Chronic myeloid leukemia – life expectancy at different stages of the disease. Chronic myeloid leukemia: symptoms, diagnosis, treatment
(CML, chronic myeloid leukemia, chronic myeloid leukemia) is a form of leukemia that is characterized by increased and unregulated growth of predominantly myeloid cells in the bone marrow with their accumulation in the blood. CML is a hematopoietic clonal disease, the main manifestation of which is the proliferation of mature granulocytes (neutrophils, eosinophils and basophils) and their precursors; a variant of myeloproliferative disease associated with a characteristic chromosomal translocation (Philadelphia chromosome). Currently, the main treatment for chronic myeloid leukemia is targeted therapy with imatinib and other drugs, which have significantly improved survival rates.
Symptoms:
The disease is often asymptomatic and is detected during routine clinical blood tests. In this case, CML should be differentiated from the leukemoid reaction, in which the blood smear may have a similar picture. CML may present with malaise, low-grade fever, gout, increased susceptibility to infection, anemia, and thrombocytopenia with bleeding (although elevated platelet counts may also occur). Splenomegaly is also noted.
CML is often divided into three phases based on clinical characteristics and laboratory findings. Without treatment, CML usually begins in the chronic phase, progresses over several years to the accelerated phase, and eventually develops into blast crisis. Blast crisis is the terminal phase of CML, clinically similar to acute leukemia. One of the factors in the progression from the chronic phase to the blast crisis is the acquisition of new chromosomal abnormalities (in addition to the Philadelphia chromosome). Some patients may already be in the accelerated phase or blast crisis at the time of diagnosis.
About 85% of patients with CML are in the chronic phase at the time of diagnosis. During this phase, there are usually no clinical manifestations or “mild” symptoms such as malaise or a feeling of abdominal fullness. The duration of the chronic phase varies and depends on how early the disease was diagnosed, as well as on the treatment provided. Ultimately, in the absence of effective treatment, the disease enters the acceleration phase.
Acceleration phase.
Diagnostic criteria for entering the acceleration phase may vary: the most widely used criteria are those established by researchers at the University of Texas MD Anderson Cancer Center, Sokal et al., and the World Health Organization. The WHO criteria are probably the most widely accepted, and distinguish the acceleration phase as follows:
* 10-19% of myeloblasts in the blood or bone marrow
* >20% basophils in blood or bone marrow
* * >1,000,000, regardless of therapy
* Cytogenetic evolution with the development of new anomalies in addition to the Philadelphia chromosome
* Progression of splenomegaly or an increase in the number of leukocytes, regardless of therapy.
The acceleration phase is assumed if any of the specified criteria is present. The acceleration phase indicates disease progression and the expected blast crisis
Blast crisis.
Blast crisis is the final stage of CML development, occurring similarly to acute leukemia, with rapid progression and short survival. Blast crisis is diagnosed based on one of the following signs in a patient with CML:
* >20% myeloblasts or lymphoblasts in blood or bone marrow
* Large groups of blasts in the bone marrow during biopsy
* Development of chloroma (solid focus of leukemia outside the bone marrow)
Causes of occurrence:
CML was the first malignant disease with an identified genetic abnormality, a chromosomal translocation that manifests itself as an abnormal Philadelphia chromosome. This chromosomal pathology got its name because it was first discovered and described in 1960 by scientists from Philadelphia, Pennsylvania, USA: Peter Nowell (University of Pennsylvania) and David Hungerford (Temple University).
With this translocation, parts of chromosomes 9 and 22 are swapped. As a result, the ABL gene from chromosome 9 is attached to part of the BCR gene from chromosome 22. This abnormal “fused” gene generates the protein p210, or sometimes p185. Since abl has a region that adds a phosphate group to a tyrosine residue (tyrosine kinase), the product of the abnormal gene is also a tyrosine kinase.
The BCR-ABL protein interacts with part of the cellular receptor for IL-3 (CD123 antigen). BCR-ABL transcription operates continuously and does not require activation by other proteins. On the other hand, BCR-ABL itself activates a protein cascade that controls the cell cycle, accelerating cell division. Moreover, the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to further genetic abnormalities. BCR-ABL activity is a pathophysiological cause of chronic myeloid leukemia. With improved understanding of the nature of the BCR-ABL protein and its action as a tyrosine kinase, targeted therapies have been developed to specifically inhibit the activity of the BCR-ABL protein. These tyrosine kinase inhibitors can promote complete remission of CML, which further confirms the leading role of bcr-abl in the development of the disease.
Treatment:
For treatment the following is prescribed:
Treatment for chronic myeloid leukemia begins after diagnosis and is usually carried out on an outpatient basis.
In the absence of symptoms of chronic myeloid leukemia against the background of a stable blood count not exceeding 40-50-109/l, hydroxyurea or busulfan is used until the leukocyte content in the blood reaches 20*109/l.
As chronic myeloid leukemia progresses, hydroxyurea (Hydra, Litalir) and α-IFN are indicated. If there is significant splenomegaly, the spleen is irradiated.
For severe symptoms of chronic myeloid leukemia, combinations of drugs used for acute leukemia are used: vincristine and prednisolone, cytarabine (Cytosar) and daunorubicin (rubomycin hydrochloride). At the onset of end-stage disease, mitobronitol (myelobromol) is sometimes effective.
Currently, a new drug has been proposed for the treatment of chronic myeloid leukemia - a blocker of mutant tyrosine kinase (p210) - Gleeveca (STI-571). During blast crisis of CML and Ph-positive ALL, the dose is increased. The use of the drug leads to complete remission of the disease without eradication of the tumor clone.
Transplantation of blood stem cells or red bone marrow, performed in patients under 50 years of age in stage I of the disease, leads to recovery in 70% of cases.
Tumor processes quite often affect not only the internal organs of a person, but also the hematopoietic system. One of these pathologies is chronic myeloid leukemia. This is a cancerous disease of the blood, in which the formed elements begin to multiply randomly. It usually develops in adults, but is rare in children.
Chronic leukemia is a tumor process, which is formed from early forms of myeloid cells. It makes up a tenth of all hemoblastoses. Doctors need to take into account that the vast majority of cases of the course of the disease in the early stages are asymptomatic. The main signs of chronic cancer of the blood system develop at the stage of decompensation of the patient’s condition, the development of blast crisis.
The blood picture responds with an increase in granulocytes, which are classified as one of the types of leukocytes. Their formation occurs in the red matter of the bone marrow; during leukemia, a large amount of them enters the systemic bloodstream. This results in a decrease in the concentration of normal healthy cells.
Causes
The trigger factors for chronic myeloid leukemia are not fully understood, which raises many questions. However, there are some mechanisms that provoke the development of pathology.
- Radiation. Proof of this theory is the fact that cases of the disease have become more frequent among Japanese and Ukrainians.
- Frequent infectious diseases, viral invasions.
- Certain chemicals trigger mutations in the red bone marrow.
- Heredity.
- The use of drugs - cytostatics, as well as the prescription of radiation therapy. This therapy is used for tumors of other locations, but it can cause pathological changes in other organs and systems.
Mutations and changes in the structure of chromosomes in red bone marrow lead to the formation of DNA chains unusual for humans. The consequence of this is the development of clones of abnormal cells. They, in turn, replace healthy ones, and the result is a predominance of mutated cells. This leads to a blast crisis.
Abnormal cells have a tendency to multiply uncontrollably; there is a clear analogy with the cancer process. It is important to note that their apoptosis, natural death, does not occur.
In the systemic bloodstream, young and immature cells are not able to perform the necessary work, which leads to a pronounced decrease in immunity, frequent infectious processes, allergic reactions and other complications.
Pathogenesis
Myelocytic leukemia, a chronic variant of the course, develops due to a translocation in chromosomes 9 and 22. The consequence is the formation of genes encoding chimeric proteins. This fact is confirmed by experiments on laboratory animals, which were first irradiated and then given bone marrow cells with translocated chromosomes. After transplantation, the animals developed a disease similar to chronic myeloid leukemia.
It is also important to consider that the entire pathogenetic chain is not fully understood. The question also remains of how the advanced stage of the disease progresses to blast crisis.
Other mutations include trisomy 8, deletion of arm 17. All these changes lead to the appearance of tumor cells and changes in their properties. The data obtained indicate that malignancy of the hematopoietic system is caused by a large number of factors and mechanisms, but the role of each of them is not fully understood.
Symptoms
The onset of the disease is always asymptomatic. The same situation occurs with other types of leukemia. The clinical picture develops when the number of tumor cells reaches 20% of the total number of formed elements. The first sign is considered general weakness. People begin to get tired faster, physical activity leads to shortness of breath. The skin becomes pale in color.
One of the main signs of pathology of the blood system is an enlargement of the liver and spleen, which manifests itself as nagging pain in the hypochondrium. Patients lose weight and complain of sweating. It is important to note the fact that it is the spleen that enlarges first; hepatomegaly occurs at slightly later stages of the process.
Chronic stage
The chronic stage makes it difficult to recognize myeloid leukemia, the symptoms of which are not clearly expressed:
- deterioration of well-being;
- quick satisfaction of hunger, pain in the left hypochondrium due to splenomegaly;
- headaches, decreased memory, concentration;
- priapism in men or prolonged painful erection.
Accelerative
During acceleration, symptoms become more obvious. At this stage of the disease, anemia and resistance to previously prescribed treatment increase. Platelets and leukocytes also increase.
Terminal
At its core, this is a blast crisis. It is not characterized by an increase in the number of platelets or other formed elements, and the clinical picture worsens significantly. The appearance of blast cells in the peripheral blood is noted. Patients are feverish and have fever symptoms. Hemorrhagic symptoms develop, and the spleen enlarges to such an extent that its lower pole ends up in the pelvis. The terminal stage ends in death.
Monocyte crisis in myeloid leukemia
Myelomonocytic crisis is a rare variant of the course of the disease. It is characterized by the appearance of atypical monocytes, which may be mature, young or atypical.
One of its signs is the appearance in the blood of fragments of the nuclei of megakaryocytes and erythrokaryocytes. Normal hematopoiesis is also suppressed here, and the spleen is significantly enlarged. Puncture of the organ shows the presence of blasts, which is a direct indication for its removal.
Which doctor should be contacted
CML is diagnosed by a hematologist. It is also possible to confirm the presence of the disease with an oncologist. They are the ones who conduct the initial examination, prescribe blood tests and ultrasound of the abdominal organs. A bone marrow puncture with biopsy and cytogenetic tests may be necessary.
The blood picture in such patients is typical.
- The chronic stage is characterized by an increase in myeloblasts in the bone marrow aspirate to 20%, and basophils above this level.
- The terminal stage leads to an increase in this threshold by cells, as well as the appearance of blast cells and their clusters.
- In the peripheral blood in this case, neutrophilic leukocytosis is characteristic.
How is myeloid leukemia treated?
Treatment of the disease depends on what form of chronic myeloid leukemia is observed in the patient. Typically used:
- chemotherapy;
- bone marrow transplantation;
- radiation therapy is carried out at different stages;
- leukopheresis;
- splenectomy;
- symptomatic treatment.
Treatment with drugs
Drug treatment for chronic myeloid leukemia involves chemotherapy and symptomatic treatment. Chemical agents include classical drugs - myelosan, cytosar, mercaptopurn, Gleevec, methotrexate. Another group is hydroxyurea derivatives - hydrea, hydroxurea. Interferons are also prescribed to stimulate the immune system. Symptomatic treatment depends on which organs and systems need correction at the moment.
Bone marrow transplantation
Bone marrow transplantation allows for a complete recovery. The operation should be carried out strictly during remission. Sustained improvement is observed over 5 years. The procedure takes place in several stages.
- Search for a donor.
- Preparation of the recipient, during which chemotherapy and radiation are performed to eliminate the maximum number of mutated cells and prevent rejection of donor tissue.
- Transplantation.
- Immunosuppression. It is necessary to place the patient on "quarantine" to avoid possible infection. Quite often, doctors support the body with antibacterial, antiviral and antifungal agents. It is important to understand that this is the most difficult period after transplantation, it lasts up to one month.
- Then the donor cells begin to take root, and the patient feels better.
- Restoration of the body.
Radiation therapy
This treatment procedure is necessary when there is no desired effect from the administration of cytostatics and chemotherapy. Another indication for its implementation is persistent enlargement of the liver and spleen. It is also the drug of choice for the development of a localized oncological process. Doctors usually resort to radiation during the advanced phase of the disease.
Chronic myeloid leukemia is treated with gamma rays, which destroy or significantly slow down the growth of tumor cells. The dosage and duration of therapy is determined by the doctor.
Removal of the spleen splenectomy
This surgical intervention is carried out strictly according to indications:
- organ infarction;
- severe platelet deficiency;
- significant enlargement of the spleen;
- rupture or threat of rupture of an organ.
Most often, splenectomy is performed at the terminal stage. This allows you to eliminate not only the organ itself, but also many tumor cells, thereby improving the patient’s condition.
Purification of blood from excess leukocytes
When the level of leukocytes exceeds 500 * 10 9, it is necessary to eliminate their excess from the bloodstream to prevent retinal edema, thrombosis, and priapism. Leukapheresis, which is very similar to plasmapheresis, comes to the rescue. Usually the procedure is performed during the advanced stage of the disease, it can act as an addition to drug treatment.
Complications from therapy
The main complications of the treatment of chronic myeloid leukemia are toxic liver damage, which can result in hepatitis or cirrhosis. Hemorrhagic syndrome, intoxication manifestations also develop, due to a drop in immunity, a secondary infection is possible, as well as viral and fungal invasions.
DIC syndrome
Doctors need to take into account that this disease is one of the mechanisms for triggering disseminated intravascular coagulation syndrome. Therefore, the patient's hemostatic system should be regularly examined in order to diagnose DIC in its early stages or prevent it altogether.
Retinoid syndrome
Retinoid syndrome is a reversible complication of tretionin use. This is a dangerous condition that can cause death. Pathology is manifested by fever, chest pain, renal failure, hydrothorax, ascites, pericardial effusion, hypotension. Patients need to be given high doses of steroid hormones quickly.
Leukocytosis is considered a risk factor for developing the condition. If the patient was treated only with tretionin, then every fourth person will develop retinoid syndrome. The use of cytostatics reduces the likelihood of its occurrence by 10%, and the appointment of dexamethasone reduces mortality to 5%.
Chronic myeloid leukemia treatment in Moscow
There are a large number of clinics in Moscow that treat this problem. The best results are shown by hospitals that are equipped with modern equipment for diagnosing and treating the process. Reviews from patients on the Internet suggest that it is best to go to specialized centers at the clinical hospital in Botkinsky Proezd or on Pyatnitskoye Shosse, where there is an interdisciplinary oncology service.
Life expectancy forecast
The prognosis is not always favorable, which is due to the oncological nature of the disease. If chronic myeloid leukemia is complicated by severe leukemia, life expectancy is usually reduced. Most patients die when the accelerated or terminal stage occurs. Every tenth patient with chronic myeloid leukemia dies in the first two years after diagnosis. After the onset of blast crisis, death occurs approximately six months later. If doctors were able to achieve remission of the disease, then the prognosis becomes favorable until its next exacerbation occurs.
Chronic myeloid leukemia (CML) is a myeloproliferative chronic disease in which there is an increased formation of granulocytes (mainly neutrophils, as well as promyelocytes, myelocytes, metamyelocytes), which are the substrate of the tumor. In most cases, the natural outcome of the disease is a blast crisis, characterized by the appearance of a large number of blast cells, refractoriness to therapy and ending in death.
Etiology and pathogenesis. The cause of pathological cell growth is considered to be a mutation in the myelopoiesis precursor cell (a partially determined pluripotent cell). This is proven by the discovery of a specific marker in patients with CML - a pathological Ph chromosome (Philadelphia) in the cells of myeloid, erythroid, monocyte and platelet lineages. The Ph chromosome is a common cellular marker that confirms the origin of the entire pathological clone of cells in CML from one mother. Despite the fact that all three bone marrow sprouts are leukemic, in the advanced stage of CML there is unlimited growth, as a rule, of one sprout - the granulocytic sprout. The production of megakaryocytes in the bone marrow and platelets in the peripheral blood increases significantly.
As the disease progresses, the monoclonal stage is replaced by a polyclonal stage, which is proven by the appearance of cells with a different incorrect set of chromosomes. This demonstrates the law of tumor progression to which this leukemia obeys.
CML is more common in adults aged 30-70 years; There is a slight predominance of men. CML is the most common of all leukemias, accounting for 20% of hemoblastoses in adults.
Classification. As noted, the disease naturally goes through two stages of development - monoclonal and polyclonal. This corresponds to three stages of chronic myeloid leukemia in clinical presentation.
Stage I - initial - myeloid proliferation of bone marrow + minor changes in the blood without symptoms of intoxication (up to 1-3% blasts are noted in the peripheral blood). ^e
Stage II - extensive - pronounced clinical and hematological manifestations (intoxication with decay products of leukemic cells, increased
E liver and spleen, myeloid proliferation of bone marrow + changes in the blood). In the peripheral blood there are up to 10% blasts. 116 Stage III - terminal (corresponds to the development of a polyclonal tumor) - refractoriness to ongoing cytostatic therapy, wasting, significant enlargement of the spleen and liver, degenerative changes in internal organs, pronounced changes in the blood (anemia, lombopenia). The terminal stage of CML is characterized by the development
I, called blast crisis, is the appearance of neoplasm cells in the peripheral blood (up to 30-90%), and therefore the disease takes on the characteristics of acute leukemia. Most often, in the bone marrow and peripheral blood, ovarian crisis is characterized by the appearance of myeloblasts, but undifferentiated blast cells can also be found. Karyological examination reveals the polyclonal nature of pathological cells. At the same time, significant inhibition of thrombocytopoiesis occurs, and hemorrhagic syndrome develops. There is also a lymphoblastic variant of blast crisis (a large number of lymphoblasts appear in the bone marrow and peripheral blood).
Clinical picture. Clinical manifestations of CML can be expressed in large syndromes.
Myeloproliferative syndrome, which is based on myeloid proliferation of the bone marrow, includes:
A) general symptoms caused by intoxication, proliferation of leukemic cells in the bone marrow, spleen and liver (sweating, weakness, weight loss, heaviness and pain in the spleen and liver), ossalgia;
B) enlargement of the liver and spleen;
B) leukemic infiltrates in the skin;
D) characteristic changes in the bone marrow and peripheral blood. Syndrome caused by complications:
A) hemorrhagic diathesis (hemorrhages and thrombosis due to disruption of the procoagulant and platelet components of hemostasis);
B) purulent-inflammatory (pneumonia, pleurisy, bronchitis, purulent lesions of the skin and subcutaneous fat), caused by a sharp decrease in immune activity;
C) uric acid diathesis (hyperuricemia due to increased breakdown of granulocytes).
The different severity of syndromes at different stages of the disease causes a rather polymorphic clinical picture. You can observe patients who do not show any complaints and are fully able to work, and patients with severe damage to internal organs, exhausted, completely incapacitated.
At stage I of the diagnostic search in the initial stage of the disease, patients may not make complaints, and the disease will be diagnosed at subsequent stages. General complaints (weakness, sweating, weight loss) can occur with a variety of diseases, THEREFORE they cannot be considered at stage I as specific to CML. Only later, when other symptoms indicating CML are identified, can they be interpreted as an expression of myeloproliferative syn-
1severity and pain in the left and right hypochondrium are usually explained by an enlargement of the spleen and liver. In combination with complaints of general Pj*KTepa and bone pain, they can direct the doctor to a myeloproliferative disease.
In the terminal stage of the disease, some complaints may be due to the occurrence of complications: purulent-inflammatory, hemorrhagic diathesis, uric acid diathesis. g°
At stage I, you can obtain information about changes in the hemogram and previous treatment (cytostatic drugs). Consequently, “if a patient who has already been diagnosed with CML comes into the doctor’s field of vision, the subsequent diagnostic search is greatly simplified. It is important to find out from patients information about the treatment carried out and the ineffectiveness of drugs that, until now, improved the general condition and reduced the number of leukocytes. Such information will allow us to assume a transition to the polyclonal (terminal) stage of the disease.
At the second stage of the diagnostic search, it is possible to obtain information that allows us to make an assumption: 1) about the nature of the pathological process, i.e. the essence of the disease itself; 2) about the stage of the disease; 3) about possible complications.
In the advanced and terminal stages, signs are revealed that significantly confirm the assumption of CML: pallor of the skin (due to increasing anemia), skin hemorrhages and infiltrates (more typical for the terminal stage of CML). An essential symptom is splenomegaly (without enlargement of the lymph nodes), combined with an enlarged liver, which, with appropriate complaints and medical history, can be regarded as a manifestation of myeloproliferative syndrome.
With the development of complications, for example, splenic infarction, there is sharp pain on palpation and friction noise of the peritoneum over the spleen. Gradually, the spleen becomes dense (its mass is 6-9 kg, descends with the lower pole into the pelvis).
The most important data for the diagnosis of CML are obtained at stage III of the diagnostic search.
In stage I of the disease, leukocytosis is detected in the peripheral blood (more than 50 109/l with neutrophilia (granulocytes of all stages of maturation - myelocytes, young, stab), eosinophilic-basophilic association. The number of platelets is not changed (sometimes slightly increased). Sometimes a small the number of blasts is up to 1-3%. The bone marrow is rich in cellular elements with a predominance of elements of the granulocytic series. The number of eosinophils, basophils, granulocytes can be increased.
In stage II, the number of leukocytes is 50-500 109/l, the content of immature forms is increased (promyelocytes make up 20-30%), blasts make up up to 10%, platelets are reduced or increased. In the bone marrow, pronounced multicellularity is noted, in the leukogram there is a sharp shift to the left, the content of promyelocytes and blasts is increased - about 10%
In stage III, the number of leukocytes is small (up to 50,109/l), there are many immature forms, blasts make up more than 10%, among them there are ugly forms. The platelet count is reduced. In the bone marrow, the content of blasts is increased, erythropoiesis and thrombocytopoiesis are suppressed.
The functional properties of leukocytes and their enzymatic content are changed: the activity of neutrophil alkaline phosphatase is reduced, and the ability to phagocytosis is impaired. When puncturing an enlarged spleen at an advanced stage of the disease, a predominance of myeloid cells is revealed (which is never normally found). y.
This stage turns out to be decisive in identifying blast P _ for: an increase in the number of blast cells in the bone marrow and periphery
0th blood (the total number of blasts and promyelocytes is equal to 20% of 1C?lle, while outside of blast crisis this amount usually does not exceed 10-15%) -
Bone sintigraphy helps to detect an increase in the bridgehead of hematopoiesis (the study is performed when the diagnosis is unclear; it is not mandatory for all patients with CML).
Diagnostics. Detection of CML in the advanced stage of the disease does not present any difficulties and is based on characteristic data from a blood test, the results of bone marrow examination, and enlargement of the liver and spleen. ^ The diagnostic criteria for the disease are: . leukocytosis more than 20-109/l;
The appearance in the leukocyte formula of proliferating forms (myeloblasts and promyelocytes) and maturing granulocytes (myelocytes, me-
Tamyelocytes);
Myeloid proliferation of bone marrow (according to myelogram
And trepanobiopsy);
Decreased neutrophil alkaline phosphatase activity (less than
Detection of the Ph chromosome in hematopoietic cells;
Expansion of the “bridgehead” of hematopoiesis (according to scintigraphy
Increased size of the spleen and liver. Differential diagnosis. CML should be differentiated from
Called leukemoid reactions, which can occur in a number of diseases (tuberculosis, cancer, various infections, kidney failure, etc.). According to the definition of A.I. Vorobyov, leukemoid reaction is “changes in the blood and hematopoietic organs, reminiscent of leukemia and other tumors of the hematopoietic system, but not transforming into the tumor they resemble.” With the leukemoid reaction, high leukocytosis is observed, immature neutrophils appear in the peripheral blood, but the basophilic-eosinophilic association is not detected. Differential diagnosis is based on identifying the underlying disease (cancer, tuberculosis, etc.), as well as on an increase in the activity of neutrophil alkaline phosphatase (instead of its decrease in CML). During sternal puncture, the leukemoid reaction is characterized by an increase in the content of myelocytes, but the Ph chromosome is never detected.
Treatment. The main goal of treating any hemoblastosis (including CML) is to eliminate or suppress the growth of the pathological cell clone. However, in relation to chronic leukemia, this does not mean that any patient who has a blood system disease immediately needs to be actively treated with cytostatic drugs that suppress tumor growth.
In the initial stage of the disease (with good health, but undoubted changes in the peripheral blood and bone marrow), we need general restorative therapy, proper nutrition, adherence to the
Ore and rest (it is very important to avoid sun exposure). The patient must be under the supervision of a physician; Periodically (once every 3-6 months) it is necessary to examine peripheral blood.
When symptoms of disease progression appear, it is necessary to administer cytostatic therapy, and the volume of such treatment depends on the stage of the disease. If clear symptoms of tumor growth appear (increase in the size of the spleen, liver, as well as an increase in
The number of leukocytes in comparison with the previous period is determined by so-called primary-containing therapy. Conventional treatment begins when the leukocyte count is 50-70-109/l. Ambulatop ° use hydroxyurea (hydrea) in low doses (with mandatory hematological monitoring); after achieving clinical and/or hematological remission, the issue of maintenance therapy is decided
In the advanced stage of the disease, the amount of chemotherapy depends on the “risk group”, determined by the presence of unfavorable signs - °T
1) leukocytosis more than 200109/l, blasts more than 3%, the sum of blasts and myelocytes in the blood more than 20%, the number of basophils in the blood more than 10%"¦
2) decrease in hemoglobin to a level of less than 90 g/l;
3) thrombocytosis more than 500 109/l or thrombocytopenia less than 100 109/l-
4) splenomegaly (the spleen is palpated 10 cm below the costal arch or more);
5) hepatomegaly (the liver is palpated 5 cm below the costal arch or more).
Low risk - presence of one sign; intermediate risk - the presence of 2-3 signs; high risk - the presence of 4 signs or more. At low and intermediate risk, monochemotherapy is initially indicated; at high risk, polychemotherapy is recommended from the very beginning.
In the advanced stage, a course of chemotherapy is carried out. Hydrea is used, but in large doses (daily 2-3 doses) under hematological control: if the number of leukocytes and platelets decreases, the dose of the drug is reduced, and if the leukocyte count is 10-20 109/l and platelet count is 100-109/l, the drug is discontinued. If previously effective drugs do not have an effect within 3-4 weeks, then a course of treatment with another cytostatic should be carried out. So, if hydrea turns out to be ineffective, then myelosan (busulfan, mileran), myelobromol are prescribed.
After a course of chemotherapy, maintenance therapy is carried out according to a scheme close to the scheme of primary restraining therapy. Drugs that have had a therapeutic effect during a course of chemotherapy are used.
Polychemotherapy is carried out in courses at high risk, as well as in the terminal stage of CML; in blast crisis - in a volume corresponding to therapy for acute illness. They use drugs that have a cytostatic effect on proliferating elements (cytosar, methotrexate, vincristine, antitumor antibiotic rubomycin hydrochloride). Polychemotherapy courses are short (5-14 days with breaks of 7-10 days).
Currently, fundamentally new methods of treating CML have emerged - the cytokine α-interferon (α-IFN). The fact is that during the process of myeloid proliferation, megakaryocytes and platelets release a large number of growth factors, which themselves contribute to the further proliferation of mutant pluripotent and oligopotent stem cells, and in addition, stromal cells. All this leads to further progression of the disease, as well as the development of fibrosis and changes in the bone marrow. Meanwhile, it has been proven that a-IFN, in its chemical structure and functional properties, is an antagonist of growth factors; it secretes substances that inhibit the stimulating effect of megakaryocytes on hematopoiesis and have antiproliferative activity towards the parent cells of hematopoiesis; in addition, α-IFN stimulates antitumor immunity ^ Consequently, conditions are created for maintaining normal blood
Ia, while α-IFN does not have a cytostatic effect, which is a very attractive property, since there is no depressive effect on normal bone marrow cells. In practice, recombinant α-IFN is used - reaferon, or
Tpon "A", which is administered intramuscularly or subcutaneously in doses of 2 to 9 MI/m2 per day (according to different authors) for 2-6 months /f MI = 1 °00 °°0 U)" allowing to achieve hematological remission -
And v many sick people. When treated with this drug, a “type-like” syndrome may appear - fever, headache, muscle soreness, general poor health, but taking paracetamol eliminates these phenomena.
Intron “A” is sometimes combined with a cytostatic drug - hydrea or cytosine arabinoside (cytosar), which improves treatment results; The 5-year survival rate when treated with intron “A” is 32-89 months (in 50% of patients), while when treated with myelosan this figure is 44-48 months.
It is very significant that during the treatment of α-IFN, not only hematological, but also cytogenetic remission can occur, when the Ph chromosome is not detected at all in the blood and bone marrow cells, which allows us to speak not so much about remission, but about complete recovery from
Currently, the main “event” in the treatment of CML is a new drug - a mutant tyrosine kinase blocker (p210 protein) - Gleevec (STI-571). The drug is prescribed at a dose of 400 mg/m2 for 28 days. For blast crisis of CML, the dose is 600 mg/(m2-day). The use of the drug leads to complete remission of the disease without eradication of the tumor clone. Currently, Gleevec is the drug of choice for CML.
When the spleen is significantly enlarged, X-ray irradiation is sometimes carried out, which leads to a decrease in its size.
For purulent-inflammatory complications, antibiotic therapy is performed.
Blood transfusions for CML are indicated in cases of severe anemic syndrome that is not amenable to cytostatic therapy, or treatment with iron supplements in cases of iron deficiency. Patients with CML are registered at a dispensary and undergo periodic examinations with mandatory hematological monitoring.
Forecast. The life expectancy of patients with CML is on average 3-5 years, in some patients it reaches 7-8 years. Life expectancy after blast crisis rarely exceeds 12 months. The use of Intran A significantly changes the prognosis of the disease for the better.
Prevention. There are no measures to prevent CML, and therefore we can only talk about secondary prevention of the disease, which consists of preventing exacerbations of the disease (maintenance therapy, avoiding sun exposure, colds, etc.).
Erythremia (polycythemia vera, Vaquez disease)
Erythremia (ER) is a myeloproliferative disease, chronic
Icical, benign current leukemia, in which there is
Increased formation of erythrocytes, as well as neutrophilic leukocytes
Ov and platelets. The source of tumor growth is the progenitor cell.
Ca myelopoiesis.
The incidence of erythremia is about 0.6 per 10,000 population. Both men and women get sick equally often. Erythremia is a disease of older people: the average age of those affected is 55-60 years, but the disease can occur at any age.
Etiology. The reasons for the development of the disease are unknown.
Pathogenesis. Erythremia is based on tumor clonal proliferation of all three hematopoietic lineages - red, granulocytic and megakaryocytic, but the growth of the red lineage dominates. In this regard, the main substrate of the tumor is red blood cells maturing in excess. Foci of myeloid hematopoiesis appear in the spleen and liver (which never happens normally). An increased number of red blood cells and platelets in the peripheral blood reduces the speed of blood flow, increases the viscosity and coagulability of the blood, which causes the appearance of a number of clinical symptoms.
Classification. The stage of the disease, the involvement of the spleen in the pathological process and the subsequent transformation of erythremia into other diseases of the blood system are taken into account.
Stage I - initial: hemoglobin content is at the upper limit of normal, a slight increase in the mass of circulating red blood cells, the spleen is slightly enlarged (due to blood overflow) or without changes. Blood pressure is normal or slightly elevated, and focal bone marrow hyperplasia is noted in the iliac trephine specimen. The duration of stage I can exceed 5 years.
Stage II - extensive: phase A - without myeloid metaplasia of the spleen (a simple version of plethora without splenomegaly). Total three-fold hyperplasia of the bone marrow. Absence of extramedullary hematopoiesis; phase B - with myeloid metaplasia of the spleen. Major myeloproliferative syndrome: pancytosis in the peripheral blood, in the bone marrow there is panmyelosis with or without focal myelofibrosis, myeloid metaplasia of the spleen with or without fibrosis.
Stage III - terminal: degeneration of a benign tumor into a malignant one (myelofibrosis with anemization, chronic myelo-leukemia, acute leukemia). Myelofibrosis develops in almost all patients for more than 10-15 years; it reflects the natural evolution of the disease. A sign of myelofibrosis is cytopenia (anemia, thrombocytopenia, and less commonly, leukopenia). The development of chronic myeloid leukemia is manifested by an increase in leukocytosis, an increase (or appearance) in the peripheral blood of myelocytes, promyelocytes, as well as the detection of the Ph chromosome in blood and bone marrow cells.
Acute leukemia usually develops in patients treated with cytostatics and radioactive phosphorus.
Anemia in patients with erythremia may be associated with frequent bloodletting, increased deposition of red blood cells, as well as their hemolysis.
Clinical picture. Erythremia manifests itself in two major syndromes.
Plethoric syndrome is caused by an increased content of red blood cells, as well as leukocytes and platelets (plethora - plethora). This syndrome is caused by: 1) the appearance of subjective symptoms; 2) disorders of the cardiovascular system; 3) changes in laboratory parameters.
1. Subjective symptoms of plethoric syndrome include headaches, dizziness, blurred vision, angina pectoris, skin itching, erythromelalgia (sudden onset of hyperemia with systemic
A pleasant tint of the skin of the fingers, accompanied by sharp pain and burning), possible sensations of numbness and chilliness of the limbs.
2. Disorders of the cardiovascular system are manifested in changes in the color of the skin and visible mucous membranes, such as erythrozzanosis, peculiarities of the color of the mucous membrane at the point of transition of the soft palate to the hard palate (Kuperman's symptom), hypertension, the development of thrombosis, and, less often, bleeding. In addition to thrombosis, swelling of the legs and erythromelalgia are possible. Circulatory disorders in the arterial system can lead to serious complications: acute myocardial infarction, strokes, visual impairment, and renal artery thrombosis.
3. Changes in laboratory parameters: an increase in the content of hemoglobin and red blood cells, an increase in hematocrit and blood viscosity, moderate leukocytosis with a shift in the leukocyte formula to the left, thrombocytosis, a sharp slowdown in ESR.
Myeloproliferative syndrome is caused by hyperplasia of all three hematopoietic lineages in the bone marrow and extramedullary. It includes: 1) subjective symptoms, 2) splenomegaly and (or) hepatomegaly, 3) changes in laboratory parameters.
1. Subjective symptoms: weakness, sweating, increased body temperature, bone pain, heaviness or pain in the left hypochondrium (due to
Splenomegaly).
2. Splenomegaly is explained not only by myeloid metaplasia of the organ (the appearance of foci of extramedullary hematopoiesis), but also by blood stagnation. Less commonly, liver enlargement is observed.
3. Among the laboratory indicators, deviations from the physiological norm in the peripheral blood have the greatest diagnostic significance: pancytosis, often with a shift in the leukocyte formula to the left; trephine biopsy reveals three-line hyperplasia of the bone marrow, and in the puncture of the spleen - foci of myeloid metaplasia of the organ.
The different severity of syndromes at different stages of the disease causes extreme variability in the clinical picture. It is possible to observe patients with undoubted erythremia, who show almost no complaints and are fully able to work, and patients with severe damage to internal organs who require therapy and have lost their ability to work.
At stage I of the diagnostic search in the initial stage of the disease, patients may not present any complaints. As the disease progresses, complaints are associated with the presence and severity of plethora and the myeloproliferative process. The most common complaints are of a “pletoric” nature, caused by increased blood supply to the vessels and functional neurovascular disorders (headaches, erythromelalgia, blurred vision, etc.). All these symptoms may be associated with other diseases, which must be clarified during further examination of the patient.
Complaints caused by the presence of myeloproliferative syndrome (sweating, heaviness in the left hypochondrium, bone pain, increased body temperature) are also nonspecific for erythremia. The skin itching that appears after taking water treatments is quite typical. This symptom is observed in 55% of patients in the advanced stage and is explained by overproduction of basophils and histaminemia. The nature of urticaria, observed in 5-7% of patients, is similar.
The listed symptoms are important for determining the stage of erythremia: usually they indicate the transition of the disease to full-blown
Or the terminal stage with the development of myelofibrosis as the most common outcome of erythremia.
Patients may have a history of complications of the disease such as strokes and myocardial infarction. Sometimes the disease debuts with precisely these complications, and the true cause of their development - erythremia - is revealed when examining a patient for a stroke or myocardial infarction
Indications of previous treatment with radioactive phosphorus, cytostatics or bloodletting may suggest the presence of some kind of tumor blood disease. A decrease in the symptoms of plethoric syndrome during treatment with these drugs suggests erythremia.
At stage II of the diagnostic search, it is possible to identify distinct symptoms only in stage II (advanced) of the disease. The main signs of plethoric syndrome are found: erythrocyanosis, injected conjunctival vessels (“rabbit eyes”), a distinct color border at the transition point of the hard palate to the soft palate. You can identify symptoms of erythro-melalgia: swelling of the tips of the fingers, feet, lower third of the leg, accompanied by local hyperemia and a sharp burning sensation.
When examining the cardiovascular system, hypertension and enlargement of the left ventricle are diagnosed, in the advanced stage of the disease - “motley legs” (changes in the color of the skin of the legs, mainly their distal part) in the form of areas of pigmentation of varying intensity, caused by impaired venous circulation.
When palpating the abdomen, one can detect an enlarged spleen, which is one of the characteristic signs of the disease. Enlargement of the spleen may be due to: 1) increased deposition of blood elements; 2) “working” hypertrophy due to an increase in its sequestering function; 3) extramedullary hematopoiesis (myeloid metaplasia with a predominance of erythropoiesis). These reasons are often combined. Liver enlargement is due to similar reasons, as well as the development of fibrosis and nonspecific reactive hepatitis. It should be borne in mind that hepatomegaly can be observed with a malignant liver tumor with the development of secondary erythrocytosis.
Complications of erythremia in the form of cerebral vascular thrombosis are expressed by a number of focal symptoms identified during the study
However, even at stage II it is impossible to definitively diagnose erythremia, since many of its symptoms can be associated with symptomatic erythrocytosis. In addition, symptoms such as hypertension, splenomegaly and hepatomegaly are characteristic of a wide variety of diseases.
In this regard, stage III of the diagnostic search becomes crucial, as it allows: a) to make a final diagnosis; b) clarify the stage of erythremia; c) identify complications; d) monitor treatment.
Analysis of peripheral blood reveals erythrocytosis, an increase in hemoglobin content and hematocrit, which, however, also occurs with symptomatic erythrocytosis. An increase in hemoglobin levels in combination with erythrocytosis, leukocytosis and thrombocytosis is of diagnostic significance. When examining the leukocyte formula, a shift to the left to immature forms of granulocytes is detected. If changes in peripheral blood are minor or the data are inconclusive (for example, erythrocytosis is not combined with thrombocytosis), then a bone marrow examination (trephine biopsy) must be performed. Presence of total-442 in trepanate
Three-line hyperplasia of the bone marrow with a predominance of formen-Hbix elements of erythropoiesis, replacement of adipose tissue with a red line of bone marrow make it possible to make a final diagnosis. The expansion of the “bridgehead” of hematopoiesis is also detected using radionuclide bone scanning with 32P. Histochemical examination reveals increased activity of neutrophil alkaline phosphatase.
Complications. The course of erythremia is complicated by: 1) vascular thrombosis (cerebral, coronary, peripheral arteries); 2) hemorrhagic syndrome: bleeding after minor surgical interventions (tooth extraction), from the vessels of the digestive tract, hemorrhoids, which is caused by poor retraction of the blood clot due to changes in the functional properties of platelets; 3) endogenous uricemia and uricosuria (due to increased cell death at the nuclear prestages of their maturation), which is manifested by symptoms of urolithiasis and gouty arthritis.
The outcomes of the disease are the situations indicated in stage III of the disease (myelofibrosis, chronic myelogenous leukemia, acute leukemia, anemia).
Diagnostics. Erythremia can be suspected in individuals with persistent erythrocytosis in combination with neutrophilic leukocytosis, thrombocytosis in the absence of diseases (or conditions) that could cause erythrocytosis.
Diagnostic criteria for erythremia (in the advanced stage) are:
Increase in the mass of circulating red blood cells.
Normal arterial blood oxygen saturation (more than 92%).
Leukocytosis is more than 12,109/l (in the absence of obvious reasons for the appearance of leukocytosis).
Thrombocytosis more than 400-109/l.
Increased levels of neutrophil alkaline phosphatase (in the absence of infection).
Increase in unsaturated vitamin B12-binding capacity of blood serum.
The diagnosis of ER is reliable in the presence of three signs of category A or two signs of category A and one sign of category B.
Difficulties in making a diagnosis are due to the development of so-called symptomatic erythrocytosis in a number of diseases. Absolute and relative erythrocytoses are distinguished. With absolute erythrocytosis, an increase in the mass of circulating erythrocytes and increased erythropoiesis are noted. Relative erythrocytosis is characterized by a decrease in the volume of circulating plasma and a normal mass of circulating erythrocytes. Relative erythrocytosis is often detected in men suffering from hypertension, obesity, neurasthenia, and taking diuretics. Secondary absolute erythrocytosis develops in smokers; it is caused by an increase in the content of carbon monoxide in the blood.
Reasons for the development of symptomatic erythrocytosis: 1) generalized tissue hypoxia (pulmonary pathology, heart disease, hemoglobinopathies, obesity, etc.); 2) paraneoplastic reactions (Nochek tumors, tumors of the cortex and medulla of the adrenal glands, pituitary gland, ovaries, vascular tumors, tumors of other organs); 3) renal ischemia
(renal artery stenosis, hydronephrosis, polycystic disease and other kidney anomalies); 4) unknown causes (CNS disease, portal hypertension).
Relative erythrocytosis is observed during exicosis (dehydration due to diarrhea, vomiting, excessive sweating, etc.). Differential diagnosis is based on taking into account the entire clinical picture. In difficult cases, it is necessary to examine the content of erythropoietin in the blood; with erythremia it does not increase.
The formulation of a detailed clinical diagnosis includes information about 1) the stage of the disease; 2) presence of complications; 3) phase of the process (exacerbation or remission); 4) the presence of pronounced syndromes (portal hypertension, hypertension, etc.).
Treatment. The entire complex of therapeutic measures for ER appears to be as follows.
In the advanced stage of the disease, in the presence of plethoric syndrome, but without leuko- and thrombocytosis, bloodletting is used as an independent method of therapy, and it is necessary to reduce the hematocrit level to normal values (less than 45%). 400-500 ml of blood are taken every other day (in a hospital setting) or after 2 days (in a clinic setting). To prevent thrombosis (develop as a result of bloodletting, and also as a complication of erythremia), acetylsalicylic acid is prescribed at a dose of 0.5-1 g/day the day before and on the day of bloodletting, and then for 1-2 weeks after the end of bloodletting. In addition to acetylsalicylic acid, other disaggregants are prescribed - ticlid, plavike, pentoxifylline. Before bloodletting, to prevent pulmonary embolism, it is advisable to administer 5000 units of heparin intravenously (through a Dufault needle), as well as 5000 units of heparin under the skin of the abdomen 2 times a day for several days after bloodletting. In case of poor tolerance to bloodletting, observed in persons with severe cerebral atherosclerosis, exfusion is limited to 350 ml (2 times a week). When bleeding, it is necessary to reduce hemoglobin to 150 g/l.
If bloodletting is not effective enough, as well as in forms of the disease that occur with pancytosis and splenomegaly, cytostatic therapy is prescribed. The age of patients over 55 years expands the indications for the use of cytostatics. Indirect indications for cytostatic therapy are other signs of myeloproliferative syndrome (itching), as well as the severity of the disease, visceral vascular complications (stroke, myocardial infarction), and exhaustion.
Contraindications to cytostatic therapy: young age of patients, refractoriness to treatment at previous stages, as well as excessively active cytostatic therapy in the past due to fear of the disease transitioning to the anemia phase. The effect of cytostatic therapy should be assessed 3 months after the end of treatment; this is explained by the fact that red blood cells produced before treatment live on average about 2-3 months. The decrease in the number of leukocytes and platelets occurs much earlier, according to their life span. The criterion for the effectiveness of cytostatic therapy is the achievement of hematological remission (complete, when all blood parameters are normalized, or partial, in which the number of red blood cells, leukocytes and/or platelets remains slightly increased).
Of the cytostatic drugs at the first stage, hydroxyurea (hydrea) is usually prescribed at a dose of 30-50 mg/(kg day) (2-3 capsules per
Day). During treatment, it is necessary to monitor the number of leukocytes. Hydrea is combined with α-interferon at a dose of 3-5 million IU subcutaneously 3-7 times a week for a long time (at least a year), which allows the relief of thrombocytosis, plethora, and skin itching.
For hyperthrombocytosis, anagrelide is used.
The outcomes of erythremia (myelofibrosis, acute leukemia, chronic myeloid leukemia) are influenced according to the principles of treatment of these diseases: for myelofibrosis, anabolic steroids, nitostatics and red blood cell transfusions are used; for acute leukemia, polychemotherapy is indicated, for chronic myeloid leukemia - cytostatic drugs.
Symptomatic therapy for attacks of erythromelalgia is carried out with the help of antiplatelet agents, non-steroidal anti-inflammatory drugs (acetylsalicylic acid, indomethacin). Arterial hypertension and angina attacks are eliminated in accordance with the rules for the treatment of these conditions.
For complications of erythremia by vascular thrombosis, anticoagulant and antiplatelet therapy is used.
Patients with erythremia are registered at the dispensary with the frequency of visiting a doctor and the appointment of peripheral blood tests once every 3 months.
Forecast. With uncomplicated erythremia, life expectancy can reach 15-20 years (further complications arise). If complications from the cardiovascular system develop early enough or the disease progresses, life expectancy is reduced. Timely initiation of therapy extends life expectancy, although this is not observed in all cases.
Prevention. There are no radical measures to prevent the disease, and therefore we can only talk about secondary prevention, which consists of dynamic monitoring of patients and anti-relapse therapy.
Chronic myeloid leukemia- tumor blood disease. It is characterized by uncontrolled growth and reproduction of all blood germ cells, while young malignant cells are able to mature into mature forms.
Chronic myeloid leukemia (synonym – chronic myeloid leukemia) – tumor blood disease. Its development is associated with changes in one of the chromosomes and the appearance chimeric (“stitched” from different fragments) gene that disrupts hematopoiesis in the red bone marrow.
During chronic myeloid leukemia, the content of a special type of leukocyte increases in the blood - granulocytes . They are formed in the red bone marrow in huge quantities and enter the bloodstream without having time to fully mature. At the same time, the content of all other types of leukocytes decreases.
Some facts about the prevalence of chronic myeloid leukemia:
- Every fifth tumor blood disease is chronic myeloid leukemia.
- Among all blood tumors, chronic myeloid leukemia ranks 3rd in North America and Europe, and 2nd in Japan.
- Every year, chronic myeloid leukemia occurs in 1 in 100,000 people worldwide.
- Over the past 50 years, the prevalence of the disease has not changed.
- Most often, the disease is detected in people aged 30–40 years.
- Men and women get sick at approximately the same frequency.
Causes of chronic myeloid leukemia
The causes of chromosomal abnormalities leading to chronic myeloid leukemia are still not well understood.The following factors are believed to be relevant:
As a result of chromosome breakdowns, a DNA molecule with a new structure appears in red bone marrow cells. A clone of malignant cells is formed, which gradually displace all others and occupy the bulk of the red bone marrow. The vicious gene provides three main effects:
- Cells multiply uncontrollably, like cancer cells.
- Natural death mechanisms stop working for these cells.
Phases of chronic myeloid leukemia
- Chronic phase. The majority of patients who see a doctor are in this phase (about 85%). The average duration is 3 – 4 years (depending on how timely and correctly the treatment is started). This is a stage of relative stability. The patient is concerned about minimal symptoms, which he may not pay attention to. Sometimes doctors detect the chronic phase of myeloid leukemia by chance, during a general blood test.
- Acceleration phase. During this phase, the pathological process is activated. The number of immature white blood cells in the blood begins to increase rapidly. The acceleration phase is, as it were, transitional from chronic to the last, third.
- Terminal phase. The final stage of the disease. Occurs when changes in chromosomes increase. Red bone marrow is almost completely replaced by malignant cells. During the terminal stage, the patient dies.
Manifestations of chronic myeloid leukemia
Symptoms of the chronic phase:
Less common symptoms of the chronic phase of myeloid leukemia
:- Signs associated with impaired platelet and white blood cell function : various bleedings or, on the contrary, the formation of blood clots.
- Signs associated with an increase in platelet count and, as a result, increased blood clotting : circulatory disorders in the brain (headaches, dizziness, decreased memory, attention, etc.), myocardial infarction, blurred vision, shortness of breath.
Acceleration phase symptoms
During the acceleration phase, signs of the chronic stage increase. Sometimes it is at this time that the first signs of the disease appear, which force the patient to visit the doctor for the first time.Symptoms of the terminal stage of chronic myeloid leukemia:
- Sharp weakness , significant deterioration in general health.
- Prolonged aching pain in joints and bones . Sometimes they can be very strong. This is due to the proliferation of malignant tissue in the red bone marrow.
- Heavy sweats .
- Periodic causeless rise in temperature up to 38 - 39⁰C, during which severe chills occur.
- Weight loss .
- Increased bleeding , the appearance of hemorrhages under the skin. These symptoms occur as a result of a decrease in the number of platelets and decreased blood clotting.
- Rapid increase in spleen size : the stomach increases in size, a feeling of heaviness and pain appears. This occurs due to the growth of tumor tissue in the spleen.
Diagnosis of the disease
Which doctor should you contact if you have symptoms of chronic myeloid leukemia?
A hematologist treats blood diseases of a tumor nature. Many patients initially turn to a general practitioner, who then refers them to a hematologist for consultation.
Examination at the doctor's office
An appointment at a hematologist’s office is carried out as follows:- Questioning the patient . The doctor clarifies the patient’s complaints, clarifies the time of their occurrence, and asks other necessary questions.
- Feeling the lymph nodes : submandibular, cervical, axillary, supraclavicular and subclavian, elbow, inguinal, popliteal.
- Feeling the abdomen to determine the enlargement of the liver and spleen. The liver is felt under the right rib while lying on the back. The spleen is on the left side of the abdomen.
When can a doctor suspect a patient has chronic myeloid leukemia?
Symptoms of chronic myeloid leukemia, especially in the initial stages, are nonspecific - they can occur in many other diseases. Therefore, the doctor cannot assume a diagnosis only on the basis of examination and complaints of the patient. Typically, suspicion arises based on one of two studies:- General blood analysis . It contains an increased number of leukocytes and a large number of their immature forms.
- Ultrasound of the abdomen . An increase in the size of the spleen is detected.
How is a complete examination performed if chronic myeloid leukemia is suspected??
| Study title | Description | What does it reveal? |
| General blood analysis | A routine clinical examination is performed if any disease is suspected. A general blood test helps determine the total content of leukocytes, their individual varieties, and immature forms. Blood for analysis is taken from a finger or vein in the morning.
| The result depends on the phase of the disease. Chronic phase:
|
| Puncture and biopsy of red bone marrow | Red bone marrow is the main hematopoietic organ in humans, which is located in the bones. During the examination, a small fragment is obtained using a special needle and sent to the laboratory for examination under a microscope. Carrying out the procedure:
| In the red bone marrow, approximately the same picture is found as in a general blood test: a sharp increase in the number of precursor cells that give rise to leukocytes.
|
| Cytochemical study | When special dyes are added to blood and red bone marrow samples, certain substances may react with them. This is the basis for a cytochemical study. It helps to establish the activity of certain enzymes and serves to confirm the diagnosis of chronic myeloid leukemia, helping to distinguish it from other types of leukemia. | In chronic myeloid leukemia, a cytochemical study reveals a decrease in the activity of a special enzyme in granulocytes - alkaline phosphatase
. |
| Blood chemistry | With chronic myeloid leukemia, the content of certain substances in the blood changes, which is an indirect diagnostic sign. Blood is taken for analysis from a vein on an empty stomach, usually in the morning.
| Substances whose content in the blood is increased in chronic myeloid leukemia:
|
| Cytogenetic study | During a cytogenetic study, the entire genome (set of chromosomes and genes) of a person is studied. For the study, blood is used, which is taken from a vein into a test tube and sent to the laboratory. The result is usually ready in 20 – 30 days. The laboratory uses special modern tests, during which various parts of the DNA molecule are identified.
| In chronic myeloid leukemia, a cytogenetic study reveals a chromosomal disorder, which was called Philadelphia chromosome
. In the cells of patients, chromosome No. 22 is shortened. The lost section is added to chromosome No. 9. In turn, a fragment of chromosome No. 9 joins chromosome No. 22. A kind of exchange occurs, as a result of which genes begin to work incorrectly. The result is myeloid leukemia. Other pathological changes on chromosome No. 22 are also detected. By their nature one can partially judge the prognosis of the disease. |
| Ultrasound of the abdominal organs. | Ultrasound is used in patients with myeloid leukemia to detect enlargement of the liver and spleen. Ultrasound helps distinguish leukemia from other diseases. |  |
Laboratory indicators
General blood analysis- Leukocytes: significantly increased from 30.0 10 9 /l to 300.0-500.0 10 9 /l
- Leukocyte formula shift to the left: young forms of leukocytes predominate (promyelocytes, myelocytes, metamyelocytes, blast cells)
- Basophils: increased amount 1% or more
- Eosinophils: increased level, more than 5%
- Platelets: normal or increased
- Leukocyte alkaline phosphatase is reduced or absent.
- A genetic blood test reveals an abnormal chromosome (Philadelphia chromosome).
Symptoms
The manifestation of symptoms depends on the phase of the disease.Phase I (chronic)
- Long time without symptoms (from 3 months to 2 years)
- Heaviness in the left hypochondrium (due to an enlarged spleen; the higher the level of leukocytes, the larger its size).
- Weakness
- Decreased performance
- Sweating
- Weight loss
- splenic infarction - acute pain in the left hypochondrium, temperature 37.5 -38.5 °C, sometimes nausea and vomiting, touching the spleen is painful.
- Priapism is a painful, excessively prolonged erection.
These symptoms are harbingers of a serious condition (blast crisis) and appear 6-12 months before its onset.
- The effectiveness of drugs (cytostatics) decreases
- Anemia develops
- The percentage of blast cells in the blood increases
- General condition worsens
- The spleen enlarges
- The symptoms correspond to the clinical picture of acute leukemia ( see Acute lymphocytic leiosis).
How is myeloid leukemia treated?
Goal of treatment reduce the growth of tumor cells and reduce the size of the spleen.Treatment of the disease should be started immediately after the diagnosis is made. The prognosis largely depends on the quality and timeliness of therapy.
Treatment includes various methods: chemotherapy, radiation therapy, removal of the spleen, bone marrow transplant.
Treatment with drugs
Chemotherapy- Classic drugs: Myelosan (Mileran, Busulfan), Hydroxyurea (Hydrea, Litalir), Cytosar, 6-mercaptopurni, alpha-interferon.
- New drugs: Gleevec, Sprycel.
| Name | Description |
Hydroxyurea drugs:
| How the drug works: Hydroxyurea is a chemical compound that can inhibit the synthesis of DNA molecules in tumor cells. When can they appoint: For chronic myeloid leukemia, accompanied by a significant increase in the number of leukocytes in the blood. How to prescribe: The drug is released in the form of capsules. The doctor prescribes them to the patient in accordance with the chosen dosage regimen. Possible side effects:
|
| Gleevec (imatinib mesylate) | How the drug works: The drug suppresses the growth of tumor cells and enhances the process of their natural death. When can they prescribe:
The drug is available in tablet form. The regimen of use and dosage is chosen by the attending physician. Possible side effects: The side effects of the drug are difficult to assess, since patients who take it usually already have severe disorders in various organs. According to statistics, the drug has to be discontinued due to complications quite rarely:
|
| Interferon-alpha | How the drug works: Interferon-alpha increases the body's immune strength and suppresses the growth of cancer cells. When is it prescribed?: Interferon-alpha is usually used for long-term maintenance therapy after the white blood cell count has returned to normal. How to prescribe: The drug is used in the form of injection solutions, administered intramuscularly. Possible side effects: Interferon has a fairly large number of side effects, and this is associated with certain difficulties in its use. With proper prescription of the drug and constant monitoring of the patient’s condition, the risk of unwanted effects can be minimized:
|
Bone marrow transplantation
Bone marrow transplantation makes it possible for patients with chronic myeloid leukemia to recover completely. The effectiveness of transplantation is higher in the chronic phase of the disease, in other phases it is much lower. Red bone marrow transplantation is the most effective treatment for chronic myeloid leukemia. More than half of transplant patients experience sustained improvement for 5 years or longer.
Most often, recovery occurs when red bone marrow is transplanted into a patient under 50 years of age in the chronic phase of the disease.
Stages of red bone marrow transplantation:
- Finding and preparing a donor. The best donor of red bone marrow stem cells is a close relative of the patient: twin, brother, sister. If there are no close relatives or they are not suitable, they look for a donor. A series of tests are carried out to ensure that the donor material will take root in the patient’s body. Today, developed countries have created large donor banks containing tens of thousands of donor samples. This gives a chance to quickly find suitable stem cells.
- Patient preparation. Typically this stage lasts from a week to 10 days. Radiation therapy and chemotherapy are carried out to destroy as many tumor cells as possible and prevent rejection of donor cells.
- The actual red bone marrow transplant. The procedure is similar to a blood transfusion. A catheter is inserted into the patient's vein, through which stem cells are injected into the blood. They circulate in the bloodstream for some time, and then settle in the bone marrow, take root there and begin to work. To prevent rejection of donor material, the doctor prescribes anti-inflammatory and antiallergic drugs.
- Decreased immunity. Donor red bone marrow cells cannot take root and begin to function immediately. This takes time, usually 2 – 4 weeks. During this period, the patient's immunity is greatly reduced. He is placed in a hospital, completely protected from contact with infections, and prescribed antibiotics and antifungal agents. This period is one of the most difficult. Body temperature rises significantly, chronic infections can be activated in the body.
- Engraftment of donor stem cells. The patient's health begins to improve.
- Recovery. Over several months or years, red bone marrow function continues to recover. Gradually the patient recovers and his ability to work is restored. But he still needs to be under the supervision of a doctor. Sometimes the new immunity cannot cope with some infections, in which case vaccinations are given about a year after the bone marrow transplant.
Radiation therapy
It is carried out in cases of no effect from chemotherapy and in case of an enlarged spleen after taking medications (cytostatics). Method of choice for the development of a local tumor (granulocytic sarcoma). In what phase of the disease is radiation therapy used?
Radiation therapy is used in the advanced stage of chronic myeloid leukemia, which is characterized by the following symptoms:
- Significant proliferation of tumor tissue in the red bone marrow.
- Growth of tumor cells in tubular bones 2 .
- Severe enlargement of the liver and spleen.
Gamma therapy is used - irradiation of the spleen area with gamma rays. The main task is to destroy or stop the growth of malignant tumor cells. The radiation dose and radiation regimen are determined by the attending physician.
Removal of the spleen (splenectomy)
Removal of the spleen is rarely used for limited indications (splenic infarction, thrombocytopenia, severe abdominal discomfort).The operation is usually performed in the terminal phase of the disease. Together with the spleen, a large number of tumor cells are removed from the body, thereby easing the course of the disease. After surgery, the effectiveness of drug therapy usually increases.
What are the main indications for surgery?
- Splenic rupture.
- Threat of splenic rupture.
- A significant increase in size of the organ, which leads to severe discomfort.
Purification of blood from excess leukocytes (leukapheresis)
With the development of blast crisis, treatment will be the same as for acute leukemia (see acute lymphocytic leukemia).
Leukocytapheresis - a treatment procedure that resembles plasmapheresis (blood purification). A certain amount of blood is taken from the patient and passed through a centrifuge, in which it is purified of tumor cells.
In what phase of the disease is leukocytapheresis performed?
Just like radiation therapy, leukocytapheresis is performed during the advanced stage of myeloid leukemia. It is often used in cases where there is no effect from the use of medications. Sometimes leukocytapheresis complements drug therapy.
Definition. Chronic myeloid leukemia is a myeloproliferative disease with the formation of a tumor bone marrow clone of progenitor cells capable of differentiating into mature granulocytes, predominantly of the neutrophilic series.
ICD10: C92.1 – Chronic myeloid leukemia.
Etiology. The etiological factor of the disease may be infection with a latent virus. The triggering factor that reveals the antigens of the latent virus can be ionizing radiation and toxic effects. A chromosomal aberration appears - the so-called Philadelphia chromosome. It is the result of a reciprocal translocation of part of the long arm of chromosome 22 to chromosome 9. On chromosome 9 there is the abl proto-oncogene, and on chromosome 22 the c-sis proto-oncogene, which is a cellular homologue of the simian sarcoma virus (transforming gene virus), as well as the bcr gene. The Philadelphia chromosome appears in all blood cells with the exception of macrophages and T-lymphocytes.
Pathogenesis. As a result of the influence of etiological and triggering factors, a tumor clone appears in the bone marrow from a progenitor cell, capable of differentiating into mature neutrophils. The tumor clone spreads in the bone marrow, displacing normal hematopoietic germs.
A huge number of neutrophils appears in the blood, comparable to the number of red blood cells - leukemia. One of the causes of hyperleukocytosis is the switching off of the bcr and abl genes related to the Philadelphia chromosome, which causes a delay in the final completion of neutrophil development with the expression of apoptosis (natural death) antigens on their membrane. Fixed spleen macrophages must recognize these antigens and remove old, expired cells from the blood.
The spleen cannot cope with the rate of destruction of neutrophils from the tumor clone, as a result of which compensatory splenomegaly is initially formed.
Due to metastasis, foci of tumor hematopoiesis appear in the skin, other tissues and organs. Leukemic infiltration of the spleen contributes to its even greater enlargement. In the huge spleen, normal red blood cells, white blood cells, and platelets are intensively destroyed. This is one of the leading causes of hemolytic anemia and thrombocytopenic purpura.
During its development and metastasis, a myeloproliferative tumor undergoes mutations and turns from monoclonal to multiclonal. This is evidenced by the appearance in the blood of cells with karyotype aberrations other than the Philadelphia chromosome. As a result, an uncontrolled tumor clone of blast cells is formed. Acute leukemia occurs. Leukemic infiltration of the heart, lungs, liver, kidneys, progressive anemia, thrombocytopenia turn out to be incompatible with life, and the patient dies.
Clinical picture. Chronic myeloid leukemia goes through 3 stages in its clinical development: initial, advanced benign (monoclonal) and terminal malignant (polyclonal).
initial stage corresponds to myeloid hyperplasia of the bone marrow in combination with minor changes in peripheral blood without signs of intoxication. The disease at this stage does not manifest any clinical symptoms and often goes unnoticed. Only in isolated cases can patients feel dull, aching pain in the bones, and sometimes in the left hypochondrium. Chronic myeloid leukemia at the initial stage can be recognized by the random detection of “asymptomatic” leukocytosis, followed by sternal puncture.
An objective examination at the initial stage may reveal a slight enlargement of the spleen.
Expanded stage corresponds to a period of monoclonal tumor proliferation with moderate metastasis (leukemic infiltration) outside the bone marrow. It is characterized by patient complaints of progressive general weakness and sweating. Body weight is lost. There is a tendency to lingering colds. They are worried about pain in the bones, in the left side in the area of the spleen, the enlargement of which the patients themselves notice. In some cases, a prolonged low-grade fever is possible.
An objective examination reveals severe splenomegaly. The organ can occupy up to half the volume of the abdominal cavity. The spleen is dense, painless, and with extremely severe splenomegaly it is sensitive. With a splenic infarction, intense pain suddenly appears in the left half of the abdomen, a friction sound of the peritoneum above the infarction area, and body temperature rises.
When pressing with your hand on the sternum, the patient may experience sharp pain.
In most cases, moderate hepatomegaly is detected, caused by leukemic infiltration of the organ.
Symptoms of damage to other organs may appear: gastric and duodenal ulcers, myocardial dystrophy, pleurisy, pneumonia, leukemic infiltration and/or hemorrhages in the retina, menstrual irregularities in women.
Excessive formation of uric acid during the breakdown of neutrophil nuclei often leads to the formation of urate stones in the urinary tract.
Terminal stage corresponds to the period of polyclonal hyperplasia of the bone marrow with multiple metastasis of various tumor clones to other organs and tissues. It is divided into the phase of myeloproliferative acceleration and blast crisis.
Phase myeloproliferative acceleration can be characterized as a pronounced exacerbation of chronic myeloid leukemia. All subjective and objective symptoms of the disease worsen. I am constantly experiencing severe pain in the bones, joints, and spine.
Due to leukemoid infiltration, severe damage to the heart, lungs, liver, and kidneys occurs.
An enlarged spleen can occupy up to 2/3 of the abdominal cavity. Leukemids appear on the skin - pink or brown spots, slightly raised above the surface of the skin, dense, painless. These are tumor infiltrates consisting of blast cells and mature granulocytes.
Enlarged lymph nodes are detected, in which solid tumors such as sarcomas develop. Foci of sarcomatous growth can occur not only in the lymph nodes but also in any other organ, bones, which is accompanied by corresponding clinical symptoms.
There is a tendency to subcutaneous hemorrhages - thrombocytopenic purpura. Signs of hemolytic anemia appear.
Due to a sharp increase in the content of leukocytes in the blood, often exceeding the level of 1000 * 10 9 / l (true “leukemia”), a clinical syndrome of hyperleukocytosis with shortness of breath, cyanosis, damage to the central nervous system, manifested by mental disorders, visual impairment as a result of edema can form optic nerve.
Blast Crisis is a sharp exacerbation of chronic myeloid leukemia and, according to clinical and laboratory data, represents acute leukemia.
The patients are in serious condition, exhausted, and have difficulty turning in bed. They are worried about severe pain in the bones and spine, debilitating fever, and heavy sweats. The skin is pale bluish with multi-colored bruises (thrombocytopenic purpura), pink or brown lesions of leukemia. The icterus of the sclera may be noticeable. Sweet's syndrome may develop: acute neutrophilic dermatosis with high fever. Dermatosis is characterized by painful lumps, sometimes large nodules, on the skin of the face, arms, and torso.
Peripheral lymph nodes are enlarged and stony in density. The spleen and liver are enlarged to the maximum possible size.
As a result of leukemic infiltration, severe damage to the heart, kidneys, and lungs occurs with symptoms of cardiac, renal, and pulmonary failure, which leads to the patient’s death.
Diagnostics.
In the initial stage of the disease:
Complete blood count: the number of red blood cells and hemoglobin is normal or slightly reduced. Leukocytosis up to 15-30*10 9 /l with a shift of the leukocyte formula to the left to myelocytes and promyelocytes. Basophilia, eosinophilia, and moderate thrombocytosis are noted.
Biochemical blood test: elevated uric acid levels.
Sternal punctate: increased content of cells of the granulocytic line with a predominance of young forms. The number of blasts does not exceed the upper limit of normal. The number of megakaryocytes is increased.
In the advanced stage of the disease:
General blood test: the content of red blood cells and hemoglobin is moderately reduced, the color indicator is about one. Reticulocytes and single erythrokaryocytes are detected. Leukocytosis from 30 to 300*10 9 /l and above. A sharp shift in the leukocyte formula to the left to myelocytes and myeloblasts. The number of eosinophils and basophils is increased (eosinophil-basophil association). The absolute content of lymphocytes is reduced. Thrombocytosis, reaching 600-1000*10 9 /l.
Histochemical examination of leukocytes: the content of alkaline phosphatase in neutrophils is sharply reduced.
Biochemical blood test: increased levels of uric acid, calcium, decreased cholesterol, increased LDH activity. Bilirubin levels may increase due to hemolysis of red blood cells in the spleen.
Sternal punctate: brain with a large content of cells. The number of cells of granulocytic lineages is significantly increased. Blasts no more than 10%. Many megakaryocytes. The number of erythrokaryocytes is moderately reduced.
Cytogenetic analysis: the Philadelphia chromosome is detected in myeloid cells of the blood, bone marrow, and spleen. This marker is absent in T-lymphocytes and macrophages.
In the terminal stage of the disease in the phase of myeloproliferative acceleration:
Complete blood count: significant decrease in hemoglobin and red blood cells in combination with anisochromia, anisocytosis, poikilocytosis. Single reticulocytes may be seen. Neutrophilic leukocytosis, reaching 500-1000*10 9 /l. A sharp shift in the leukocyte formula to the left to blasts. The number of blasts can reach 15%, but there is no leukemic failure. The content of basophils (up to 20%) and eosinophils is sharply increased. Reduced platelet count. Functionally defective megathrombocytes and fragments of megakaryocyte nuclei are identified.
Sternal punctate: the erythrocyte germ is suppressed more significantly than in the advanced stage, the content of myeloblastic cells, eosinophils and basophils is increased. Reduced number of megakaryocytes.
Cytogenetic analysis: a specific marker of chronic myeloid leukemia is detected in myeloid cells - the Philadelphia chromosome. Other chromosomal aberrations appear, which indicates the emergence of new clones of tumor cells.
The results of a histochemical study of granulocytes and biochemical blood parameters are the same as in the advanced stage of the disease.
In the terminal stage of the disease in the blast crisis phase:
General blood test: a deep drop in the content of red blood cells and hemoglobin with a complete absence of reticulocytes. Slight leukocytosis or leukopenia. Neutropenia. Sometimes basophilia. Lots of blasts (over 30%). Leukemic failure: the smear contains mature neutrophils and blasts, and there are no intermediate maturing forms. Thrombocytopenia.
Sternal punctate: the number of mature granulocytes, cells of the erythrocyte and megakaryocytic lines is reduced. The number of blast cells is increased, including abnormal ones with enlarged, deformed nuclei.
In histological preparations of skin leukemid, blast cells are detected.
Generalized criteria for clinical and laboratory diagnosis of chronic myeloid leukemia:
Neutrophilic leukocytosis in peripheral blood over 20*10 9 /l.
The presence in the leukocyte formula of proliferating (myelocytes, promyelocytes) and maturing (myelocytes, metamyelocytes) granulocytes.
Eosinophilic-basophilic association.
Myeloid hyperplasia of the bone marrow.
Decreased neutrophil alkaline phosphatase activity.
Detection of the Philadelphia chromosome in blood cells.
Splenomegaly.
Clinical and laboratory criteria for assessing risk groups necessary to select the optimal treatment tactics for advanced stage chronic myeloid leukemia.
In peripheral blood: leukocytosis over 200*10 9 /l, blasts less than 3%, the sum of blasts and promyelocytes more than 20%, basophils more than 10%.
Thrombocytosis is more than 500*10 9 /l or thrombocytopenia is less than 100*10 9 /l.
Hemoglobin is less than 90 g/l.
Splenomegaly - lower pole of the spleen 10 cm below the left costal arch.
Hepatomegaly is the anterior edge of the liver below the right costal arch by 5 cm or more.
Low risk – the presence of one of the signs. Intermediate risk – 2-3 signs. High risk – 4-5 signs.
Differential diagnosis. It is carried out with leukemoid reactions, acute leukemia. The fundamental difference between chronic myeloid leukemia and similar diseases is the detection of the Philadelphia chromosome in blood cells, a reduced level of alkaline phosphatase in neutrophils, and an eosinophilic-basophilic association.
Survey plan.
General blood analysis.
Histochemical study of the content of alkaline phosphatase in neutrophils.
Cytogenetic analysis of blood cell karyotype.
Biochemical blood test: uric acid, cholesterol, calcium, LDH, bilirubin.
Sternal puncture and/or trepanobiopsy of the iliac wing.
Treatment. When treating patients with chronic myeloid leukemia, the following methods are used:
Therapy with cytostatics.
Administration of alpha-2 interferon.
Cytopheresis.
Radiation therapy.
Splenectomy.
Bone marrow transplantation.
Therapy with cytostatics begins at the advanced stage of the disease. At low and medium risk, monotherapy with one cytostatic agent is used. At high risk and in the terminal stage of the disease, polychemotherapy with several cytostatics is prescribed.
The drug of first choice in the treatment of chronic myeloid leukemia is hydroxyurea, which has the ability to suppress mitosis in leukemic cells. Start with 20-30 mg/kg/day per os at a time. The dose is adjusted weekly depending on changes in the blood picture.
If there is no effect, use myelosan 2-4 mg per day. If the level of leukocytes in the peripheral blood is reduced by half, the dose of the drug is also halved. When leukocytosis drops to 20*10^9/l myelosan is temporarily discontinued. Then they switch to a maintenance dose - 2 mg 1-2 times a week.
In addition to myelosan, myelobromol can be used at 0.125-0.25 once a day for 3 weeks, then maintenance treatment at 0.125-0.25 once every 5-7-10 days.
Polychemotherapy can be carried out according to the ABAMP program, which includes the administration of cytosar, methotrexate, vincristine, 6-mercaptopurine, prednisolone. There are other schemes of multicomponent therapy with cytostatics.
The use of alpha interferon (reaferon, intron A) is justified by its ability to stimulate antitumor and antiviral immunity. Although the drug does not have a cytostatic effect, it still promotes leukopenia and thrombocytopenia. Alpha interferon is prescribed in the form of subcutaneous injections of 3-4 million units/m 2 2 times a week for six months.
Cytopheresis reduces the content of leukocytes in the peripheral blood. A direct indication for the use of this method is resistance to chemotherapy. Patients with hyperleukocytosis and hyperthrombocytosis syndrome with predominant damage to the brain and retina need urgent cytopheresis. Sessions of cytopheresis are carried out from 4-5 times a week to 4-5 times a month.
Indications for local radiation therapy are giant splenomegaly with perisplenitis, tumor-like leukemides. The dose of gamma-ray exposure to the spleen is about 1 Gy.
Splenectomy is used for threatening rupture of the spleen, deep thrombocytopenia, and severe hemolysis of red blood cells.
Bone marrow transplantation gives good results. In 60% of patients undergoing this procedure, complete remission is achieved.
Forecast. The average life expectancy of patients with chronic myeloid leukemia in its natural course without treatment is 2-3.5 years. The use of cytostatics increases life expectancy to 3.8-4.5 years. A more significant extension of the life expectancy of patients is possible after bone marrow transplantation.
