What is Acute Lymphoblastic Leukemia?
Acute lymphoblastic leukemia is a group of heterogeneous malignant neoplasms from cells – lymphoid precursors (lymphoblasts) that have certain genetic and immunophenotypic characteristics.
Acute lymphoblastic leukemia is the most common leukemia in childhood and adolescence. The peak incidence occurs at the age of 1 year to 6 years. They occur with damage to the bone marrow, lymph nodes, spleen, thymus, and other organs.
Acute lymphoblastic leukemia often affects children. Its peak falls on 2-4 years. Among adults, this form of acute leukemia occurs in 10-15% of patients.
Causes of Acute Lymphoblastic Leukemia
The genetic basis for the development of acute lymphoblastic leukemia lies in changes in the structure of chromosomes, i.e. chromosomal aberrations. In leukemia, specific or primary and nonspecific aberration chromomonoms are distinguished. The primary ones include translocation, deletion, inversion, amplification of chromosome regions containing oncogenes, genes of cell receptors, genes of growth factors. Such changes can form new DNA sequences and the appearance of new properties in the cell, the formation of a specific clone. Secondary chromosomal aberrations appear at the stage of tumor progression as a result of changes in the formed clone. Moreover, similar aberrations can be observed with different variants of leukemia. So, the Philadelphia chromosome can be detected in both acute and chronic leukemia.
The reasons for the development of acute lymphoblastic leukemia in children are still not precisely established, however, there is evidence of a large importance of infectious diseases in infancy, the effects of various physical ones (for example, X-ray diagnostics, radiation therapy, ionizing radiation), the effect of chemical mutagens. when exposed to benzene, among patients receiving cytostatic immunosuppressants (imuran, cyclophosphamide, leukaran, sarcolysin, mustargen, etc.), biological (viral) mutagens on the mother’s body during pregnancy. The relationship between many congenital chromosomal abnormalities and the development of acute leukemia has also been proven.
Pathogenesis during Acute Lymphoblastic Leukemia
In bone marrow, peripheral blood, and other organs, tumor cells such as lymphoblasts with SEC-positive granules in the cytoplasm are found that do not give reactions to peroxidase, esterases, and lipid-free ones.
In 2/3 of cases, tumor cells show cytogenetic disorders in the form of polyploidy, the Philadelphia chromosome and reciprocal translocation between the chromosomes.
The cytogenesis of acute lymphoblastic leukemia is associated with the precursors of T and B lymphocytes. T-cell leukemia in Europe accounts for 10-15% of cases. B-cell leukemia predominates.
Guided by the immunological phenotypes of tumor cells, several forms of lymphoblastic leukemia are distinguished, which is important for the choice of therapy and prognosis. The predominant B-lymphoblastic leukemia is represented by early, intermediate and late variants, differing in the expression of CD10 paraglobulin, surface immunoglobulin and terminal dioxinucleotide transferase activity. Markers of T-lymphoblastic leukemia are CD7 and T-receptor antigens.
Symptoms of Acute Lymphoblastic Leukemia
There are two types of acute lymphoblastic leukemia: B-linear and T-linear, depending on the type of cells – lymphoid precursors.
All leukocytes in the human body are divided into 2 types – granulocytic and agranulocytic (granular and non-granular), these two groups, in turn, are divided into eosinophils, basophils, neutrophils (granulocytic), and lymphocytes (B- and T-type) and monocytes (agranulocytic). In the process of maturation and development (differentiation), all cells go through several stages, the first of which is the blast stage (lymphoblasts). Due to a tumor in the bone marrow, the lymphocytes do not have enough time to develop in order to fully perform their protective functions. For the most part, in acute lymphoblastic leukemia, B-lymphocytes are affected (in about 85% of cases), which are responsible for the formation of antibodies in the body.
Clinical signs of acute lymphoblastic leukemia:
- Intoxication syndrome – weakness, fever, malaise, weight loss. Fever may also be associated with the presence of a bacterial, viral, fungal or protozoal (less commonly) infection, especially in children with neutropenia (less than 1,500 neutrophils in 1 μl).
- Hyperplastic syndrome – an increase in all groups of peripheral lymph nodes. Infiltration of the liver and spleen leads to their increase, which can be manifested by abdominal pain. Bone pain and aches can occur due to leukemic infiltration of the periosteum and articular capsule and tumor growth in bone marrow volume. At the same time, radiographs reveal changes characteristic of leukemic infiltration, especially in the tubular bones, near large joints.
- Anemic syndrome – pallor, weakness, tachycardia, bleeding of the oral mucosa, hemorrhagic syndrome on the skin, pallor. Weakness results from anemia and intoxication.
- Hemorrhagic syndrome is associated with both thrombocytopenia and intravascular thrombosis (especially with hyperleukocytosis) and leads to the appearance of petechiae, ecchymoses on the skin and mucous membranes, hemorrhages, melena, vomiting with blood.
- In boys, an initial testicular enlargement can be detected (5-30% of cases of primary ALL). These are painless, dense, single or bilateral infiltrates. This is especially common with hyperleukocytosis and the T-cell variant of ALL.
- Respiratory disorders associated with an increase in the mediastinal lymph nodes, which can lead to respiratory failure. This feature is characteristic of T-linear ALL.
- Retinal hemorrhages, optic edema may appear. With ophthalmoscopy, leukemic plaques in the fundus can be detected.
- Due to the greatly reduced immunity, any damage to the skin is the focus of infection, and paronychia, panaritium, infected insect bites and signs of injection may appear.
Quite rare complications can be kidney damage due to infiltration (clinical manifestations may not be present) and effusion pericarditis due to impaired lymphatic flow between the endocardium and the epicardium.
Diagnosis of Acute Lymphoblastic Leukemia
The clinical onset of the disease may coincide with the aleukemic and leukemic phases. Often there are nonspecific changes in the blood associated with a violation of the structure of the bone marrow: single red blood cells, myelocytes, promyelocytes – signs of myeloma. Puncture of bone marrow, revealing blast cells in a large percentage, resolves all diagnostic difficulties.
The morphology of blast cells has some features: a nucleus with a delicate chromatin network, like all blasts, is usually round, has 1-2 large nucleols in many nuclei, and does not contain granular cytoplasm. As with all acute leukemia, the shape of the nucleus changes during the disease: it becomes irregular, its size grows; the rim of the cytoplasm also increases.
Specific histochemical features of this leukemia: blast cells do not detect peroxidase, phospholipids, esterases, and the glycogen detected by the PAS reaction is distributed in the cytoplasm by clumps in the form of a necklace around the nucleus.
The study of T– and B-markers on blast cells of acute lymphoblastic leukemia showed that it is a heterogeneous group. There are at least 3 forms of this leukemia detected by antigenic markers: acute lymphoblastic leukemia with blast cells having markers of B-lymphocytes, markers of T-lymphocytes and not having markers of T- or B-lymphocytes.
The B-form of acute lymphoblastic leukemia includes leukemic stages of lymphosarcoma, Burkitt’s lymphosarcoma, and very rare blast crises of chronic lymphocytic leukemia. Leukemia cells with this form are characterized by a high density of IgM on their surface.
The features of the T-form of acute lymphoblastic leukemia are clinically more clearly studied. The above form is most often detected in children of an older age group, while the average age of patients is 10 years. According to most data, the average life expectancy of patients with this form of acute leukemia is less than 24 months, exacerbation in half of cases begins with extramedullary growth – more often with damage to the nervous system.
Blast cells in their antigenic structure are more likely to resemble thymocytes and pretimocytes than peripheral T cells. Also, these cells retain some of the functional properties of suppressors. The cytochemical feature of T-blasts is the high activity of acid phosphatase, its localization in the cytoplasm.
The general characteristic of acute lymphoblastic leukemia refers mainly to its neither T- nor B-form, which includes about 70% of cases.
By antigenic and enzymatic features, neither T– nor B-form cells are lacking the determinants of peripheral T- and B-lymphocytes. However, such cells have the features of thymocyte precursors: they react with an antiserum to thymic antigens, with some antisera of chronic lymphocytic leukemia, and contain a lot of deoxynucleotidyl transferase. Another feature of these cells is that they have a lot of Ia antigen, which is characteristic of B cells.
In acute lymphoblastic leukemia, in addition to the 3 main forms isolated by antigenic markers of lymphocytes (T-acute lymphoblastic leukemia, B-acute lymphoblastic leukemia and neither T- nor B-acute lymphoblastic leukemia), several more were determined.
New forms are basically separated from neither the T- nor the B-form. So, the pre-B form of acute lymphoblastic leukemia was isolated: the blasts representing it belong to the early cells – the precursors of B-lymphocytes, since they contain cytoplasmic immunoglobulin – the IgM heavy chain – and do not have immunoglobulins on the surface. The above-described form of acute, essentially B-cell leukemia has a significantly more favorable course than the B-form.
Leukemia, represented by lymphoblasts with the same antigenic markers but containing the Ph’chromosome, separated from neither the T– nor the B-form. This form of acute lymphoblastic leukemia occurs in older children – after 10 years; it flows unfavorably, giving a short improvement.
In a small percentage of cases, acute lymphoblastic leukemia occurs, the blasts of which are immunologically characterized as pre-T lymphocytes, and as progenitor cells of T lymphocytes. In contrast to the pre-B-form of acute lymphoblastic leukemia, pre-T, like other T-cell acute leukemia, refers to unfavorable forms of the course.
T-cell forms of acute lymphoblastic leukemia can be accompanied by high eosinophilia. In this case, leukocytosis occurs in the blood, eosinophilia reaches 80-90%, and blast cells may be absent. High eosinophilia requires bone marrow puncture, in which, in the case of leukemia, a high percentage of blast cells is found. In remission, eosinophilia disappears and reappears, sometimes as the first sign of relapse.
In children, an increase in submandibular lymph nodes is often due to chronic tonsillitis, and an enlargement of the spleen is a common reaction to infection. Leukemic infiltration of the lymph nodes gives them density (the nodes are usually painless), the supraclavicular lymph nodes increase more often, and not the submandibular ones, as with tonsillitis. In doubtful cases, organ puncture is always indicated: this is especially true for the spleen, since it may contain local recurrence with an almost continuous blast content in punctate. Timely diagnosis of acute lymphoblastic leukemia as a “fast” leukemia is of great importance not only because of the speed of the process itself, but also because of the entry of pathological cells into the meninges.
According to the clinical picture, the ability to keep normal hematopoiesis sprouts intact, the frequency of the first remission, acute lymphoblastic leukemia in adults is similar to the childhood version.
The spleen and lymph nodes in acute lymphoblastic leukemia increase for the most part simultaneously with the process in the bone marrow. In contrast to acute myeloid leukemia, this increase in this leukemia is not a new stage of progression. Leukemic cells, infiltrating lymph nodes and the spleen, are usually sensitive to the same cytostatic drugs as the cells in the bone marrow.
As a rule, improvement is achieved by using a complex of cytostatic agents. Further continuous treatment with cytotoxic drugs keeps the improvement for months or years. However, adults often have exacerbations of the disease. An exacerbation can be either only local: the appearance of neuroleukemia, nerve root infiltration or testicular infiltration, leukemic episiscleritis (inflammation of the outer shell of the eyeball), or bone marrow. Local exacerbation is determined by spinal puncture, or patients develop pain due to infiltration of the roots. Bone marrow exacerbation may not be accompanied by the release of blast cells into the blood, therefore, the doctor performs a thoracic puncture regularly: every month in the first year of improvement, and then once every 3 months. In addition, thoracic puncture is done when blasts appear in the blood and cytopenia independent of cytostatics.
An obvious indication for a bone marrow examination should be obvious clinical signs of exacerbation: an increase in lymph nodes, the appearance of bone pain, radicular syndrome, subfebrile condition, and simply unmotivated deterioration of the general condition. The signs of the disease during the period of exacerbation of acute lymphoblastic leukemia are stronger than during its first attack. Each subsequent exacerbation develops more malignant than the previous ones, and has a worse prognosis.
Metastasis of the process into the testes and meninges, the most frequent in acute lymphoblastic leukemia of children, represents a new stage of tumor progression, the process of mediastinal nodes, early damage to the central nervous system and age younger than 1 year and older than 10 years.
Acute Lymphoblastic Leukemia Treatment
There are several different ways to treat adult ALL patients.
Some treatments are standard (currently used), and some new treatments are undergoing clinical trials. A clinical trial is a research study whose goal is to improve the standard treatment method or to obtain information about the results of new treatments for cancer patients. If clinical trials show that the new treatment is better than the standard, the new treatment can subsequently become the standard treatment. Patients may also participate in clinical trials. In some clinical trials, only patients who have not received any treatment may participate.
Treatment of adult acute lymphoblastic leukemia usually takes place in two stages.
Stages of treatment of adult acute lymphoblastic leukemia:
- Remission-induction therapy. The goal of this stage of treatment is to destroy leukemia cells in the blood and bone marrow and achieve remission.
- Post-remission therapy. This is the second stage of treatment. It begins as soon as remission is achieved. The goal of post-remission therapy is to destroy the remaining leukemia cells, which may not be active, but can subsequently begin to grow and this will lead to relapse. This stage is also called the continuation of remission therapy.
Treatment and prophylactic therapy of the central nervous system is usually carried out at each stage of treatment. Due to the fact that chemotherapeutic drugs are taken orally or injected intravenously, the drug often can not destroy the leukemia cells that enter the central nervous system (brain and spinal cord). Leukemic cells take refuge (hide) in the central nervous system. Intrathecal chemotherapy and radiation therapy can destroy leukemia cells that have fallen into the central nervous system, and thereby prevent a relapse of the disease. This type of treatment is called treatment and prophylactic therapy of the central nervous system.
Today, there are four standard methods of treatment:
Chemotherapy is a method of treating cancer with potent chemotherapeutic drugs. Chemotherapeutic drugs can stop and destroy the growth of cancer cells, prevent their separation and penetration into other tissues and organs. With chemotherapy, medications can be taken orally (in the form of tablets, capsules) or injected intravenously or intramuscularly. The drug enters the bloodstream, spreads throughout the body and infects cancer cells (systematic chemotherapy). If chemotherapeutic drugs are injected directly into the spine (intrathecal chemotherapy), an organ or cavity (e.g., abdominal), the drug mainly affects cancer cells in these areas (regional chemotherapy). Combination chemotherapy is a treatment in which more than one anti-cancer chemotherapeutic drug is used. The way chemotherapy is used depends on the type and stage of the cancer.
Intrathecal chemotherapy can be used to treat adult ALL, which tends to spread to the brain and spinal cord. Therapy used to prevent the spread of cancer cells in the body and their penetration into the brain or spinal cord is called treatment and prophylactic therapy of the central nervous system. Intrathecal chemotherapy is carried out in combination with conventional chemotherapy, in which medications are taken orally or by injection.
Antineoplastic agents are injected into the intrathecal cavity of the spinal canal, where cerebrospinal fluid is located (CSF is shown in blue in the figure). There are two different ways to administer chemotherapy drugs. The first method, depicted at the top of the figure, is a drug administered in an Ommaya reservoir. (A convex container that is inserted into the ventricles of the brain. The container holds the bulk of the drug so that the drug can slowly enter the brain through small tubes). Another method, shown at the bottom of the figure, is the drug injected directly into the cerebrospinal fluid into the spinal column at the level of the lower back. The procedure is carried out under local anesthesia.
Radiation therapy is a cancer treatment method that uses hard X-rays or other types of radiation to kill cancer cells or prevent the growth of cancer cells. There are two types of radiation therapy. External radiation therapy – a special device focuses radiation in the tumor area. Radiation internal therapy – the use of radioactive substances hermetically sealed in needles, capsules, rods or catheters, which are placed directly in or near the tumor. External radiation therapy can be used to treat adult ALL, which tends to spread to the brain and spinal cord. This is called treatment and prophylactic therapy of the central nervous system.
Chemotherapy followed by stem cell transplantation
Chemotherapy is performed before stem cell transplantation. Stem cell transplantation is used to replace abnormal blood-forming cells with full ones. Stem cells (immature blood cells) are taken from the blood or bone marrow of a patient or donor, frozen and stored. At the end of the chemotherapy course, the stored stem cells are thawed and administered to the patient in the form of stem cell infusions. Transplanted stem cells take root and help restore bone marrow cells producing blood cells.
Tyrosine Kinase Inhibitor Therapy
Anticancer drugs called tyrosine kinase inhibitors are used to treat certain types of adult ALL. The drug blocks an enzyme, tyrosine kinase, which promotes the development of a large number of white blood cells (granulocytes or blast cells) from stem cells. To date, two such drugs, Imatinib (imatinib mesylate) (Gleevec) and Dasatinib, are used.
Some new treatments are undergoing clinical trials.
This section describes the types of treatments that are in clinical trials. It is impossible to talk about all the new treatments that are being studied. Clinical trial information is available on the NCI website.
Biological therapy is a treatment method that uses the patient’s immune system to fight cancer. Substances that are produced in the body or that are synthesized in the laboratory are used to stimulate or restore the natural mechanisms of protection and the fight against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.
Patients may also participate in clinical trials.
For some patients, participating in clinical trials is the best choice. Clinical trials are part of the research process. The purpose of conducting clinical trials is to establish: whether the new treatment is safe and effective, or better than the standard treatment.
Many of the current standard treatments are based on early clinical trials. Patients participating in clinical trials may receive standard treatment or undergo a new treatment regimen.
Patients who take part in clinical trials contribute a lot to research and help improve the way they treat cancer in the future. Even if the results of clinical trials do not indicate the effectiveness of the new treatment method, but they often provide answers to very important questions and help to take the research one step further.
Patients may participate in clinical trials before, during, and after they have begun treatment.
In some clinical trials, only patients who have not received any treatment may participate. Patients in whom the disease is not treatable can also participate in clinical trials. There are also clinical trials that are exploring new ways to prevent relapse or eliminate side effects that result from cancer treatment.
Some tests that were done to diagnose cancer or the stage or form of the disease can be repeated. Sometimes the tests are repeated to monitor the effectiveness of the treatment. The decision to continue, change, or discontinue treatment is based on the results of these tests.
Some tests need to be done from time to time and after treatment. The results of the tests can show a change in the patient’s condition or the presence of a relapse of the disease. Sometimes such analyzes are called control.
Prevention of Acute Lymphoblastic Leukemia
A dose of 24 grams per head is given for 3 weeks at 1.5 grams per session from two lateral fields.
One of two injections of methotrexate, administered 2 times a week into the spinal canal, during head irradiation is advisable to be done on Saturday, as there is usually no radiation therapy on this day, and the other on one of the first days of the week. After a session of irradiation of the head; on the day of the endolumbar administration of methotrexate, the patient remains in the hospital.
During the prevention of neuroleukemia using both irradiation and the administration of methotrexate and cytosar, patients receive 6-mercaptopurine daily at a dose of 25 mg / m2 and cyclophosphamide at a dose of 100 mg / m2 once a week.
After the end of the prophylaxis of neuroleukemia, bone marrow puncture is performed, and if there are no signs of relapse, then maintenance therapy is started.
The second method for the prevention of neuroleukemia is the endolumbar administration of methotrexate and cytosar. Drugs are administered with an interval of 3-4 days, with poor tolerance once a week.
Both methods of prevention of neuroleukemia are reliable and allow you to abandon the supporting intralumbal administration of methotrexate.
Continuous maintenance treatment during the period of improvement of acute lymphoblastic and undifferentiated leukemia of children is carried out on an outpatient basis, for 5 years until complete improvement. They begin treatment immediately after achieving full improvement or after courses consolidating the achieved improvement.
Children receive continuous treatment with three drugs according to the following scheme: 6-mercaptopurine orally daily; methotrexate inside on the 6th day of the week; cyclophosphamide inside on the 7th day of the week, these days 6-mercaptopurine is not canceled.
For the “risk group” during the period of continuous maintenance treatment with three drugs every 1.5-2 months, a course of AR AR is performed. During this course, within a week after it, maintenance treatment with three drugs is canceled, and then during the week is carried out in half doses. After that, maintenance treatment is carried out in full doses.
Continuous treatment conditions:
1) a blood test with the determination of platelets and reticulocytes 1 time per week;
2) with a decrease in the level of leukocytes to 1 H 103 – 2 H 103 (1000-2000) in 1 μl, the doctor halves the dose of cytostatic drugs, with a subsequent increase of more than 2.5 H 103 (2500) in 1 μl, restore the previous dose;
3) treatment is interrupted at any stage when the level of leukocytes in the blood falls below 1000 in 1 μl, with a significant increase in temperature, stomatitis, diarrhea;
4) a bone marrow puncture in the first year of improvement is performed 1 time per month; on the 2-5th year of improvement – 1 time in 3 months.
The treatment of acute lymphoblastic leukemia is enhanced when it comes to the process of T-cell nature. According to the program of American pediatric oncologists, to eliminate the manifestations of the disease in T-lymphoblastic acute leukemia, they begin with intravenous administration of cyclophosphamide at 1200 mg / m2 on the 1st day of treatment or between the 2nd and 5th day (with a leukocyte level of more than 5 × 104 (50,000) in 1 μl and significant organomegaly requiring prior administration of allopurinol due to the high level of uric acid in serum and the risk of developing uric acid diathesis). From the 3-4th day (or on the 1st day, if cyclophosphamide administration is delayed) weekly (1 time per week), according to this program, as well as according to the Aur program, vincristine is administered for 4 weeks, and prednisolone and rubomycin are also used in doses and in terms corresponding to Scheme 2 of treatment of acute lymphoblastic leukemia.
When remission is achieved, a course of its consolidation is carried out, including 5-day continuous administration of cytosar 100 mg / (m2 / day), thioguanine (or 6-mercaptopurine) 50 mg / m2 every 12 hours for 5 days of cytosar administration. Conduct 3 courses of treatment with cytosar and thioguanine (6-mercaptopurine) with an interval between courses of 14 days.
Then, within 7-14 days, L-acnapaginase is administered dropwise at 200-300 U / kg. In the case of a high level of leukocytes and a large mass of tumor lymph nodes of splenomegaly or hepatomegaly, therapy should be carried out by prescribing a large amount of liquid, alkaline drink, along with allopurinol for the prevention of uric acid diathesis.
If with T-cell acute leukemia in the mediastinum, enlarged lymph nodes are determined, which are poorly contracted by chemotherapy, then local irradiation of this area at a dose of 30 Gy is recommended; local radiation is also advisable with a significant increase in the lymph nodes of any other area.
Treatment during the improvement period with T-cell leukemia should be enhanced: along with continuous therapy with 6-mercaptopurine, methotrexate, cyclophosphamide.