21) translocation, which is associated with a favorable outcome.