Leucemie acuta limfoblastica: simptome, analize, tratament si reactii adverse - PlusMedical

Acute lymphoblastic leukemia (LAL) is a severe haematological disorder, caused by the uncontrolled proliferation in the hematogenous bone marrow of immature cells called lymphoblasts. Although the diagnosis of LAL has a major impact on you and those around you, you must be aware that there are currently many therapeutic means by which this disease can be controlled and even cured. 

In contrast to chronic leukemias, acute leukemias occur within a few weeks and cause early onset of symptoms, severe in some situations, which makes their diagnosis and treatment extremely important.

There are two large groups of acute leukemias: acute lymphoblastic leukemias and acute myeloblastic leukemias.

In the case of acute lymphoblastic leukemia, immature cells that multiply uncontrolled (lymphoblasts) are the precursors of lymphocytes.

Lymphocytes are blood cells that belong to the immune system and are mainly located in the hematogenous bone marrow, blood, lymph nodes and spleen.

The consequence of the uncontrolled multiplication of lymphoblasts determines:

1. alteration of the production of blood cells (platelets, red blood cells and leukocytes) and consequently the production of hemorrhages, anemia and the increased susceptibility to infections of any kind.

2. Infiltration of organs (especially of the lymph nodes, liver and spleen) by these cells with increasing their size and altering their functions. Any organ can be potentially affected.

The uncontrolled proliferation of abnormal cells that occurs in LAL is the result of altering the mechanisms of control and regulation of cell growth and differentiation. These mechanisms are regulated by genes. Alteration of these genes results in the malignant transformation of the cells by mechanisms currently only partially known.

Currently, there are a number of specific techniques (classical cytogenetics, in situ hybridization, molecular genetics) that allow the study of these genes. In this way, the changes that allow the diagnosis and classification of the type of leukemia can be detected and the treatment will be oriented according to these changes.

The causes of these changes are not yet fully elucidated. It is considered that both genetic and environmental factors (eg ionizing radiation, toxic substances such as benzol derivatives and pesticides) and even some viruses could be incriminated in the etiology of Leukemia.

Recognized carcinogenetic substances such as alcohol and tobacco do not increase the risk of LAL production.

However, in many cases a cause of leukemia cannot be detected. Although certain genetic changes are identified in leukemias, it is important to emphasize that LAL is not an inherited disease! In addition, LAL is not a disease
Infectious, there is no risk of transmission from one person to another.

Based on the characteristics of lymphoblasts, several types of LAL can be identified. Thus, specifying the type of LAL requires a series of complementary techniques:

  • Morphological examination - observation of cells under a microscope
  • Cytochemical examination - specific staining of cells
  • Immunophenotypic examination by flow cytometry - detection of proteins on the surface of lymphoblasts
  • Cytogenetic examination or in situ hybridization - identification of specific changes in lymphoblast chromosomes
  • Molecular biology examination - identification of changes in lymphoblast genes

Establishing the specific type of leukemia is essential for the choice of subsequent therapeutic behavior, predicting the response to treatment and for establishing the prognosis of the disease. 

LAL classification, according to the WHO (World Health Organization):

  • Acute lymphoblastic leukemia Precursor B
  • Precursor T
  • Burkitt type

De asemenea, in practica curenta mai este utilizata o clasificare care se bazeaza pe profilul imunofenotipic al limfoblastilor, determinat prin citometrie in flux. Aceasta presupune identificarea cu anticorpi specifici a anumitor proteine prezente pe suprafata limfoblastilor sau in citoplasma acestora.

By using these methods, LAL can be split into two groups

  • ALL B - characterized by the presence of characteristic markers of line B on the surface of these cells and which represents 75% of all cases of LAL.
  • LAL T - characterized by the presence of characteristic markers of line B on the surface of these cells and which represents 75% of all cases of LAL....

There are also two types of LAL that are well differentiated from the other types by their characteristics and by the different treatment, namely:

  1.  LAL with Philadelphia chromosome (LAL Ph +) - corresponds to the type of LAL that has a gene exchange between chromosomes 9 and 22. Ph + leukemia is most commonly encountered in the elderly (although it can occur at almost any age). The response to conventional chemotherapy is unsatisfactory but in recent years specific drugs have been introduced that block the formation of abnormal protein, which has greatly improved the prognosis of this form of leukemia. LAL Ph + is in some situations and the final stage of another form of leukemia, chronic granulocytic leukemia in which this modification is present.
  2.  LAL Burkitt - corresponds to the subtype of LAL in which genetic material exchange occurs between chromosomes 8 and 14. This subtype of leukemia, also called mature LAL, represents about 5% of all cases of LAL. The treatment is also different from the other forms of LAL, but, unlike the previous situation, the response to the treatment is generally good.

Signs and symptoms of LAL are caused by infiltration of bone marrow and other organs and tissues with leukemic cells, as a consequence of uncontrolled lymphoblast multiplication. In some cases, the diagnosis of leukemia is done on the occasion of the analyzes carried out for other reasons, but in general it is accompanied by a series of constitutional symptoms as follows:

Common LAL symptoms:

They are generally perceived as a feeling bad, discomfort and include:

  • weakness (called in medical terms asthenia), caused by the inefficient production of red cells by infiltration of the marrow with leukemic cells
  • decreased appetite
  • weight loss
  • fever - encountered in about half of the patients, due to the disease itself and to the concomitant presence of infections by reducing the number of leukocytes as a result of infiltration of the leukemia cells.
  • osteo-articular pain - present in about 1/3 of the patients, especially in children

Symptoms caused by leukemia infiltration of the spinal cord:

  • Bleeding - caused by the reduction of bone marrow production in the platelets (blood elements involved in coagulation). These are usually mild and affect the skin and mucous membranes (bleeding bubbles in the buccal mucosa, sometimes nasal mucosa, bladder mucosa, rectal mucosa)
  • Infections - occur due to inefficient production of leukocytes with normal functions. Infections can be located anywhere for example in the lungs (pneumonia) or in the urinary tract and are usually accompanied by fever.
  • Anemia - by insufficient production of red cells, causing pallor, weakness, fatigue

Symptoms caused by infiltration of tissues and organs:

  • Increased lymph nodes, spleen and liver by blast infiltration of these organs.
  • Central nervous system infiltration: although unconsciously, lymphoblasts can invade the spinal cord, brain or meninges (membrane covering the brain and spinal cord). Paralysis of the cranial nerves (nerves that control the movement of the eyes and muscles of the face) may occur with double vision, palpebral ptosis, displacement of the mouth and other symptoms. Alteration of perception and sensitivity (tingling in the chin and other body segments) may occur. Headaches may occur, with or without vomiting.
  • Infiltration of other organs and tissues (skin, mucous membranes, testis or breast): these are not common at the time of diagnosis, but may be relapses

Other symptoms include:

Some types of LAL produce special symptoms. For example, LAL T (T precursor) affects men more often than women and in more than half of cases causes tumor in the mediastinum (space between lungs). On the other hand, mature LAL B and Burkitt leukemia may be accompanied by abdominal tumor (with hepato- and splenomegaly)

As in most cases, the first step begins with obtaining patient data and performing the clinical examination to identify the signs and symptoms reported above. For the final confirmation of the diagnosis, a series of further investigations. Although they do not involve any risk, they can cause a degree of discomfort. These consist of blood analysis, spinal cord aspiration (for myelogram) and lumbar puncture.

Blood analysis shows:

  • Anemia (reduction of hematopoiesis and hemoglobin value)
  • Thrombocytopenia (reduction of platelet count)
  • Leukocytosis (increased leukocyte count) and less often leukopenia (reduced leukocyte count)

Spinal cord aspiration or myelogram consists in performing with local anesthesia the medullary puncture, at the level of the sternum or posterior iliac crest (extraction of several ml of blood from the bone marrow). Follow the exam at
the optical microscope, through which will be identified the lymphoblasts that constitute over 20% of all the cells in the spinal cord. In addition, after the morphological identification of the lymphoblasts (by optical microscopy), a number of additional techniques are required (of cytochemistry, flow cytometry, cytogenetics and molecular biology). Thus, the type of acute lymphoblastic leukemia can be accurately established and the most appropriate treatment can be instituted.

Lumbar puncture it is performed at the level of the lower lumbar spine, with the patient sitting in the lateral decubitus or in the sitting position. This technique is similar to that of spinal anesthesia. A needle is inserted into the space between two vertebrae and several ml of cerebrospinal fluid (the fluid surrounding the spinal cord) are extracted. The cerebrospinal fluid is examined at the diagnosis of LAL to determine whether or not there is neurological impairment. In case of neurological impairment, cytostatic administration will be administered directly at this level to destroy lymphoblasts (repeated intrathecal sessions will be performed). If the extracted liquid is normal, it is also administered cytostatically for prophylactic purposes, but with a lower frequency. As a side effect of intrathecal drug administration, the headache may develop, which may take several days but is well controlled with analgesics.

The basis of the treatment is administration of cytostatic agents, that is, drugs that have the ability to destroy tumor cells (lymphoblasts). Cytostatic treatment depends on the specific type of acute lymphoblastic leukemia, but also by other factors such as the age of the patient, the presence of other conditions (heart, lung).

Moreover, besides chemotherapy, there are other important aspects as well the need for red blood cell or platelet transfusions, antibiotic treatment to control the cytostatic side effects.

Broadly speaking, in all types of LAL,ratamentul cuprinde mai multe faze: prima faza este inductia, a doua consolidarea iar a treia faza este faza de mentinere.

In some cases of LAL there is one increased risk of relapse and after carrying out the consolidation treatment it is necessary hematopoietic stem cell transplantation.

The overall duration of treatment (including all these phases) is long and it can last up to 2 years. Some stages are completed in hospital with periods of discharge of 1-3 weeks between cycles. Between the cycles of chemotherapy the patient can remain at home. It is very important that the treatment program is strictly adhered to without prolonging the break time between treatment cycles. Maintenance treatment is usually performed outpatient.

Induction of remission

Some cytostatic drugs are administered for 4 to 5 weeks. During administration appears medullary aplasia, adica lipsa producerii de leucocite, trombocite si globule rosii din cauza chimioterapiei care nu actioneaza doar asupra limfoblastilor, ci si asupra celulelor normale din maduva.

The objective of induction treatment is reduction in the number of lymphoblasts in the marrow below 5%, with obtaining what is called complete remission. To highlight the complete remission, once the induction treatment is completed, when the analysis shows an increase in leukocytes, platelets and hemoglobin, a new bone marrow aspirate will be performed to determine the number of lymphoblasts in the spinal cord.

If complete remission is not achieved, cytostatic therapy will be prolonged until remission is obtained. A bone puncture is also required in the middle of the induction stage to evaluate the response to treatment and if deemed necessary, the dose of chemotherapy is increased in the latter part of the induction to obtain a maximal response.

Intensification / Consolidation

It consists in the administration of several short cycles of chemotherapy (about one week at intervals of about 2-3 weeks), comprising cytostatics in large doses. In many cases, different cytostatics from the induction stage are administered in different combinations in order to strengthen the response and eliminate the residual cells.

Maintenance therapy

It is administered for a long period (18 - 24 months). Includes the combination of an orally administered cytostatic (mercaptopurine) and a parenterally administered (methotrexate). In some cases of LAL, reinforcement cycles will be interspersed during the maintenance period.

CNS prophylaxis

Given the possibility of CNS infiltration with lymphoblasts, it is necessary to administer low doses of cytostatic directly at this level (intrathecal administrations). Some lumbar punctures are performed during the duration of treatment. At cytostatic administration, a few ml of cerebrospinal fluid is extracted and subjected to analysis to verify the presence / absence of lymphoblasts. In some units, at the same time as intrathecal administrations, radiotherapy is also performed as an additional method of preventing cerebral disease determinations.

Transplantation of hematopoietic stem cells (marrow or peripheral)

This procedure is indicated only in cases selected by the LAL, those with an increased risk of relapse, and is performed after the consolidation stage. It lasts on average 4 to 6 weeks and is done within a hospitalization.

The highest success rate is achieved when chemotherapy has eliminated most of the malignant cells (ie when complete remission was obtained) prior to transplantation. Transplantation consists of the administration of cytostatic treatment, generally associated with radiotherapy, followed by the administration of hematopoietic progenitors. The goal of chemo and radiotherapy is the complete elimination of lymphoblasts. However, this type of treatment not only eliminates the malignant cells, but also destroys the normal ones in the spinal cord. Thus, progenitor cells administered during transplantation counteract the toxic effect of chemo and radiotherapy and restore hematopoiesis.

Transplantation of peripheral hematopoietic or spinal cord cells may be autologous (if the progenitor cells are harvested from the patient himself) or allogeneic (if the progenitor cells are harvested from a compatible, related or unrelated donor selected from the donor register). They can also be transplanted cells collected from the umbilical cord blood.

Allogeneic transplantation is subject to more severe complications than autologous transplantation, but the therapeutic benefits (curability) are greater after allogeneic transplantation.

The type of transplant is established by the team of current doctors taking into account the characteristics of the disease, the age of the patient, the general status of the patient and the existence of a compatible donor. Thus, if the form of the disease has an increased risk of relapse, the patient's compatibility with his brothers (if any) will be tested early after the induction period by analyzing HLA molecules (in a sample collected from peripheral blood).

If there is no related donor, a potential unrelated donor will be sought in the donor registry (national or international) or in the umbilical cord blood bank.

For progenitor cell harvesting, there are currently three methods: progenitors from peripheral blood, hematogenous spine and umbilical cord. Choosing one or the other method depends on the experience and preference of the transplant center and the donor. At present, the preferred method of harvesting is that of peripheral blood, being the most accessible and without the need for hospitalization.

In order to obtain the progenitor cells from the blood of the patient in the case of autologous transplant or of the donor in the case of allogeneic transplant, the person is connected to a special apparatus that separates the progenitor cells from the rest of the circulating cells, a process called apheresis. The necessary cells are obtained within a few hours and then frozen until the transplant and the patient or donor can leave home.

Clinical trials

In certain situations, the medical team may propose you to participate in a clinical trial aimed at improving the results of the treatment and, consequently, to sign an informed consent. As already mentioned, associated with cytostatic treatment, a number of are needed supportive measures and treatments to prevent side effects of chemotherapy. These include:

  • Transfusions of red blood cells to correct anemia
  • Platelet transfusions to control or prevent bleeding (if platelet count is very low as a consequence of treatment)
  • Antibiotics, antivirals and antifungals: they are used to fight infections caused by infectious agents (bacteria, viruses, fungi).
  • Granulocyte growth factors: these substances are injected subcutaneously after the completion of chemotherapy to stimulate leukocyte production and prevent the risk of infections.

hydration: In order to protect the kidney from the toxic effects of chemotherapy and to avoid damage to other organs by releasing toxic metabolites following the destruction of tumor cells, large amounts of fluids are administered to the patient.

Oral hygiene: During the administration of chemotherapy and especially during the period of aplasia, it is not recommended to use the toothbrush because it can promote gingival bleeding and facilitate the passage of microbes from the normal flora of the oral cavity into the circulation, increasing the risk of systemic infection. It is recommended to rinse the oral cavity with different antiseptic solutions indicated by the medical team.

Most of the side effects are caused by the cytostatic treatment, which besides the effect of destroying the lymphoblasts also affects the production of cells from the remaining normal cells of the spinal cord and other tissues and oranges.

Most of these complications are reversible and can be successfully treated. The following are some of these complications:

  • nausea and vomiting: these are directly related to chemotherapy but fortunately, there are currently drugs that can control these symptoms.
  • anemia: caused by red cell deficiency causing fatigue and weakness. Each patient has their own tolerable threshold for anemia, but in some cases, red blood cell transfusions are administered regardless of tolerance.
  • bleeding: reduction of platelet production increases the risk of bleeding. Regular determinations of platelet count will determine the need for platelet mass transfusion if they decrease.
  • infections: reducing the number of leukocytes increases the risk of infections of any type and with any localization. Infections, among other manifestations also produce fever. Therefore, if the patient presents with fever during the treatment, cultures will be collected for the research of infections in the urine, blood and other premises, a lung x-ray will be performed and the antibiotic treatment will be initiated urgently.
  • mucositis: at the level of the mucosa of the oral cavity and of the intestine small ulcerations can develop (what is called mucositis). These ulcers cause pain in the diet and diarrhea respectively. These ulcerations occur due to the reduction of the number of leukocytes as a result of cytostatic effects
  • permanent sterilityChemotherapy does not usually produce permanent sterility, but this is practically unavoidable in patients who will undergo stem cell transplantation. Therefore, in order to maintain the reproductive function, sperm will be cryopreserved in men and repetitive ovarian tissue or eggs fertilized in women.
  • alteration of other organs: In some cases chemotherapy can have toxic effect on some organs and systems that affect their function: heart, liver, peripheral nerves. If these effects are severe, they may prevent the continuation of chemotherapy or may require dose adjustments or elimination of certain cytostatics from the treatment schedule.
  • emotional problems: they derive from the impact produced by the communicated diagnosis on the patient and the entourage. Many hospitals benefit from a specialist psychologist and psychiatrist who can provide patient and family counseling.
  • fatigue: After therapy, some patients may experience extreme physical asthma due to lack of "energy". These symptoms, called "Fatigue", may be acute or chronic. The causes of this fatigue are not fully known, but a number of chemical, physical, and behavioral factors are incriminated.

Regarding the capacity of work, the patient will not work during the treatment but may resume his activity after the completion of the treatment program depending on the physical status and the effort involved in the respective activity.

In some cases, relapse may occur after treatment is completed. However, the likelihood of relapse decreases as time elapses after treatment is longer. Therefore, after the end of the treatment it is necessary repeated checks over several years.

In case of relapse, the medical team will indicate the subsequent treatment possibilities. Despite all the complications, an increasing number of patients remain in long-term remission and require only periodic checks throughout their lives.

In children, the overall cure rate of LAL is about 70% and in adults it is 35-40%. For each patient these results depend on the subtype of LAL and on certain prognostic factors, such as age, the presence of specific chromosomal aberrations, the duration until obtaining the remission and the presence of minimal residual disease.

Controalele efectuate dupa terminarea tratamentului vor fi efectuate de obicei in regim ambulator. Periodicitatea si tipul controalelor, tipul complicatiilor si efectele secundare variaza de la pacient la pacient precum si in functie de tratamentul administrat (transplant sau doar chimioterapie). La fiecare vizita vor fi efectuate un examen fizic, analize de sange si reconsiderarea tratamentului daca se impune. In functie de situatie. vor fi necesare si alte investigatii (ex. examenul maduvei).

The quality of the patient's life is more or less influenced depending on the type of treatment and the side effects. In the case of stem cell transplantation, if no serious complications have occurred, the patient can resume normal activity after about 6-12 months.

The most common long-term problems are those of an emotional nature, fatigue, visual disturbances, difficulty concentrating, memory and sleep disorders. Other problems may also arise:

  • persistence of incompetence: it appears by diminishing the salivary secretion, altering the taste and smell or following the continuation of the treatment; 
  • cataract: is a common problem and generally occurs 5 years or later after transplantation, especially in cases where total body irradiation has been performed during conditioning or if prednisone has been administered for a longer duration.
  • hormonal disorders: especially hypothyroidism (reducing the function of the thyroid gland with the need for thyroid hormone replacement therapy) and early menopause (which can be prevented with hormone replacement therapy which, although it does not induce the resumption of reproductive function, prevents symptoms related to menopause such as blisters, dry skin and mucous membranes and libido reduction)
  • sterility: it is practically unavoidable after the transplant. That is why the special measures mentioned above are required.

In exceptional cases, a second cancer may occur, de obicei la mai multi ani de la efectuarea transplantului.

The possibility of relapse decreases with the passage of time after the transplant. In case of relapse after transplantation, the medical team will indicate the possible therapeutic measures.

For patients receiving only chemotherapy, long-term complications are lower, recovery is faster and patients will be able to resume their activity faster. 

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