Pathophysiology
Summary
Leukemia originates from the bone marrow, characterized by an overflow of abnormal cells into the peripheral blood. Acute myeloid leukemia (AML) stems the rapid growth of immature granulocyte and monocyte precursors called myeloblasts in the bone marrow, AML primarily affects older adults, especially those over 65 yrs with a history of prior chemotherapy, ionizing radiation, or benzene exposure. Down syndrome also increase the risk of AML. Myeloproliferative disorders and myelodysplastic syndrome can progress into AML.
Clinically, AML presents with symptoms of functional pancytopenia such as thrombocytopenia, anemia, and functional neutropenia, which often coexists with leukocytosis from proliferating myeloblasts. Symptoms of AML include weakness, fatigue, fever, bone pain, signs of thrombocytopenia like petechiae and ecchymosis. CML is diagnosed as > 20% myeloblasts (basophilic cytoplasm, faint granules, and prominent bilobed nuclei) in bone marrow cells or peripheral WBCs. A key feature in some AML variants is the presence of Auer rods, pink structures in the myeloblast cytoplasm due to crystallization of the myeloperoxidase enzyme.
Acute promyelocytic leukemia (APL) is subtype of AML that features promyelocytes filled with Auer rods. APL occurs from a translocation between chromosomes 15 & 17, producing the PML/RARalpha fusion protein. This abnormal protein inhibits myeloid differentiation at the promyelocytic stage. A critical clinical implication of APL is the risk of disseminated intravascular coagulation (DIC) due to the release of tissue factor by promyelocytes. All-trans-retinoic acid, a Vitamin A analog, prompts the abnormal promyelocytes to mature into neutrophils and is used to treat APL.
Chronic myelogenous leukemia (CML) originates from the proliferation of mature granulocyte progenitor cells in the bone marrow and typically manifests during its chronic phase. CML is more common in the elderly and is associated with exposure to ionizing radiation. The hallmark of CML is the BCR-ABL fusion gene, which stems from a translocation merging the ABL gene from chromosome 9 with the BCR gene on chromosome 22, forming the distinctive Philadelphia chromosome. This fusion results in a continuously active receptor tyrosine kinase.
Clinically, CML presents with leukocytosis, dominated by variety of granulocytes, but with increased number of myelocytes compared to other myeloid precursors. Complications due to excessive platelets include thrombocytosis or hemorrhage from the consumption of available von Willebrand factor. Moreover, patients may develop normochromic, normocytic anemia, splenomegaly from extramedullary hematopoiesis, and even splenic infarcts. Over time, CML can transition from the chronic phase to an ‘accelerated stage,’ marked by thrombocytopenia, eventually culminating in ‘blast crisis’ from a surge in myeloblasts that mirrors the presentation of AML. Treatment predominantly involves tyrosine kinase inhibitors like imatinib, dasatinib, and nilotinib that target the kinase activity of the BCR-ABL protein.
A leukemoid reaction is a benign state characterized by a WBC exceeding 50,000—primarily neutrophils—and is often triggered by infections. Peripheral blood smear shows bands or slightly immature neutrophils, leading to a left shift in WBC distribution. Leukocyte alkaline phosphatase (LAP) can be used to differentiate CML from a leukemoid reaction, which is either normal or elevated in leukemoid reactions but reduced in CML. Additionally, during infections or inflammation, neutrophils in a leukemoid reaction may exhibit toxic granulation, Dohle bodies, & cytoplasmic vacuoles, features not typically seen in CML.
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FAQs
AML originates from the rapid proliferation of immature granulocyte and monocyte precursors, known as myeloblasts, in the bone marrow. This leads to an acute onset of the disease. In contrast, CML involves the proliferation of more mature granulocyte progenitor cells in the bone marrow. The term ‘chronic’ denotes that most patients experience a gradual onset of symptoms, indicating a slower disease progression compared to AML.
Individuals with AML often experience weakness and fatigue due to anemia. They may also present with fever, which can be attributed to either an infection or the disease itself. Bone pain can occur because of bone marrow expansion. Additionally, due to thrombocytopenia, patients may exhibit petechiae and ecchymosis. While AML can lead to leukocytosis, the white blood cells are typically non-functional.
APL is a specific subtype of AML. It is characterized by the presence of promyelocytes, which are immature myeloid cells that contain Auer rods (crystallization of MPO enzyme). A common cause of APL is a translocation between chromosomes 15 and 17, resulting in a PML/RARalpha fusion protein. This fusion protein disrupts myeloid differentiation at the promyelocytic stage. APL has the potential to cause disseminated intravascular coagulation (DIC). Treatment includes all-trans-retinoic acid, which encourages the differentiation of these cells into mature neutrophils.
Patients with CML often present with leukocytosis, which is attributed to an increase in mature and partially mature granulocytes. CML can also cause thrombocytosis, resulting in complications like thrombosis and hemorrhage. Anemia is also common in CML patients, as well as splenomegaly due to extramedullary hematopoiesis. Over time, CML can progress to an aggressive 'accelerated stage' characterized by a rise in immature granulocytes, which may evolve to a 'blast crisis' that mirrors AML.
A leukemoid reaction is typically a benign condition marked by a significant increase in white blood cell count, predominantly neutrophils, often in response to an infection. In contrast, CML is a malignant condition characterized by an overproduction of granulocytes. A key distinguishing factor between the two is the leukocyte alkaline phosphatase (LAP) score. In a leukemoid reaction, the LAP score is usually normal or elevated due to the presence of functional neutrophils. However, in CML, the LAP score tends to be low as the neutrophils are dysfunctional.
