What is Chronic Myelogenous Leukemia?
Chronic myeloid leukemia is a tumorous disease that is clonal in nature and arises from the early predecessors of myelopoiesis, whose morphological substrate is predominantly mature and mature granulocytes, mainly neutrophils.
Causes of Chronic Myeloid Leukemia
In the structure of the incidence of hemoblastoses, chronic myelogenous leukemia takes the fifth place (8.9% of cases). The non-standardized average annual incidence rate per 100,000 population is 1 case. It is rarely diagnosed in childhood and adolescence, chronic myelogenous leukemia is equally common among men and women, usually people aged 30–70 years get sick, and in childhood and adolescence the disease is rare.
Pathogenesis during Chronic myelogenous leukemia
A significant increase in the incidence of chronic myelogenous leukemia in Hiroshima and Nagasaki among people in the area of the atomic bomb is one evidence of the role of radiation in its development. There is evidence of the effects of chemical compounds and birth defects of chromosomes. In most cases of chronic myelogenous leukemia, a Ph ‘chromosome is detected. This anomaly is often combined with trisomy 8, 9, 19, 21, deletion 5, and other chromosome defects. Sometimes there are cases of Ph’-negative variant of the disease.
The mitotic index and the label index of promyelocytes, bone marrow myelocytes and peripheral blood in patients with chronic myelogenous leukemia do not differ from the normative indicators, while the myeloblast fraction is characterized by kinetic parameters found in acute myeloid leukemia.
Symptoms of Chronic Myeloid Leukemia
In 86-88% of cases of chronic myeloid leukemia in the granulocytes, monocytes, erythro- and megakaryocytes of the bone marrow, a Ph’-chromosome is detected. Its absence in lymphocytes is characteristic. The number of cells with a Ph’-chromosome in the bone marrow is about 98-100%. A variant of chronic myelogenous leukemia with the absence of the Philadelphia chromosome is rare, has a more unfavorable course and a shorter average life expectancy of patients.
There are chronic, progressive and acute (blast crisis) stages of chronic myelogenous leukemia, characterized by a complex of certain signs.
The approximate formulation of the diagnosis:
- Chronic myeloid leukemia (with the presence or absence of a Ph’-chromosome) in the chronic stage with a slightly enlarged spleen, liver, slight leukocytosis and thrombocytosis.
- Chronic myeloid leukemia in a progressive stage with a marked increase in the spleen and liver, an increase in leukocytosis, anemia, thrombocytopenia, ossalgia.
- Chronic myeloid leukemia in the stage of imperious crisis, resistant to cytostatic therapy, with deep anemia, thrombocytopenic hemorrhagic syndrome of various localization, enlargement of the spleen, liver, ossalgia, intoxication.
In the early stages of the chronic stage of the disease, patients may complain of fatigue and decreased performance. The progressive stage sometimes develops after 2-10 or more years from the moment of diagnosis. It is characterized by a significant increase in the number of leukocytes mainly due to myelocytes and promyelocytes, an increase in the size of the liver and spleen, and the possible development of spleen infarcts and perisplenitis.
In patients in the stage of imperious crisis, a sharp deterioration in the general condition, signs of intoxication, fever, bone pain, anemia, hemorrhage are noted. A significant number of myeloblasts are found in the hemogram and / or in the bone marrow. In isolated cases, lymphoblasts are detected, which indicates the defeat of hematopoiesis at the level of a polypotent stem cell.
The severity of the disease is aggravated by the joining bacterial infections against the background of a decrease in the phagocytic activity of granulocytes, lysozyme content and serum beta-lysine levels, inhibition of complement production and antibody formation.
The appearance of an imminent crisis is predicted by the emergence of signs of resistance to chemotherapy and a change in the karyological profile of leukemia cells (aneuploidy mainly in the form of hyperdiploid clones, large ugly cell nuclei). The monoclonal population of cells with the Ph’chromosome is replaced by a polyclonal one, characterized by a sharp anaplasia of cells (ugliness and an increase in the diameter of cells, etc.), they extend beyond the bone marrow, metastasize to the spleen, lymph nodes, liver, bones, other organs and tissues. At the same time, individual groups of lymph nodes significantly increase, the hemogram changes: it normalizes or sharply anaplastic elements are found in it, which are difficult to identify morphologically and cytochemically. In punctate, fingerprints and biopsies of the lymph nodes, similar cells are detected. A similar course of chronic myeloid leukemia is considered the equivalent of tumor progression.
Diagnosis of Chronic Myeloid Leukemia
The stage of the course of chronic myelogenous leukemia is established on the basis of a set of clinical data and changes from the hematopoiesis taking into account the data of hemogram, myelogram, histological examination. Sometimes an insufficiently clear clinical and hematological picture at the initial stage of the chronic stage of the disease does not allow a confident diagnosis of chronic myelogenous leukemia. In these cases, the detection of the Ph’-chromosome in granulocytes, monocytes, erythro- and megakaryocytes of the bone marrow is important for diagnosis (it should be remembered about the variants of chronic myelogenous leukemia without the Ph’-chromosome).
Sometimes it is necessary to differentiate chronic myelogenous leukemia with idiopathic myelofibrosis (osteomyelosclerosis), in which for many years leukocytosis in the blood does not reach high numbers, an increase in the spleen and liver is detected; in bone marrow trepanobioptate, significant growth of fibrous tissue is detected. In the hemogram with myelofibrosis, thrombocytosis can be observed, in the bone marrow – megakaryocytosis, red cell hyperplasia, sometimes combined with an increase in the number of red blood cells in the peripheral blood. Unlike chronic myelogenous leukemia, the Ph’-chromosome is not detected, a characteristic x-ray picture of the skeleton bones is noted; the passage of the needle with a puncture of the sternum and trepanobiopsy of the ilium is difficult.
Treatment of Chronic Myeloid Leukemia
The treatment of chronic myelogenous leukemia is determined by the stage of the disease. In cases of mild clinical and hematological manifestations of the chronic stage, general strengthening therapy, good nutrition, rich in vitamins, and regular follow-up are recommended. There is evidence of a beneficial effect of α-interferon on the course of the disease.
With leukocytosis 30-50 * 109 / l, myelosan is prescribed at 2-4 mg / day, with leukocytosis up to 60-150 * 109 / l and its dose increases to 6 mg / day, with a higher leukocytosis, the daily dose of the drug can be increased to 8 mg The cytopenic effect begins to appear no earlier than on the 10th day after the start of taking myelosan. Normalization of the hemogram and a decrease in the size of the spleen usually occur at 3-6 weeks of treatment with a total dose of 250-300 mg. In the future, maintenance therapy is prescribed in the form of taking 2-4 mg of myelosan 1 time per week or periodically taking courses of myelosanotherapy when the first signs of an exacerbation of the process appear (increasing the number of leukocytes to 20-25 * 109 / l, increasing the size of the spleen), the number of platelets decreases to 100 * 109 / l, myelosan is temporarily discontinued.
Radiation therapy can be prescribed as a primary treatment mainly in cases where splenomegaly is the main clinical symptom. At the same time, the level of leukocytes should not be lower than 100 * 109 / l. Radiation therapy is stopped with a decrease in the number of leukocytes to 7-20 * 109 / L. Further supportive treatment with myelosan is prescribed no earlier than 1 month later. after the abolition of radiation therapy.
In the progressive stage of chronic myelogenous leukemia, mono- and polychemotherapy are used.
Myelobromol is prescribed for significant leukocytosis, in cases of insufficient effectiveness of myelosan at 125-250 mg per day under strict control of peripheral blood counts. Hemogram normalization usually occurs within 2-3 weeks from the start of treatment. For maintenance therapy, myelobromol is used in doses of 125-250 mg once every 5-7-10 days.
Dopan is used for significant splenomegaly, when other anti-leukemia drugs are ineffective, it is prescribed 6-10 mg / day once, 1 time in 4-6-10 or more days. The intervals between the individual receptions depend on the speed and degree of decrease in the number of leukocytes and the size of the spleen. Dopan treatment is stopped with a decrease in the number of leukocytes to 5-7 * 109 / L. Since dyspeptic symptoms may occur, the drug is prescribed after dinner followed by taking sleeping pills. Dopan can also be recommended for maintenance treatment of 6-10 mg once every 2-4 weeks under the control of hemogram data.
Hexaphosphamide is indicated mainly in cases of developed resistance to myelosan, dopan, myelobromol and radiation therapy. With a white blood cell count of more than 100 * 109 / l, it is prescribed at 20 mg per day, and at 40-60 * 109 / l – 10-20 mg 2 times a week. The dose is reduced depending on the rate of decrease in the number of leukocytes. When they decrease to 10-15 * 109 / l, the drug is canceled. The course dose is an average of 140-600 mg, the course of treatment is 10-30 days. Positive dynamics in response to treatment with hexaphosphamide appears, as a rule, after 1-2 weeks. Maintenance therapy with hexaphosphamide is carried out in doses of 10 and 20 mg once every 5, 7, 10 or 15 days.
In the treatment of the progressive stage of chronic myelogenous leukemia, the AVAMP or CVAMP programs are used. AVAMP is prescribed in the form of 1% of 2- or 10-day courses with an interval of 10 days. It includes cytosar (30 mg / m intramuscularly on the 1st and 8th day), methotrexate (12 mg / m intramuscularly on the 2nd, 5th and 9th day), vincristine (1.5 mg / m2 intravenously on the 3rd and 10th day), 6-mercaptopurine (60 mg / m2 daily), prednisone (50-60 mg / day with thrombocytopenia less than 100 * 109 / l). With preserved thrombocytopoiesis, hypertrombocytosis and the number of leukocytes in excess of 40 * 109 / l, prednisone should not be prescribed. The TsVAMP program is similar to the previous one, but instead of cytosar on the 1st, 3rd, 5th, 7th, 9th day, cyclophosphamide is administered intramuscularly in a dose of 200-400 mg. Polychemotherapy courses are carried out 3-4 times a year. In between, myelosan is prescribed according to the generally accepted methodology and 6-mercaptopurine (100 mg daily every 10 days with 10-day intervals).
The agent of choice for chronic myeloid leukemia, including blast crises, is hydroxycarbamide. Contraindications to its use: leukopenia (below 3 * 109 / l) and thrombocytopenia (below 100 * 109 / l). The initial dose of the drug is 1600 mg / m daily orally. When the number of leukocytes is less than 20 * 10 / l, the dose of hydroxycarbamide is reduced to 600 mg / m2, with their number of 5 * 109 / l or less, treatment is stopped.
With the development of resistance to cytostatic therapy at the stage of progression of the process, leukocytapheresis can be used in combination with one of the chemotherapy regimens. Urgent indications for leukocytapheresis are the clinical signs of stasis in the vessels of the brain (headaches, feeling of “heaviness” in the head, hearing loss, sensation of “hot flashes”) caused by hyperleukocytosis and hypertrombocytosis.
In blast crisis, chemotherapy programs are used for acute leukemia. The development of anemia, thrombocytopenic hemorrhage and infectious complications is an indication for transfusions of red blood cells, platelet concentrate and antibiotic therapy.
In the presence of extramedullary tumor formations that threaten the patient’s life (tonsils, closing the lumen of the larynx, etc.), radiation therapy is used.
Bone marrow transplantation can be used in patients with chronic myelogenous leukemia in the chronic phase of the disease. It provides the development of clinical and hematological remission in 70% of patients.
An urgent indication for splenectomy in chronic myelogenous leukemia is rupture and a threatening rupture of the spleen. Relative indications include severe abdominal discomfort associated with large organ sizes, repeated perisplenitis with a pronounced pain syndrome, “wandering” spleen with the danger of torsion, deep thrombocytopenia due to hypersplenism (rare), severe hemolytic crises.