Chronic Myeloid Leukaemia

Symptoms

The stage of the illness affects the clinical picture. The chronic phase can extend up to 10 years, with an average duration of two to three years. This stage of chronic myeloid leukaemia is characterised by an asymptomatic course or the progressive emergence of "mild" symptoms, such as weakness, a sense of fullness in the belly, some malaise, and a diminished capacity to function. An enlarged spleen may be seen during an objective examination of a patient with chronic myeloid leukaemia. Blood tests indicate an increase in granulocytes of up to 50–200 thousand/l in cases with asymptomatic illness and up to 200–1000 thousand/l in cases of "mild" symptoms.

Haemoglobin levels may drop a little in the early stages of chronic myeloid leukaemia. Anaemia with normochromic normocytic characteristics follows. Patients with chronic myeloid leukaemia have a preponderance of juvenile granulocyte forms, such as myelocytes, promyelocytes, and myeloblasts, on a blood smear. There are variations (abundant or very sparse) from the typical degree of granularity in both directions. Cells have basophilic, immature cytoplasm. Anisocytosis has been identified. The chronic phase transitions into the acceleration phase in the absence of therapy.

Both a change in test parameters and a decline in patients' conditions may signal the start of the acceleration phase. Increased weakness, an enlarged liver, and a gradual expansion of the spleen are possible symptoms. Clinical symptoms of anaemia and thrombocytopenia or thrombocytosis, such as pallor, weariness, dizziness, petechiae, haemorrhage, and increased bleeding, are seen in individuals with chronic myeloid leukaemia. Leukocyte counts in the blood of individuals with chronic myeloid leukaemia steadily rise despite continued therapy. Single blast cells might occur concurrently with an increase in the number of metamyelocytes and myelocytes.

A patient with chronic myelogenous leukaemia has a dramatic decline in their health along with a blast crisis. A monoclonal neoplasm changes into a polyclonal one, and new chromosomal abnormalities appear. When normal hematopoietic sprouts are inhibited, cellular atypia increases. Thrombocytopenia and anaemia are clearly present. More than 30% of all blasts and promyelocytes are found in peripheral blood, while more than 50% are found in bone marrow. Loss of appetite and weight are common in people with chronic myeloid leukaemia. Chloromas, or extramedullary foci of immature cells, exist. Significant infection problems and bleeding occur.
 

Causes

Chronic myeloid leukemia is considered the first disease in which a link between the development of pathology and a specific genetic disorder has been reliably established. In 95% of cases, the confirmed cause of chronic myeloid leukemia is a chromosomal translocation known as the "philadelphia chromosome". The mutual replacement of chromosomal 9 and 22 regions is the fundamental component of translocation. This replacement results in the formation of a stable open reading frame. The emergence of a frame accelerates cell division and inhibits DNA repair, which raises the possibility of further genetic anomalies.

Among the possible factors contributing to the appearance of the philadelphia chromosome in patients with chronic myeloid leukemia, ionizing radiation and contact with certain chemical compounds are called.
 

Treatment

Depending on the stage of the disease and the severity of the clinical signs, the treatment strategy is chosen. They are only allowed to use restorative treatments during the chronic phase, which has an asymptomatic course and slight laboratory abnormalities.Patients with chronic myelogenous leukemia are advised to follow the regime of work and rest, eat food rich in vitamins, etc. Treatment may include:
1.  Tyrosine kinase inhibitors. Imatinib is used as a first-line treatment for newly diagnosed cml. More than 80% of patients achieve complete cytogenetic remission. Another tyrosine kinase inhibitor, dasatinib, is used in patients for whom imatinib has not been effective.
2.  Chemotherapy in high doses and bone marrow transplantation. Allogeneic transplantation is used from a related or unrelated donor, selected according to the hla system. This method (especially if it is used during the first year of the disease) makes it possible to achieve complete clinical and hematological remission in 60% of patients for 5 years or more.
3.  Biotherapy or immunotherapy - a 2 -interferon. Interferon, providing antiproliferative, immunomodulatory and antiviral effects, induces cell differentiation. The drug significantly reduces the number of leukocytes and platelets. With a decrease in the number of leukocytes below 4 x 10 9 / l and 2 -interferon should not be used. With severe thrombocytopenia, treatment with a 2 -interferon is not carried out. When using one a 2 -interferon, complete hematological remission occurs slowly and mainly in untreated patients with a short duration of the disease.
4.  Chemotherapy with hydroxyurea, busulfan.
5.  Surgical treatment - splenectomy. Indications for splenectomy in cml are:
• urgent - rupture and threatening rupture of the spleen;
• relative - severe abdominal discomfort associated with the large size of the spleen, repeated perisplenitis with a pronounced pain syndrome; wandering spleen with danger of pedicle torsion, deep thrombocytopenia due to hypersplenism; significant hemolytic crises. It is generally accepted to start treatment for chronic cml with imatinib 400 mg/day. The exceptions are children who have an identical hla brother or sister, and patients who have an identical twin. In this case, bone marrow transplantation is possible. So, a patient from a developing country is not able to pay for imatinib for a long time, but can pay once for a bone marrow transplant.
At the stage of acceleration, the following methods of treatment can be used.
1.  Bone marrow transplantation.
2.  Tyrosine kinase inhibitors.
3.  Biotherapy or immunotherapy.
4.  Chemotherapy in high doses.
5.  Chemotherapy.
6.  Infusion of donor erythrocytes, platelets, sometimes lymphocytes to relieve symptoms and improve quality of life.
If cml is diagnosed at the accelerated stage, imatinib therapy can be started at a dose of 600-800 mg/day. If disease has progressed to the accelerated stage on imatinib therapy, a second-generation tyrosine kinase inhibitor should be given. If a suitable donor is available, allogeneic bone marrow transplantation is possible.
At the stage of blast crisis, the following methods of treatment can be used.
1.  Tyrosine kinase inhibitors.
2.  Mono or polychemotherapy.
3.  Chemotherapy in high doses.
4.  Donor bone marrow transplantation.
5.  Palliative chemotherapy to relieve symptoms and improve quality of life.
The following methods can be used to treat recurrent cml.
1.  Tyrosine kinase inhibitors.
2.  Donor bone marrow transplantation.
3.  Infusion of donor lymphocytes.
4.  Biotherapy or immunotherapy.
Other treatments.
1.  Radiation therapy. The main indications are:
-  extramedullary tumor formations that threaten the life of the patient (tonsils, lumen of the larynx, etc.);
-  pronounced splenomegaly and perisplenitis. Gamma therapy or telegamma therapy is applied to the area
Spleen at a dose of approximately 1 gy. The number of sessions is determined by the degree of reduction in the size of the spleen and the dynamics of the parameters of the general blood test (leukocytes, platelets).
2.  Leukocytopheresis. The purpose of this method is to reduce the mass of tumor cells. The main indication is resistance to cytostatic therapy. Urgent indications are clinical signs of stasis in the vessels of the brain, due to hyperleukocytosis and hyperthrombocytosis.
Intermittent (4-5 r / month) or intensive (4-5 r / week) leukocytopheresis reduces leukocytosis by 75%, thrombocytosis - by 35%. Typically used in combination with cytostatic therapy.
Symptomatic therapy consists in carrying out detoxification measures, treatment of infectious complications, anemia, thrombocytopenia. Given the increased cellular decay, accompanied by increased intoxication, hyperuricemia, infusion therapy, allopurinol, is prescribed in the treatment with cytostatic drugs.

Tests Required for Diagnosis

The diagnosis is established on the basis of the clinical picture and the results of laboratory tests. The first suspicion of chronic myeloid leukemia often occurs with an increase in the level of granulocytes in the general blood test, prescribed as a preventive examination or examination in connection with another disease. 

To clarify the diagnosis, data from a histological examination of the material obtained by sternal puncture of the bone marrow can be used, however, the final diagnosis of chronic myeloid leukemia is made when the philadelphia chromosome is detected using pcr, fluorescent hybridization, or cytogenetic studies.

The question of the possibility of making a diagnosis of chronic myeloid leukemia in the absence of the philadelphia chromosome remains debatable. Many researchers believe that such cases can be explained by complex chromosomal disorders, due to which the identification of this translocation becomes difficult. In some cases, the philadelphia chromosome can be detected using reverse transcription pcr. With negative test results and an atypical course of the disease, one usually speaks not of chronic myeloid leukemia, but of an undifferentiated myeloproliferative / myelodysplastic disorder.

Useful info

The timing of therapy beginning (during the chronic phase, the activation phase, or the blast crisis) has a significant impact on the prognosis for chronic myeloid leukaemia. A significant increase in the liver and spleen (liver protrudes 6 cm or more from under the edge of the costal arch, spleen by 15 cm or more), leukocytosis over 100x10 9 /l, thrombocytopenia less than 150x10 9 /l, thrombocytosis more than 500x10 9 /l, and anaemia are all considered unfavourable prognostic signs of chronic myeloid leukaemia, an increase of at least 1% in the proportion of blast cells in the peripheral blood and an increase of at least 30% in the combined proportion of promyelocytes and blast cells.

As the number of symptoms rises in chronic myelogenous leukaemia, the chance of a bad result rises as well. Infectious complications or major haemorrhages are the causes of mortality. Patients with chronic myeloid leukaemia have a median life expectancy of 2.5 years, however this number can rise to many decades with prompt therapy beginning and a favourable course of the illness.