Acute Promyelocytic Leukemia

What is Acute Promyelocytic Leukemia?

Acute leukemia is a promyelocytic subtype of acute myeloid leukemia (AML), cancer from the blood and bone marrow. It is also known as acute progranulocytic leukemia; APL AML with T (15, 17) (q22; q12), PML-PAPA and variants; FAB subtype M3 and M3 option.

In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized by chromosomal translocation involving the retinoic acid alpha receptor (RARα or PAPA) gene and the only other form of anti-money laundering in its ability to respond to all trans-retinoic acid (ATRA) therapy.

Acute promyelocytic leukemia was first characterized in 1957. In the 1950s and 1970s, APL had 100% mortality and there was no effective treatment. No one knew how cancer formed.

Causes of Acute Promyelocytic Leukemia

Acute promyelocytic leukemia represents 5-8% AML in adults. The average age is approximately 40 years, which is significantly younger than other subtypes of AML (70 years). Without proper treatment and medication, APL is fatal. Incidence increases in patients originated in Latin America.

APL has a high relapse rate with conventional chemotherapy.

The normal differentiation of white blood cells in the bone marrow begins with several powerful hematopietic stem cells (HSCs). Several transcriptions of factors such as PU.1 and C / E. B. protein alpha have been identified to be extremely important in the differentiation of white blood cells. HSC generates lymphoid (B cells and T cells of our immune system) cell lines and myeloid cell lines. The myeloid cell lines in the granules are in their cytoplasm, and they are called granulocytes and play an important role in the fight against infections.

The accumulation of promyelocytes in the bone marrow results in a decrease in the production of normal red blood cells and platelets, resulting in anemia and thrombocytopenia. The bone marrow is not able to produce healthy red blood cells. Either leukopenia (low white body count) or leukocytosis (high white blood cell count) can occur in peripheral blood.

Pathogenesis during Acute Promyelocytic Leukemia

Acute promyelocytic leukemia is characterized by chromosomal translocation involving retinoic acid alpha gene receptor on chromosome 17 (RARα). In 95% of cases of APL, the retinoic acid receptor-alpha (RARα) gene of Nachromosome 17 is involved in mutual translocations from the promyelocytic leukemia gene (PML) on chromosome 15, translocation is designated as T (15; 17) (q22; q12). RAR receptors are dependent on retinoic acid to regulate transcription.

Four other gene permutations have been described in the fusion of RARα APL in finger promyelocytic zinc leukemia (PLZF), nucleophosmin (NPM), nuclear matrix linked (NUMA), or a 5b signal transducer and activator (STAT5B) of the genes. All these permutations are ATRA-sensitive, with the exception of PLZF / RARα, which is resistant to ATRA.

The fusion of PML and RAR creates a fusion protein with altered functions. This fusion protein binds to increased affinity for sites on cell DNA, blocking transcription and differentiation of granulocytes. This is achieved by enhancing the interaction of the nuclear co-repressor (NCOR) molecule and histone deacetylase (HDACL). Although chromosomal translocations involving RARα are thought to be the initial event, additional mutations are necessary for the development of leukemia.

APL is the most distinguishable feature of true overt coagulopathy (DIC) at the time of diagnosis. Hemorrhagic diathesis is associated with enhanced fibrinolytic activity due to annexin II overexpression and expression of tissue factor by abnormal promyelocytes.

The hypergranular form of APL features fagot cells. The term applies to these blast cells due to the presence of numerous Auer rods in the cytoplasm. The accumulation of these Auer rods gives rise to brushwood, from which the cells get their name.

Symptoms of Acute Promyelocytic Leukemia

Symptoms include:

  • Fatigue, weakness, shortness of breath (from anemia) – a decrease in normal red blood cell production or lack of it
  • Easy bruising and bleeding (from thrombocytopenia and coagulopathy), which causes blood clotting
  • Fever and infections (due to lack of normal white blood cells)
  • An enlarged spleen can cause minor discomfort in the abdomen.

In addition, acute promyelocytic leukemia is often associated with bleeding caused by disseminated intravascular coagulation (DIC). It is characterized by the rapid growth of immature white blood cells as a result of the rapid progression of malignant cells and a crowd of bone marrow. This will lead to very low red blood cells (anemia) and low platelets, which can lead to serious bleeding.

Diagnosis of Acute Promyelocytic Leukemia

Acute leukemia of promyelocytic can be distinguished from other types of anti-money laundering on the basis of a morphological study of bone marrow or biopsy, as well as to establish characteristic permutations. Final diagnosis requires testing for PML / RARα gene fusion. This can be done by polymerase chain reaction (PCR), luminescent hybridization (FISH), or the usual cytogenetics of peripheral blood or bone marrow. This mutation involves translocation of long arm chromosomes from 15 to 17.

RARα is a member of the nuclear family of receptors, its ligand, retinoic acid is a form of vitamin A and acts as a regulator of DNA transcription at several sites.

Relapse monitoring using PCR tests for PML / RARα transcript allows early re-treatment of which is successful in many cases.

Treatment of Acute Promyelocytic Leukemia

It is effective to treat rubomycin or rubomycin in combination with cytosar, the full dose of which is possible with a decrease in hemorrhage and an increase in platelet count.

In case of acute promyelocytic leukemia, the doctor should keep in mind the frequency of DIC, the existence of consumption thrombocytopenia, the need to use contracal, heparin, and freshly frozen plasma to suppress DIC.

Since deep neutropenia is often observed with this form of acute leukemia, the patient is hospitalized in an isolation ward. In the early days of monitoring such a patient, if there is no platelet mass, large doses of prednisolone, which impede the release of proteolytic enzymes from the cells, are used to reduce hemorrhage, and contricated 80,000–100,000 units several times a day, intravenously, as an antiproteolytic agent and an agent that helps maintain normal hemodynamics, which is necessary in cases of severe intoxication. DIC-syndrome requires the use of heparin 1000-2000 units every 2-4 hours intravenously. Bleeding caused by DIC-syndrome, stops along with large doses of contracal and heparin, the transfusion of large quantities of freshly frozen plasma – 600 ml or more simultaneously.

Platelet transfusion at a dose of 2-4 doses 2-3 times a week is an event necessary for sufficient cytostatic therapy with both promyelocytic and other forms of leukemia with deep thrombocytopenia (below 20 × 103 in 1 μl). With an increase in platelet count, the use of rubomycin or rubomycin with cytosar in the combination of “5 + 2” or “7 + 3” becomes less dangerous. Rubomycin in these courses is administered in a total dose of 120-200 mg per course for 3-5 days. In the absence of platelet mass, rubomycin must be administered in small doses (20-40 mg per day), adding prednisolone, transfusing countercal; 6-mercaptopurine can be used in combination with prednisone and vincristine, but achieving remission becomes significantly less likely.

Erythrocyte mass transfusion or whole blood sludge in acute promyelocytic leukemia is performed only for health reasons (the appearance of hemodynamic disturbances); they are possible only after the suppression of hemorrhagic syndrome, as they enhance the DIC. In acute promyelocytic leukemia, cytotoxic drugs leading to the elimination of leukemic cells are the main means of persistent suppression of DIC.

Cytostatic therapy gives poor results in acute non-lymphoblastic leukemia, which for some time flows with a relatively low percentage of blasts in the bone marrow, but with partial cytopenia or pancytopenia, namely those forms that are classified as so-called myelopoietic dysplasia. At the stage of low blastosis and during the leukemia of the process, it is usually not controlled by cytostatics, administered in combination or separately. The percentage of improvements in these forms of acute leukemia is not more than 20%.

Only in 10% of cases is it possible to achieve improvement in the so-called secondary acute non-lymphoblastic leukemia that develops in people treated with cytostatics and radiation or only cytostatics for lymphogranulomatosis, cancer and other diseases. Such improvements are short and last about 3 months.

A low-percentage form of acute leukemia does not require active treatment with cytostatic drugs. Treatment is limited to prescribing small doses of steroid hormones (20 mg / day), or connecting small doses of 6-mercaptopurine (100 mg) for 10-14 days of each month, if it does not cause an increase in neutropenia, or small doses of cytosar (10 mg / day). Most often, such patients need to maintain indicators of red blood, hemoglobin approximately at the level of 8.3 g / l with repeated transfusions of red blood cells (preferably frozen).