Leukemia

Leukemia is a term that unites numerous tumors of the hematopoietic system, originating from the hematopoietic cells and affecting the bone marrow. The division of leukemia into two main groups-acute and chronic-is determined by the structure of tumor cells: leukemias are classified as acute, the cellular substrate of which is represented by blasts, and chronic leukemia, in which the bulk of tumor cells is differentiated and consists mainly of mature elements. Duration of the disease does not determine the attribution of a leukemia to a group of acute or chronic.

Etiology, pathogenesis. The cause of acute leukemia and chronic myelogenous leukemia can be a violation of the composition and structure of the chromosome apparatus, hereditary caused or acquired under the influence of some mutagenic factors. One of them is ionizing radiation. The cause of leukemia development is also the action of chemical mutagens. Acute leukemia is more frequent among people exposed to benzene, as well as among patients who received cytostatic immunosuppressants (imarant, cyclophosphamide, leukaran, sarcolysin, Mustargen, etc.); The frequency of acute leukemias among this contingent of patients is increased hundreds of times. There are facts of acute myeloblastic leukemia, acute erythromyelosis on the background of chronic chemotherapy of chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, myeloma, lymphogranulomatosis and other tumors. The role of hereditary defects in myeloid and lymphatic tissue is predisposed to gluten. Observations of the dominant and recessive inheritance of chronic lymphocytic leukemia have been reported, a low incidence of this leukemia in some ethnic groups and an elevated incidence in others. More often in these cases, not leukemia itself is inherited, but increased variability - chromosome instability, predisposing the ancestral myeloid or lymphatic cells to leukemic transformation.

The use of chromosome analysis made it possible to establish that, in any leukemia, a clone of tumor leukemia cells descended from one originally mutated cell. The instability of the genotype of malignant cells in leukemia causes the emergence of new clones in the initial tumor clone, among which in the process of vital activity of the organism, and under the influence of therapeutic agents, the most autonomous clones are selected. This phenomenon explains the progression of leukemia, their escape from the control of cytostatics.

Leukemia acute. The following basic forms of acute leukemia are distinguished according to morphological (mainly cytochemical) criteria: lymphoblastic, myeloblastic, promyelocytic, myelomonoblast, monoblast, megakaryoblastic, erythromyelosis, plasmablastic, undifferentiated, low-percentage acute leukemia.

All acute leukemias are characterized by an increasing "causeless" weakness, malaise, sometimes shortness of breath, dizziness caused by anemia. Increased body temperature, intoxication - frequent symptoms of non-lymphoblastic acute leukemia. The enlargement of the lymph nodes, liver and spleen in the expanded stage occurs not with all acute leukemias, but can develop independently of the form of acute leukemia in the terminal stage. It is often hemorrhagic syndrome caused primarily by thrombocytopenia: bleeding of the mucous membranes, petechial rash on the skin, especially the legs. In the lungs, myocardium and other tissues and organs, leukemic blast infiltrates can appear.

Diagnosis of acute leukemia is based on data from a cytological study of blood and bone marrow, revealing a high percentage of blast cells. In the early stages, they are usually not present in the blood, but cytopenia is expressed. Therefore, in cytopenia, even concerning one germ, a bone marrow puncture is necessary, which can be done on an outpatient basis. In the bone marrow there is a high (ten percent) blast content for all acute leukemias, with the exception of acute low-grade leukemia, in which the percentage of blast cells may be less than 15-20 for many months in the blood and bone marrow, and in the bone marrow with this form , As a rule, the percentage of blasts is less than in blood. The form of acute leukemia is established using histochemical methods.

The most frequent forms of acute leukemia in adults are myeloblastic and myelomonoblastic leukemia. At the beginning of the disease with these forms, the liver and spleen are usually of normal size, the lymph nodes are not enlarged, but deep granulocytopenia, anemia, thrombocytopenia are also common. Often expressed intoxication, increased body temperature. Powerful cells have structural nuclei with a delicate network of chromatin, often several small nucleoli; The cytoplasm of blast cells contains an azurophilic granularity or Auer's bodies that give a positive reaction to peroxidase and lipids. With myelomonoblastic leukemia in the cytoplasm, not only these substances are detected, but also alpha-naphthyl esterase, characteristic of the monocytic series; Alpha-naphthyl esterase is suppressed by sodium fluoride.

Acute lymphoblastic leukemia is more common in children. As a rule, from the very beginning it proceeds with lymphadenopathy, enlarged spleen, and ossalgia. In the blood at first, only moderate normochromic anemia, leukopenia, can be noted, but in the bone marrow - total blastosis. Blastic cells have a rounded nucleus with a delicate chromatin network and 1-2 nucleoli, a non-grained narrow cytoplasm. In the Schick reaction in the cytoplasm, clots of glycogen are identified, concentrated in the form of a necklace around the nucleus. Acute promyepocyte leukemia is very rare; Until recently, it was characterized by a rapid flow. He has a pronounced intoxication, bleeding and hypofibrinogenemia due to DIC syndrome. Lymph nodes, liver and spleen are usually not enlarged. In the hemogram, anemia, expressed thrombocytopenia, in the bone marrow a large percentage of atypical blasts. Powerful cells of various sizes and shapes have a cytoplasm, densely filled in some cells with a large purple-brown granularity, located on the nucleus, in others - shallow abundant azurophilic granularity; Outer bull bodies are not uncommon. The granularity contains acid sulfated mucopolysaccharides. The nuclei of these leukemia cells in the blood often have a bilobate shape, even more often their shape is difficult to distinguish because of the abundance of granularity in the cytoplasm. The immediate cause of death of the patient is most often cerebral hemorrhage.

Acute monoblastic leukemia is relatively rare. The typical beginning of this form differs little from the myeloblastic, but more pronounced intoxication and fever to febrile figures. A common symptom is hyperplasia of the gingival mucosa due to leukemia proliferates in them. In the blood, a granulocyte germ can be relatively early preserved, along with the blast, many mature, more or less ugly monocytes are found. Powerful cells have a bean-shaped structural nucleus with several nucleoli and a grayish-blue cytoplasm, sometimes with scant azurophilic granularity. Cytochemicals reveal a positive reaction to alpha-naphthyl esterase, suppressed by sodium fluoride, a weakly positive reaction to peroxidase and lipids. In serum and urine of these patients, the level of lysozyme is high.

Acute plasmablastic leukemia is characterized by the appearance in the bone marrow and blood of plasmablasts and plasmocytes with features of cellular atypism; In addition, many undifferentiated blasts are found. The characteristic cytochemical signs of this form of acute leukemia are unknown; Its feature is the detection of paraprotein in the serum. Often extramedullary leukemic foci are noted-enlargement of lymph nodes, liver, spleen, leukemids in skin, testicles.

Acute megakaryoblastic leukemia is very rare. It is characterized by the presence in the bone marrow and blood of megacaryoblasts (cells with a blasted but hyperchromic nucleus, a narrow cytoplasm with filiform outgrowths), as well as undifferentiated blasts. Often in the blood and bone marrow there are ugly megakaryocytes and fragments of their nuclei. Characterized by thrombocytosis (more than 1000-lO (in the fourth degree) μl). Acute erythromyelosis is relatively rare. The disease is characterized by hyperplasia of red cells without signs of severe hemolysis. Clinical symptoms: progression of normo- or hyperchromic anemia without reticulocytosis (usually up to 2%), blurred icterism due to erythrocaryocyte disintegration, increasing leukopenia and thrombocytopenia. In the bone marrow the content of red cells is increased with the presence of multicore erythroblasts and undifferentiated Power cells. Unlike other forms of acute leukemia, tumor cells of the red series are often differentiated to the oxyphilic normocyte stage or to the erythrocyte. Acute erythromyelosis is often transformed into acute myeloblastic. Neuroleukemia is one of the frequent complications of acute leukemia, less often chronic myelogenous leukemia. Neuroleukemia is leukemia (infiltration) of the nervous system. Especially often this complication occurs in acute lymphoblastic leukemia of children, less often in other forms of acute leukemia. The emergence of neiroleukemia is caused by the metastasis of leukemia cells in the membranes of the brain and spinal cord or into the brain substance (prognostically this is the heavier type of tumor growth).

The neuroleukemia clinic consists of meningeal and hypertensive syndromes. They note persistent headache, repeated vomiting, lethargy, irritability, edema of the optic discs, nystagmus, strabismus and other signs of cranial nerve damage and meningeal signs. In cerebrospinal fluid, high blastocytosis. Detection of high cytosis and blast cells in cerebrospinal fluid is an earlier sign of nairoleukemia than the described clinical picture. With intracerebral metastases - a picture of a brain tumor without cytosis.

Treatment. In acute leukemia, urgent hospitalization is indicated. In some cases, with an accurate diagnosis, cytostatic treatment is possible on an outpatient basis. Apply pathogenetic treatment to achieve remission with the combined injection of cytotoxic drugs in order to eliminate all apparent and suspected leukemic foci, with a pronounced hematopoiesis depression. Remission in acute leukemia is a condition in which the blood platelet count is higher than 10 -104 in 1 μl, leukocytes are above 3000 μl, in the bone marrow of blasts less than 5%, and in lymphoid cells less than 30%, there are no extramedullary leukemic proliferates. In acute lymphoblastic leukemia of children, a normal criterion for the completeness of remission is the normal composition of cerebrospinal fluid.

In children suffering from acute lymphoblastic leukemia, the combination of vincristine administered at a dose of 1.4 mg / m2 (not more than 2 mg) once a week IV, and prednisolone daily at a dose of 40 mg / m2 is most effective. With this therapy, remission is achieved in about 95% of children in 4-6 weeks. Already in the period of remission, neuroleukemia is prevented: the first spinal tap should be taken the next day after the diagnosis of acute lymphoblastic leukemia and at the same time, intramedientally administering methotrexate (ametopterin) at a dose of 12.5 mg / m2. Spinal punctures with the introduction of methotrexate in this dose are repeated every 2 weeks until remission is obtained. Immediately after reaching remission, a special preventive course is carried out, including head irradiation at a dose of 2,400 rad from two-lateral fields with the capture of I and II cervical vertebrae, but with protection of the eyes, mouth, the entire area of ​​the facial skull, and simultaneous 5-fold (3 weeks of irradiation) Intra-lumbal administration of methotrexate in the same dose (12.5 mg / m2). When neuroleukemia is diagnosed during lumbar puncture, prophylactic head irradiation is canceled, neuroleukemia is administered with the intraluminal administration of two cytotoxic drugs: methotrexate 10 mg / m2 (maximum 10 mg) and cytosar (the initial dose of 5 mg / m2 is gradually increased to 30 mg / M2).

During the remission of acute lymphoblastic leukemia, children undergo continuous cytostatic therapy with three cytostatics - 6-mercaptopurine (50 mg / m2 per day) daily, cyclophosphamide (200 mg / m21 once a week), methotrexate (20 mg / m21 once a week); Treatment continues for 3.5-5 years.

In acute lymphoblastic leukemia in adults and children with unfavorable baseline indications (late and interrupted treatment before admission to therapy according to the program, age over 10-12 years old, baseline level of leukocytes more than 20 000 in 1 μl) in the first week of remission received by the program , Including vincristine, prednisolone and rubomycin, one of the cytostatic combinations: COAP, or CHOP, or POMP, is prescribed. The combination of COAR consists of cyclophosphamide and cytosar, administered from the 1st to the 4th day of the IV course 50 mg / m2 3 times a day with a syringe; Vincristine, administered at a dose of 1.4 mg / m2 IV on the 1st day, and prednisolone given daily from day 1 to day 4 at a dose of 100 mg / m2. The combination of CHOP consists of cyclophosphamide administered intravenously at a dose of 750 mg / m2 on the first day of the course, adriamycin 50 mg / m2 IV on day 1, vincristine 1.4 mg / m2 (maximum 2 mg ) On the 1st day of IV and prednisolone given daily from the 1st to the 5th day of the course at a dose of 100 mg / m2 per day. The combination of POMP is designed for a 5-day course, including 6-mercaptopurine (purinethol) 300-500 mg / m2 per day orally from day 1 to day 5, vincristine 1.4 mg / m2 IV in the 1 st Day, methotrexate, 7.5 mg / m2 IV every day from day 1 to day 5 and prednisolone administered daily at 200 mg / m2 per day. One of these courses is conducted at the beginning of remission for consolidation. Then (after coming out of cytopenia - raising the level of leukocytes to 3000 cells per 1 mm3), a remission maintenance therapy is initiated; In acute lymphoblastic leukemia, it is carried out continuously with the same three drugs (6-mercaptopurine, methotrexate and cyclophosphamide) as in children 2-10 years of age, but every 1.5 months instead of this therapy given either as tablets or as cyclophosphamide in powder, Spend alternately the course. COAR, CHOP, or POMP (for the entire duration of maintenance therapy, ie, 5 quintals, choose any two of these three courses for this patient). Regardless of age, patients with acute lymphoblastic leukemia are prevented by two cytostatic drugs: methotrexate (10 mg / m 2, maximum 10 mg) and cytosar (in an increasing dose of 5 to 30 mg, only 5 intraluminal injections) or head irradiation (d424 Hrza 15 Sessions) and methotrexate administered intralumbally 5 times simultaneously with irradiation at a dose of 12.5 mg / m2.

In acute non-lymphoblastic leukemia, the main drugs used to achieve remission are cytosar and rubomycin (or adriamycin). They can be prescribed in combination "7 + 3": cytosar is administered 7 days continuously at a daily dose of 200 mg / m2 or 2 times a day every 12 hours at 200 mg / m2 for 2 hours IV; Rubomycin is given intravenously with a syringe at a dose of 45 mg / m2 (30 mg / m2 to persons over 60 years) on the 1st, 2nd and 3rd days of the course. Cytosar and rubomycin can be supplemented with 6-mercaptopurine, administered every 12 hours at a dose of 50 mg / m2, with a dose of cytosar reduced to 100 mg / m2 administered every 12 hours. Cytosar is administered 8 days, 6-mercaptopurine - from the 3rd to the 9th day. When the remission is reached, the consolidating course-consolidation-can be the same as that leading to remission.

To maintain remission, either the same combination of cytosar and rubomycin (course "7 + 3"), administered every month at intervals of 2.5 or 3 weeks, or a 5-day administration of cytosar at 100 mg / m2 every 12 h in (On the first day of the course) with one of such cytostatics as cyclophosphamide (750 mg / m2) or rubomycin (45 mg / m2) or vincristine (1.4 mg / m2 on day 1) and prednisolone (40 mg / M2 from the 1st to the 5th day) or methotrexate (30 mg / m2). Supportive therapy continues for 5 years, as in acute lymphoblastic leukemia. All patients underwent prophylaxis of neiroleukemia. The first lumbar puncture with the introduction of methotrexate at a dose of 12.5 mg / m2 (maximum 15 mg) is produced in all forms of acute leukemia in all age groups in the first days after the diagnosis of acute leukemia. In adults, the main course of prevention of neiroleukemia is carried out after remission is achieved; In children with acute lymphoblastic leukemia, during the induction of remission every 2 weeks, methotrexate is re-administered at a dose of 12.5 mg / m2 (maximum 15 mg). In the case of reactions before administration, prednisolone IV is given in a dose of 120 mg.

Leukemia is chronic. Lymphatic leukemia, myeloleukemia, myeloma, erythremia, less often chronic subleukemic myelosis (osteomyelosclerosis, myelofibrosis), chronic monocytic leukemia, Waldenstrom macroglobulinemia are more common.

In chronic myelogenous leukemia, the granulocyte as well as the platelet and erythrocyte sprouts of the bone marrow are affected by the tumor process. The ancestor of the tumor is the precursor cell of myelopoiesis. The process can extend to the liver, spleen, and in the terminal stage of the affected can be any tissue. In the clinical course of chronic myelogenous leukemia, the developed and terminal stages are isolated. At the beginning of the developed stage the patient has no complaints, the spleen is not enlarged or slightly enlarged, the composition of the peripheral blood is changed.

At this stage, the diagnosis can be established by analyzing the "unmotivated" nature of neutrophilic leukocytosis with a shift in the formula to myelocytes and promyelocytes, detecting a significantly increased ratio of white blood cells / erythrocytes in the bone marrow and the "Philadelphia" chromosome in blood granulocytes and bone marrow cells. In the trephine of the bone marrow, in this period, as a rule, almost complete fat replacement by myeloid tissue is observed. The unfolded stage can last for an average of 4 years. With proper therapy, the condition of patients remains satisfactory, they remain able to work, they lead a normal lifestyle with outpatient supervision and treatment. At the terminal stage, the course of chronic myelogenous leukemia acquires the features of malignancy: high fever, rapidly progressive depletion, bone pain, severe weakness, rapid enlargement of the spleen, liver, sometimes enlarged lymph nodes. This stage is characterized by the appearance and rapid growth of signs of suppression of normal hematopoietic germs - anemia, thrombocytopenia complicated by hemorrhagic syndrome, granulocytopenia complicated by infection, necrosis of mucous membranes.

The most important hematologic sign of the terminal stage of chronic myelogenous leukemia is blast crisis - an increase in the content of blast cells in the bone marrow and blood (first more often myeloblasts, then undifferentiated blasts). Karyologically, in the terminal stage, in more than 80% of cases, the appearance of aneuploid clones of cells-hematopoietic cells containing an abnormal number of chromosomes is determined. The life expectancy of patients in this stage often does not exceed 6-12 months.

Treatment of chronic myelogenous leukemia is carried out from the moment of diagnosis. In the expanded stage, effective therapy with myelosan in a dose of 2-4 mg / day (with a level of leukocytes more than 100,000 in 1 mm3 appoint up to 6 mg / day). The treatment is done on an outpatient basis.

When myelosan is ineffective, myelobromol is prescribed (with significant splenomegaly, irradiation of the spleen can be performed). When the process goes to the terminal stage, combinations of cytostatic drugs are used, usually used to treat acute leukemias: vincristine and prednisolone, VAMP, cytosar and rubomycin. At the beginning of the terminal stage, myelobromol is often effective.

Chronic lymphocytic leukemia is a benign tumor of the immunocompetent system; The basis of the tumor is formed by morphologically mature lymphocytes. The onset of the disease can often not be determined: among the overall health and the absence of any unpleasant subjective sensations in the blood, the patient displays a small but gradually increasing lymphocytosis. In the early stages, the number of white blood cells can be normal. A characteristic sign of the disease is an increase in the lymph nodes. Sometimes their increase is detected simultaneously with changes in blood, sometimes later. Enlargement of the spleen is a common symptom; The liver is less often enlarged. In the blood, along with an increase in the number of lymphocytes, the presence of single prolymphocytes and sometimes rare lymphoblasts, it is often possible to note the so-called Humprecht shadows characteristic of chronic lymphocytic leukemia - the nuclei of lymphocytes destroyed during the preparation of the smear, in which you can see nucleogens among the chromatin. In the developed stage of the disease, the content of neutrophils, platelets and erythrocytes may remain normal for many years. In the bone marrow of chronic lymphocytic leukemia, a high percentage of lymphocytes is found.

The development of the disease is often accompanied by a decrease in the overall level of gamma globulins. Oppression of humoral immunity is manifested by frequent infectious complications, especially pneumonia. Another common complication is cytopenia, more often anemia and thrombocytopenia. This complication may be due to the occurrence of autoantibodies against erythrocytes and platelets or against erythrocaryocytes and megakaryocytes. But this is not the only mechanism of cytopenia in chronic lymphocytic leukemia; Perhaps the inhibitory effect of lymphocytes (in particular, T-lymphocytes) on the progenitor cells of erythropoiesis or thrombocytopoiesis. The terminal stage of chronic lymphocytic leukemia, manifested by sarcoma growth or blast crisis, is observed infrequently, especially blast crisis. The development of lymphosarcoma in a number of cases can be accompanied by a change in lymphocytosis in the blood by neutrophilia.

Hairy cell leukemia is a special form of chronic lymphocytic leukemia, in which lymphocytes have a homogeneous nucleus resembling the nucleus of the blast, the villous outgrowths of the cytoplasm. The cytoplasm of these cells contains a lot of acidic phosphatase, resistant to the action of tartaric acid. The clinical picture is characterized by an increase in the spleen, a slight increase in peripheral lymph nodes and pronounced cytopenia. In 75% of cases of hairy cell leukemia, which proceeds with an increase in the spleen, splenectomy is effective. If cytopenia is not associated with an increase in the spleen or there are any other organ changes or lymphadenopathy, the therapy of choice is the use of "alpha interferon (3 000 000-9 000 000 units per day for many months, taking into account the positive dynamics of blood counts, changes in Affected tissues).

A separate form is chronic lymphatic leukemia with skin lesions - the form of Cesari. The process begins often with skin lesions, skin itching, the appearance of local lymphatic infiltrates under the epidermis, which can then become total. Gradually grow lymphocytosis and the percentage of ugly lymphocytes in the blood. These are usually large cells with cut out contours of the core of the loop structure, but the cells can also be small with a bean-shaped nucleus. The affiliation of these lymphocytes to T cells is proved. Lymphadenopathy can be of a mixed nature: some lymph nodes are enlarged reactively due to infection in the skin, others - due to their leukemia infiltration. The spleen can increase in the course of the disease. In the treatment of Cesary's form, the long-term use of small doses of chlorbutin (2-4 mg / day daily for several months under the control of blood tests, especially the platelet level - once every 2-3 weeks) often results in an effect that removes skin itching, reduces leukemia Infiltration of the skin.

Treatment of chronic lymphocytic leukemia, manifested by the growth of leukocytosis, mild lymphadenopathy, begins with the use of chlorbutin. If the size of the lymph nodes is significant, cyclophosphamide is used. Steroid therapy is prescribed for autoimmune complications, hemorrhagic syndrome, and inefficiency of individual cytotoxic agents (in the latter case, chlorbutin or cyclophosphamide with prednisolone are sometimes combined). Long-term use of steroids in chronic lymphocytic leukemia is contraindicated. With a significant density of peripheral lymph nodes, involving in the process of lymph nodes of the abdominal cavity, combinations of drugs such as VAMP or a combination of cyclophosphamide, vincristine or vinblastine and prednisolone (COP or CVP) are successfully used. The spleen, lymph nodes, and skin are irradiated. One of the methods of treatment of autoimmune cytopenia in chronic lymphocytic leukemia is splenectomy. Of particular importance is the treatment of infectious complications. Recently, leucocytopheresis has been used to treat lymphocytic leukemia with high leukocytosis and cytopenia. Patients with chronic lymphatic leukemia for many years remain well-being and working capacity.

Chronic monoritic leukemia refers to rare forms of leukemia, characterized by high monocytosis in peripheral blood (20-40%) with a normal or slightly elevated number of leukocytes. Along with mature monocytes, there are single promonocytes in the blood. In the bone marrow the percentage of monocytes is increased insignificantly, but in trepanate hyperplasia of bone marrow tissue with diffuse growth of monocytic elements is observed. Blood and urine contain high lysozyme content. In 50% of patients, the spleen is palpable. Prolonged successful course of chronic monocytic leukemia can be replaced by terminal stage, which has the same features as terminal stages of chronic myelogenous leukemia. In the expanded stage the process does not require special treatment, only with deep anemia it is necessary to periodically transfuse the erythrocyte mass, which can be performed on an outpatient basis