A COMPREHENSIVE REVIEW OF ACUTE LEUKEMIAS

Introduction

Acute leukemias are a group of aggressive blood cancers that affect the white blood cells, which are responsible for fighting infections and diseases in the body. There are two main types of acute leukemias: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

ALL is more common in children, while AML is more common in adults. Both types of leukemia are characterized by the rapid growth and accumulation of abnormal white blood cells in the bone marrow, which can eventually spread to other parts of the body.

Symptoms of acute leukemia may include fatigue, fever, frequent infections, easy bruising or bleeding, and bone pain. Diagnosis usually involves blood tests, bone marrow biopsy, and imaging tests to determine the extent of the disease.

Treatment for acute leukemia typically involves chemotherapy, radiation therapy, and stem cell transplant. Supportive care such as blood transfusions and antibiotics may also be needed to manage symptoms and prevent complications.

The prognosis for acute leukemia varies depending on several factors, including the age of the patient, the type of leukemia, and the extent of the disease. However, with prompt and aggressive treatment, many patients can achieve remission and may be cured of the disease.

 

The French-American-British (FAB) system was a classification system used to further subdivide AML and ALL based on the morphology, or appearance, of the blasts. The FAB system was developed in the 1970s and was based on the analysis of thousands of leukemia cases by a group of pathologists from France, the United States, and Britain. The FAB system divides AML into eight subtypes, designated M0 through M7, based on the percentage of blasts in the bone marrow and the appearance of those blasts under the microscope. ALL is divided into three subtypes, designated L1, L2, and L3, based on the appearance of the blasts under the microscope.

 

The subtypes of FAB classification of leukemia are as follows:

1) Acute myeloid leukemia (AML): AML is divided into eight subtypes based on the type and maturation stage of the leukemic cells. The eight subtypes include M0 through M7, with M0 being the least differentiated and M7 being the most differentiated.

 

2) Acute lymphoblastic leukemia (ALL): ALL is divided into three subtypes, L1, L2, and L3, based on the morphology of the leukemic cells. L1 is the most common subtype and is characterized by small, uniform blasts, while L2 is characterized by larger blasts with more variable morphology. L3, also known as Burkitt’s leukemia, is a rare subtype characterized by large, uniform blasts with basophilic cytoplasm and multiple nucleoli.

 

Here is a brief explanation of each subtype of AML and ALL in the FAB classification:

AML subtypes:

• M0: Undifferentiated acute myeloblastic leukemia
• M1: Acute myeloblastic leukemia with minimal differentiation
• M2: Acute myeloblastic leukemia with differentiation
• M3: Acute promyelocytic leukemia
• M4: Acute myelomonocytic leukemia
• M4eo: Acute myelomonocytic leukemia with eosinophilia
• M5: Acute monocytic leukemia
• M6: Acute erythroid leukemia
• M7: Acute megakaryoblastic leukemia

 

ALL subtypes:

• L1: Small uniform lymphoblasts
• L2: Large, more variable lymphoblasts
• L3: Large, uniform lymphoblasts with basophilic cytoplasm and multiple nucleoli.

It’s worth noting that the FAB classification is an older system that has largely been replaced by newer classifications, such as the World Health Organization (WHO) classification.

 

The term “blast” refers to an immature blood cell that has not yet developed into a mature blood cell. Blasts are typically found in the bone marrow and in the peripheral blood of individuals with acute leukemias. The presence of blasts in the blood or bone marrow is one of the key diagnostic criteria for acute leukemia. Under the microscope, blasts appear larger and less mature than normal blood cells, with a high nucleus-to-cytoplasm ratio and a large, prominent nucleolus.

 

B and T lymphocytes undergo a series of phenotypic changes during their differentiation and maturation. These changes are critical for their proper development and function in the immune system.

In B lymphocytes, the earliest precursor cells express the B-cell receptor (BCR) and CD19. As they mature, they acquire additional surface markers such as CD10, CD20, and CD21. Mature B cells also express immunoglobulins (Igs) on their surface, which are used to recognize and bind to specific antigens.

Similarly, in T lymphocytes, the earliest precursor cells express the T-cell receptor (TCR) and CD3. As they mature, they acquire additional surface markers such as CD4 or CD8, which determine their function as helper T cells or cytotoxic T cells, respectively. Mature T cells also express CD45RO or CD45RA, which reflect their memory or naïve status, respectively.

In acute lymphoblastic leukemia (ALL), there is an uncontrolled proliferation of lymphoid precursor cells, leading to the accumulation of immature lymphocytes. These cells often display aberrant expression of surface markers and may lack some of the typical markers seen in normal B or T cells. For example, in B-cell ALL, the leukemic cells may express CD10, CD19, and CD20, but not surface immunoglobulin, which is normally present on mature B cells. In T-cell ALL, the leukemic cells may express CD3, but not CD4 or CD8, which are normally present on mature T cells.

Furthermore, ALL cells may express additional markers not typically seen in normal lymphocytes, such as CD33 or CD34. The presence of these abnormal surface markers can be used to diagnose and classify different subtypes of ALL, as well as guide treatment decisions.

 

 

Complications:

• Infection: Patients with acute leukemia are at a high risk of developing infections due to low white blood cell counts.
• Bleeding: Low platelet counts can result in bruising and bleeding, which can be life-threatening.
• Organ failure: Leukemia cells can infiltrate organs, leading to organ failure.
• Tumor lysis syndrome: Rapid breakdown of leukemia cells can lead to a build-up of uric acid, potassium, and phosphate in the blood, which can cause kidney failure and cardiac arrest.

 

Patient management:

• Chemotherapy: The main treatment for acute leukemia is chemotherapy, which is given in cycles over several months. The goal is to eradicate all leukemia cells from the body.
• Stem cell transplant: In some cases, a stem cell transplant may be necessary to replace the patient’s bone marrow with healthy stem cells.
• Supportive care: Patients with acute leukemia may require transfusions of red blood cells, platelets, and other blood products to manage complications such as anemia and bleeding. Antibiotics and antifungal medications may also be given to prevent and treat infections. Pain management and psychological support are also important components of patient care.
• Monitoring: Regular blood tests and bone marrow biopsies are used to monitor the patient’s response to treatment and detect any relapses.

 

Myeloperoxidase, non-specific esterase, and TDT (terminal deoxynucleotidyl transferase) are enzymes that are commonly used in the diagnosis of acute leukemias.

1) Myeloperoxidase: This enzyme is present in myeloid cells and is used to differentiate acute myeloid leukemia (AML) from acute lymphoblastic leukemia (ALL). AML cells are positive for myeloperoxidase, while ALL cells are negative. Myeloperoxidase can be detected using a cytochemical staining technique on bone marrow or blood samples.

 

2) Non-specific esterase: This enzyme is present in monocytes and some granulocytes. It is used to differentiate acute monocytic leukemia (AML-M5) from other types of AML. AML-M5 cells are positive for non-specific esterase, while other types of AML are negative. Non-specific esterase can be detected using a cytochemical staining technique on bone marrow or blood samples.

 

3) TDT: This enzyme is present in early lymphoid and myeloid precursor cells. It is used to diagnose acute lymphoblastic leukemia (ALL) and to differentiate it from other types of leukemia. TDT is detected using immunohistochemical or flow cytometric techniques on bone marrow or blood samples.

In summary, myeloperoxidase and non-specific esterase are used to differentiate AML from ALL and to distinguish AML-M5 from other types of AML, respectively. TDT is used to diagnose ALL and to differentiate it from other types of leukemia. These tests are important in the accurate diagnosis of acute leukemias and in guiding appropriate treatment decisions.

 

Chromosomal abnormalities are common in acute leukemias and can be useful for diagnosis, risk stratification, and treatment planning. Here are six chromosomal abnormalities associated with acute leukemias and their oncogenes:

t(8;21)(q22;q22): This chromosomal translocation is found in 5-10% of cases of acute myeloid leukemia (AML) and results in the fusion of the RUNX1 (also known as AML1) gene on chromosome 21 with the ETO (also known as RUNX1T1) gene on chromosome 8. The resulting RUNX1-ETO fusion protein blocks myeloid differentiation and promotes leukemogenesis. AML patients with this translocation have a favorable prognosis and are usually treated with chemotherapy.

 

t(15;17)(q22;q21): This chromosomal translocation is found in most cases of acute promyelocytic leukemia (APL) and results in the fusion of the PML gene on chromosome 15 with the RARA gene on chromosome 17. The resulting PML-RARA fusion protein blocks myeloid differentiation and promotes leukemogenesis. APL patients with this translocation have a high risk of bleeding and require aggressive management. However, with all-trans retinoic acid (ATRA) and chemotherapy, they have a good prognosis.

 

inv(16)(p13.1q22) or t(16;16)(p13.1;q22): These chromosomal abnormalities are found in 5-10% of cases of AML and result in the fusion of the CBFB (core-binding factor subunit beta) gene on chromosome 16 with the MYH11 (myosin heavy chain 11) gene on chromosome 16. The resulting CBFB-MYH11 fusion protein blocks myeloid differentiation and promotes leukemogenesis. AML patients with this abnormality have a favorable prognosis and are treated with chemotherapy.

 

t(9;22)(q34;q11): This chromosomal translocation is found in 25-30% of cases of chronic myeloid leukemia (CML) and in a small percentage of cases of acute lymphoblastic leukemia (ALL). It results in the fusion of the BCR (breakpoint cluster region) gene on chromosome 22 with the ABL1 (Abelson murine leukemia viral oncogene homolog 1) gene on chromosome 9. The resulting BCR-ABL1 fusion protein is a constitutively active tyrosine kinase that promotes leukemogenesis. Patients with this translocation have a poor prognosis and require targeted therapy with tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, or nilotinib.

 

t(12;21)(p13;q22): This chromosomal translocation is found in approximately 25% of cases of childhood ALL and results in the fusion of the ETV6 (ETS variant transcription factor 6) gene on chromosome 12 with the RUNX1 (AML1) gene on chromosome 21. The resulting ETV6-RUNX1 fusion protein blocks lymphoid differentiation and promotes leukemogenesis. Patients with this translocation have a good prognosis and are usually treated with chemotherapy.

 

t(1;19)(q23;p13): This chromosomal translocation is found in approximately 5% of cases of childhood ALL and results in the fusion of the PBX1 (pre-B-cell leukemia homeobox 1) gene on chromosome 1 with the E2A (transcription factor 3). The prognosis for patients with this chromosomal translocation is variable and depends on several factors, including the age of the patient, the initial white blood cell count, and the response to treatment. However, in general, patients with t(1;19)(q23;p13) have a higher risk of relapse and a poorer overall survival compared to other subtypes of ALL. Therefore, this subtype of ALL may require more intensive treatment and close monitoring to improve the chances of a successful outcome.