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Chronic myeloid leukemia (CML) is a chronic neoplastic disease of the haematopoietic system. What are the causes and symptoms of chronic leukocytic leukemia? How is the treatment going? And what is the prognosis?

Chronic myeloid leukemia( CML , Chronic Myeloid Leukemia, Latinmyelosis leukaemica chronica) accounts for approximately 15 percent of all leukemias.

Adults suffer from it much more often, in children it is diagnosed extremely rarely.

The peak incidence is between the ages of 45 and 55, men suffer from chronic myeloid leukemia slightly more often than women (1.3: 1). It is a malignant neoplasm that occurs in the population at a frequency of about 1-2 / 100,000 people / year.

Its typical feature is the clonal, pathological growth of the multipotent bone marrow stem cell, which, under the influence of growth factors, transforms into cells of the granulocytic system, i.e. leukocytes (white blood cells).

It is worth noting that overproduced granulocytes in CML patients are functionally efficient and maintain their functions.

Chronic myeloid leukemia: risk factors for CML

The known risk factors for developing chronic myeloid leukemia include exposure to ionizing radiation and benzene. However, in most cases the etiology is unknown.

Chronic myeloid leukemia: causes

In the genome of 90-94 percent of people with CML, the Philadelphia chromosome (Ph chromosome) is detected, which is the result of a translocation between chromosomes 9 and 22, t (9,22).

Thanks to genetic testing, it is possible to detect the presence of a fusion gene, the BCR-Abl1 oncogene, which is the result of this mutation.

The abnormal gene leads to the synthesis of a defective protein with tyrosine kinase activity. Physiologically, it plays an important role in how cells perceive the impulses that drive the division, apoptosis, differentiation and maturation of bone marrow cells.

The mutation bcr-abl protein shows constant tyrosine kinase activity, which causes increased and uncontrolled proliferation of the myeloid stem cell clone.

Chronic myeloid leukemia: clinical forms

There are two forms of chronic myeloid leukemia. The division is closely related to the presence of the Philadelphia chromosome in the genome of patients and its absence.

The typical form of CML, in which the Philadelphia chromosome is described, affects approximately 90-94% of patients, while 5% of patients with atypical CML have no presence of it.

These patients have a worse prognosis because they show resistance to standard pharmacological treatment.

Chronic myeloid leukemia: symptoms

In the early stage of chronic myeloid leukemia, no characteristic symptoms of cancer occur. The vast majority of patients feel well, have a he althy appetite, and maintain a constant body weight.

The disease can be suspected at this stage of advancement only on the basis of laboratory changes in the general blood test (morphology), which is why it is so important to perform regular preventive checkups.

In as many as 50% of cases the disease is detected during routine checkups ordered by the general practitioner.

In the later stages of chronic myeloid leukemia, patients begin to experience unconventional ailments that are often underestimated, such as:

  • feeling tired
  • weight loss
  • excessive sweating
  • low fever
  • bone pain
  • abdominal pain
  • stinging sensation in the left hypochondrium

In this case, you should urgently go to the GP who should talk to the patient, examine them and, if necessary, arrange laboratory tests.

People suffering from haematological diseases are treated by a specialist hematologist, to whom you should bring a referral from your GP.

The symptoms presented by patients in the later stage of the disease include:

  • unintentional weight loss in a relatively short period of time (due to accelerated metabolism)
  • lack of appetite
  • chronic fatigue, weakness, drowsiness, easy fatigue, decreased exercise tolerance
  • excessive sweating
  • fever and low-grade fever for no apparent reason
  • recurring infections
  • hepatomegaly, or enlargement of the liver, which is palpable in the abdominal examination performed by a doctor in the right hypochondrium projection
  • splenomegaly or magnificationthe spleen, palpable on the abdomen performed by a doctor in the left hypochondrium projection. May cause prickly pains in the left epigastric region. In the course of chronic myeloid leukemia, the spleen can reach very large dimensions and even reach the pubic symphysis (physiologically it is under the left hypochondrium, it is not palpable on abdominal examination)

Chronic myeloid leukemia: diagnosis

Laboratory tests

The typical features of chronic myeloid leukemia that are reported in the results of laboratory tests include:

  • Leukocytosis

A characteristic feature of chronic myeloid leukemia, which immediately draws the attention of a doctor after receiving the results of a general blood test (morphology), is high leukocytosis, i.e. an increased number of leukocytes (white blood cells) in the peripheral blood.

Physiologically, the number of leukocytes should be in the range of 4.0-10.8x109 / l (4.0-10.8 thousand / µl), while in people suffering from CML, the number of white blood cells fluctuates most often within 20-50x109 / l (20-50 thousand / µl) .

It is worth noting that CML is leukemia with the highest number of leukocytes (even over 500,000 / µl) !

After receiving such test results, the family doctor should immediately refer the patient for an urgent consultation with a specialist hematologist and order a general blood test extended with a thorough analysis of the number of individual leukocyte fractions (blood count with smear).

A typical feature of CML is the increased amount of two fractions of leukocytes - basophils (basophilia) and eosinophils (eosinophilia).

Patients with very high white blood cells and / or platelets may develop symptoms related to leukostasis and forming leukemic embolism, such as stroke, heart attack, visual disturbances, and venous thrombosis.

  • Presence of myeloblasts in peripheral blood

Physiologically blasts are present only in the bone marrow, not described in the peripheral blood.

The percentage of myeloblasts is one of the criteria that define the stage of disease advancement. The presence of between 10 and 19% of myeloblasts indicates the acceleration phase of the disease, while>20% informs the doctor about a blast crisis.

  • Anemia

Correct, increased or decreased number of platelets depending on the stage of the disease.

Increased concentration of uric acid in the blood serum - it results from increased metabolismin the course of proliferative disease.

  • Increased lactate dehydrogenase (LDH) activity

It results from increased cellular metabolism in the course of a proliferative disease.

Significantly reduced activity of alkaline phosphatase in leukocytes (a characteristic feature of CML, in other myeloproliferative diseases the activity of this enzyme is increased).

  • Bone marrow fibrosis

It occurs in the later, advanced stage of the disease.

Bone marrow examination

To establish the diagnosis, the doctor orders a histopathological examination of the bone marrow. To collect bone marrow for examination, a fine needle aspiration biopsy or percutaneous bone marrow biopsy should be performed, i.e. invasive procedures performed in a hospital setting.

  • BAC (Fine Needle Aspiration Biopsy)involves collecting the bone marrow using a specialized needle with a syringe.
  • Percutaneous bone marrow biopsyinvolves taking a bone fragment together with the bone marrow with a thick, sharp needle, after prior skin anesthesia.

Most often, the bone marrow is collected from one of the iliac bones (they form the pelvis together with the pubic, ischial and sacrum bones), and more specifically from the posterior superior iliac spine and from the sternum.

The method of choice is fine-needle bone marrow aspiration, but in some cases this method does not provide material for testing due to bone marrow fibrosis.

In this case, a percutaneous bone marrow biopsy should be performed.

The results of bone marrow examination in patients with chronic myeloid leukemia show a rich-cell image of the bone marrow, with a predominance of the granulocytic system and the presence of an increased amount of granulocytopoiesis precursors ("left shift", i.e. the appearance of younger forms of myeloid lineage in the blood).

Performing a fine-needle aspiration biopsy is necessary due to the need to assess the percentage of blasts, which allows to determine the stage of neoplastic disease, as well as to perform a cytogenetic test, during which the karyotype of bone marrow cells is assessed.

Cytogenetic and biomolecular testing

Cytogenetic (bone marrow material) and biomolecular (peripheral blood material) tests performed on people suffering from chronic myeloid leukemia are considered the "gold standard" in diagnosis and treatment monitoring.

It shows the presence of a chromosomePhiladelphia and the fusion gene, the oncogene BCR-Abl1, which is the result of a mutation t (9,22).

It is of key importance not only in determining the diagnosis of neoplastic disease, treatment method, and its prognosis, but also in monitoring the response to therapy.

The supervision of chronic myeloid leukemia treatment is the determination of the number of cells containing the Philadelphia chromosome.

A complete cytogenetic response to treatment is defined as a state in which no Ph + cells are found in the material tested, and a partial cytogenetic response - when the number of Ph + cells ranges between 1 and 35%.

Chronic myeloid leukemia: clinical phases of the typical form

Chronic myeloid leukemia is characterized by a three-phase course. There are 3 stages of the disease advancement:

  1. chronic phase (stable chronic period)At this stage the disease is usually secretive, without any typical clinical symptoms. Patients may notice fatigue, night sweats or decreased exercise tolerance. 85% of patients are diagnosed at this stage of neoplastic disease advancement, which is a favorable prognosis. It takes an average of 3-5 years.
  2. acceleration phase (acceleration period)This period of the disease is diagnosed when the percentage of myeloblasts in the peripheral blood, according to WHO is between 10 and 19%. Patients develop the first clinical symptoms of neoplastic disease, such as spleen enlargement, fever, leukocytosis, anemia and thrombocytopenia. The median survival of patients in this phase of the disease is 1-2 years.
  3. blast phase (orifice, blast crisis)The third stage of the disease is characterized by the percentage of>20% of myeloblasts and promyelocytes in the peripheral blood (the formerly used criterion is 30%). The course of blast crisis is severe, similar to acute leukemia, characterized by resistance to treatment, poor prognosis, and usually fatal. The median survival of patients is 3-6 months. According to the literature, smoking significantly accelerates the onset of blast crisis in people suffering from chronic myeloid leukemia!

CRITERIA FOR THE RECOGNITION OF THE ACCELERATION PHASE AND THE BLASTIC BREAKTHROUGH OF CHRONIC LEELLONOMA ACCORDING TO THE WORLD HEALTH ORGANIZATION (WHO)

CRITERIA ACCELERATION PHASE (presence>=1 symptom)

  • percentage of blasts in peripheral blood or bone marrow 10-19%
  • basophilia>=20%
  • thrombocytopenia<100tys./µl
  • thrombocythemia>1 million / µl (refractory to treatment)
  • clonalcytogenetic evolution (additional chromosomal aberrations)
  • spleen enlargement or treatment-resistant leukocytosis increase

BLASTIC BREAK CRITERIA (presence of>=1 symptom)

  • blast percentage>=20%
  • extramedullary leukemia infiltrates

CRITERIA FOR THE RECOGNITION OF THE ACCELERATION PHASE AND THE BLASTIC BREAK OF CHRONIC LEUKEMIA BY ELN

CRITERIA ACCELERATION PHASE

  • 15-29% blasts in blood or bone marrow
  • a total of 30% of blasts and promyelocytes in blood or bone marrow, but<30% samych blastów
  • percentage of basophils in peripheral blood or bone marrow>=20%
  • long-term thrombocytopenia<100G/l niezwiązana z terapią
  • emergence of clonal evolution in Ph (+) cells

BLASTIC PHASE CRITERIA

  • blasts are>=30% of peripheral blood leukocytes or marrow nucleated cells
  • extramedullary blast proliferation

ASSESSMENT OF THE RISK OF PROGRESSION IN PATIENTS WITH CHRONIC LEMONOMY LEATHERIA

Risk assessment of chronic myeloid leukemia progression is based on the Hasford formula, which takes into account the patient's age, spleen size below the costal arch, percentage of basophils (basophils), percentage of eosinophils, and number of platelets. Based on the results, there are 3 groups of patients: low, intermediate and high risk of disease progression.

Chronic myeloid leukemia: treatment

There are several methods of treating chronic myeloid leukemia, a specialist hematologist decides which treatment regimen is appropriate for the patient, taking into account his age, he alth condition, risk index, and the availability of drugs. The goal of the therapy is to recover completely or to survive as long as possible.

  • Bone marrow transplantation

Allogeneic bone marrow transplantation is performed most often after myeloablative treatment. This is the only method of therapy that gives the patient a chance of full recovery.

Recipients are transplanted bone marrow obtained from a donor of the same species, usually from family and relatives. In the absence of relatives who can donate bone marrow for transplant, transplantation from unrelated people is also possible, unfortunately such a donor is difficult to find.

The condition for qualifying for allogeneic bone marrow transplantation is the patient's age below 55-60. years of age.

The literature reports that the best results in the treatment of chronic myeloid leukemia are obtainedwhen the bone marrow transplant is performed in the first year of the disease, in the first chronic phase, and the donor is the patient's siblings compatible with the major histocompatibility complex HLA (Human Leukocyte Antigens).

This method of treatment is considered to be the most beneficial for patients when used in the early stages of CML.

The probability of cure is estimated at 40-70% when bone marrow transplantation is performed in the chronic phase of the disease, 10-30% during the acceleration phase, and less than 10% during the blast phase (then it is additionally burdened with a high risk of death).

It is worth noting that bone marrow transplantation is burdened with a number of complications, the most common of which in practice is Graft versus Host Disease (GvHD).

It is the leading cause of death in people treated with this method. It has been shown that the probability of acute GvHD in patients after bone marrow transplantation is 47%, and in chronic - 52%.

  • Pharmacotherapy

Imatinib (tyrosine kinase blocker)

It is the drug of choice in patients for whom bone marrow transplantation is not possible for various reasons.

Alpha interferon

This medicine is used in patients with a typical type of chronic myeloid leukemia. It has been proven that in 30% of patients it causes a long-term, high cytogenetic response and extends the life of patients by an average of 20 months, compared to treatment with hydroxycarbamide. It is often used in combination with cytarabine or hydroxycarbamide.

Hydroxyurea (hydroxycarbamide)

Pharmaceutical used in the initial phase of treatment of chronic myeloid leukemia, in order to reduce the mass of leukemic cells, as well as in symptomatic and palliative treatment. Also used when the patient is not eligible for bone marrow transplantation due to his he alth, age or comorbidities, and has not achieved clinical improvement after treatment with interferon alfa and imatin.

  • Leukepheresis

Leukapheresis is a method of short-term reduction of the number of leukocytes in the peripheral blood with the use of professional centrifugal cell separators.

This treatment is performed only in specialized centers that have the required equipment. It consists in performing two intravenous punctures in both elbows, after disinfecting the injection sites.

Peripheral whole blood is collected from a vein on one upper limb to a separator where white blood cells are separated from the restblood and plasma morphotic elements.

After the end of the procedure, the blood depleted of the excessive amount of leukocytes returns to the bloodstream by the needle on the other upper limb.

This method is used only in exceptional situations, when the doctor wants to avoid exposure to specialist pharmacological treatment, e.g. during pregnancy, and also in the case of very high leukocytosis, which poses a risk of leukemia embolism.

This procedure is expensive and technically complicated, therefore it is rarely used in practice.

Chronic myeloid leukemia: remission assessment and post-treatment follow-up

Not only during the therapy, but also after completing the treatment, it is very important to stay in constant contact with the hematologist treating the therapy and to perform the prescribed check-ups.

These are blood count tests, biochemical tests (to assess possible toxicity and effects on the liver), cytological and cytogenetic tests of the bone marrow and molecular tests of the amount of BCR / ABL transcript.

Assessment of molecular remission is performed every 3 months in the first year of treatment, and then every 6 months in the following years while the patient is still in remission.

Chronic myeloid leukemia: differentiation

Chronic myeloid leukemia should be differentiated from other forms of myeloproliferative neoplasms, with bone marrow fibrosis, leukemic reactions, as well as chronic neutrophilic leukemia and chronic myelomonocytic leukemia. In these disease states, however, the Philadelphia chromosome is absent!

Chronic myeloid leukemia: prognosis

Median survival of people with chronic myeloid leukemia is approximately 3-6 years. After bone marrow transplantation, 10-year survival is observed in approximately 55% of patients.

30% of patients who received only pharmacological chemotherapy live 5 years after the end of treatment (the average survival time of patients treated with hydroxycarbamide is 3-4 years).

A complete recovery is possible only with an allogeneic bone marrow transplant. It is very important to early diagnose a neoplastic disease and to promptly introduce treatment in a specialized center.

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Category:

Oncology