Acute lymphoblastic leukemia ( ALL ) is a blood cell lymphoid cancer characterized by the development of large numbers of immature lymphocytes. Symptoms may include fatigue, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain. As acute leukemia, ALL develop rapidly and usually fatal within weeks or months if left untreated.
In many cases, the cause is unknown. Genetic risk factors may include Down syndrome, Li-Fraumeni syndrome, or type 1 neurofibromatosis. Environmental risk factors may include significant radiation exposure or previous chemotherapy. Evidence of electromagnetic or pesticide fields is unclear. Some people hypothesize that an abnormal immune response to common infections can be a trigger. The underlying mechanism involves several genetic mutations resulting in rapid cell division. Excessive mature lymphocytes in the bone marrow disrupt the production of new red blood cells, white blood cells, and platelets. Diagnosis is usually based on blood tests and bone marrow examination.
ALL is usually treated initially with chemotherapy that aims to relieve pain. This is then followed by further chemotherapy usually for several years. Additional treatments may include intrathecal chemotherapy or radiation therapy if spread to the brain has occurred. Stem cell transplantation may be used if the disease recurs after standard treatment. Additional treatments such as immunotherapy are being studied.
ALL affected about 876,000 people globally by 2015 and resulted in about 111,000 deaths. This happens most often in children, especially those between the ages of two and five. In the United States it is the most common cause of cancer and cancer deaths among children. ALL is famous for the first disseminated cancer to be cured. Survival for children increased from below 10% in 1960 to 90% by 2015. Survival rates remained lower for infants (50%) and adults (35%).
Video Acute lymphoblastic leukemia
Signs and symptoms
Early symptoms may be nonspecific, especially in children. More than 50% of children with leukemia have one or more of five features: one liver can feel (64%), the spleen can feel (61%), pale skin (54%), fever (53%), and bruising ( 52%). In addition, recurrent infections, fatigue, arm or leg pain, and enlarged lymph nodes can be a prominent feature. Symptoms B, such as fever, night sweats, and weight loss, are often present.
The central nervous system (CNS) symptoms such as skull neuropathy due to meningeal infiltration are identified in less than 10% of adults and less than 5% of children, especially B-cell ALL (Burkitt leukemia) at presentation.
ALL signs and symptoms are variable and include:
- Complete weakness and fatigue
- Anemia
- Dizzy
- Headache, vomiting, lethargy, nuchal stiffness, or cranial nerve palsy (CNS involvement)
- Fever and frequent or unexplained infections
- Weight loss and/or loss of appetite
- Excessive and unexplained bruises
- Bone pain, joint pain (caused by the spread of "explosive" cells to the bone surface or to the joints of the marrow cavity)
- Shortness of breath
- Enlarged lymph nodes, liver and/or spleen
- Treat edema (swelling) in the lower limb and/or stomach
- Petechiae, small red spots or lines on the skin due to low platelet count
- Testicular enlargement
- Mass mediastinum
Maps Acute lymphoblastic leukemia
Cause
Cancer cells in ALL are lymphoblasts. Normal lymphoblasts develop into adult B cells or fight infections or T-cells, also called lymphocytes. The signals in the body control the number of lymphocytes so that not too little or too much is made. In ALL, both normal development of lymphocytes and control over the number of lymphoid cells become damaged.
ALL arises when a single lymphoblast obtains many mutations in genes that affect the development and proliferation of blood cells. In ALL childhood, this process begins in conception with the inheritance of some of these genes. These genes, in turn, increase the risk that more mutations will occur in developing lymphoid cells. Certain genetic syndromes, such as Down Syndrome, have the same effect. Environmental risk factors are also needed to help create enough genetic mutations to cause disease. The evidence for environmental roles is seen in ALL childhoods among twins, in which only 10-15% of both genetically identical twins get ALL. Because they have the same genes, different environmental exposures explain why one twin gets ALL and the other does not.
ALL baby is a rare variant that occurs in infants less than one year. KMT2A (formerly MLL ) gene rearrangement is the most common and occurs in the embryo or fetus before birth. This rearrangement results in increased expression of blood cell development genes by promoting gene transcription and through epigenetic changes. In contrast to ALL children, environmental factors are not considered to play an important role. In addition to the KMT2A rearrangement, only one additional mutation is normally found. Environmental exposure is not necessary to help create more mutations.
Risk factors
Genetic risk factors
Common inherited risk factors include mutations in ARID5B , CDKN2A/2B , CEBPE , IKZF1 , GATA3 , PIP4K2A and, more rarely, TP53 . These genes play an important role in cell proliferation, proliferation, and differentiation. Individually, most of these mutations are low risk for ALL. A significant risk of illness occurs when a person inherits some of these mutations together.
Unequal distribution of genetic risk factors may help explain differences in disease rates among ethnic groups. For example, the ARID5B mutation is less common in African ethnic populations.
Several genetic syndromes also carry an ALL increase in risk. These include: Down syndrome, Fanconi anemia, Bloom syndrome, X-linked agammaglobulinemia, severe combined immunodeficiency, Shwachman-Diamond syndrome, Kostmann syndrome, neurofibromatosis type 1, ataxia-telangiectasia, paroxysmal nocturnal hemoglobinuria, and Li-Fraumeni syndrome. Less than 5% of cases are associated with known genetic syndromes.
Rare mutations at ETV6 and PAX5 are related to ALL family forms with autosomal dominant legacy patterns.
Environmental risk factors
The environmental exposure that contributes to the emergence of ALL is the debate and subject of ongoing debate.
The high level of radiation exposure from nuclear fallout is a known risk factor for developing leukemia. Evidence of whether less radiation, such as from x-ray imaging during pregnancy, increases the risk of disease remains inconclusive. Studies have identified the relationship between x-ray imaging during pregnancy and ALL found little increased risk. Exposure to strong electromagnetic radiation from power lines has also been associated with a slight increase in ALL risks. This result is questionable because there is no causal mechanism linking electromagnetic radiation with known cancers.
High birth weight (greater than 4000g or 8.8 lbs) is also associated with a small increased risk. The mechanisms linking high birth weight to ALL are also unknown.
Evidence suggests that secondary leukemia can develop in individuals treated with certain types of chemotherapy, such as epipodophyllotoxins and cyclophosphamide.
Pending Hypothesis of infection
There is some evidence that common infections, such as influenza, can indirectly increase the appearance of ALL. The delayed infection hypothesis states that ALL results from an abnormal immune response to infection in a person with genetic risk factors. Delay in the development of the immune system due to limited disease exposure can lead to excessive lymphocyte production and increase the rate of mutation during an illness. Several studies have identified lower levels of ALL among children with greater disease exposure early in life. Very young children who attend child care have lower ALL levels. Evidence from many other studies that look at exposure to the disease and ALL can not be inferred.
Mechanism
Some characteristic genetic changes lead to the creation of lymphoblast leukemia. These changes include chromosome translocation, intrachromosom rearrangements, changes in the number of chromosomes in leukemia cells, and additional mutations in individual genes. Translocation of chromosomes involves moving most of the DNA from one chromosome to another. This step can result in placing a gene from one chromosome that promotes cell division to a more actively transcribed area on another chromosome. The result is cells that divide more often. Examples of this include the translocation of C-MYC, a gene encoding transcription factors leading to increased cell division, in addition to gene-chain or heavy-chain gain immunoglobulins, leading to an increase of C-MYC expression and increased cell division. Other major changes in chromosome structure can result in the placement of two genes directly next to each other. The result is a combination of two proteins that usually separate into new fusion proteins. This protein can have a new function that encourages the development of cancer. Examples include the fusion gene ETV6 - RUNX1 which combines two factors that promote the development of blood cells and BCR - ABL1 > i> Philadelphia chromosome fusion genes. BCR - ABL1 encodes an always-on tyrosine kinase that causes frequent cell division. These mutations produce cells that divide more frequently, even in the absence of growth factors.
Other genetic changes in ALL B cells include changes in the number of chromosomes in leukemia cells. Getting at least five additional chromosomes, called hyperdiploidy high, occur more often. Less often, missing chromosomes, called hypodiploidy, are associated with a worse prognosis. Additional general genetic changes in ALL B cells involve mutations not inherited to PAX5 and IKZF1 . In T-cell ALL, LYL1 , TAL1 , TLX1 , and TLX3 rearrangements may occur.
ALL results when quite a lot of these genetic changes are present in a single lymphoblast. In ALL childhood, for example, a fusion gene translocation is often found along with six to eight genetic changes associated with ALL others. Early leukemic lymphoblasts copy themselves into a large number of new lymphoblasts, which can not develop into functioning lymphocytes. These lymphoblasts form in the bone marrow and can spread elsewhere in the body, such as lymph nodes, mediastinum, spleen, testes, and brain, leading to common symptoms of the disease.
Diagnosis
Diagnosis ALL begins with a thorough medical history, physical examination, full blood count, and blood spots. While many of ALL symptoms can be found in common ailments, persistent or unexplained symptoms cause cancer suspicion. Because many features in medical history and exams are not specific to ALL, further testing is often required. A large number of white blood cells and lymphoblasts in circulating blood can be suspicious for ALL because they exhibit rapid lymphoid cell production in the bone marrow. The higher these numbers usually indicate a worse prognosis. While the number of white blood cells at initial presentation can vary significantly, lymphoblast cells are circulating seen in peripheral blood smear in most cases.
Bone marrow biopsy provides absolute proof of ALL, usually with & gt; 20% of all cells are lymphoblast leukemia. Lumbar punctures (also known as spinal taps) can determine whether the spine and brain have been attacked. Brain and spinal involvement can be diagnosed either by confirmation of leukemia cells in lumbar puncture or through clinical signs of CNS leukemia as described above. Laboratory tests that may indicate abnormalities include blood count, renal function, electrolytes, and liver enzyme tests.
Pathologic examination, cytogenetics (especially the presence of Philadelphia chromosomes), and immunophenotyping determine whether leukemia cells are myeloblastic (neutrophils, eosinophils, or basophils) or lymphoblastic (B lymphocytes or T lymphocytes). Cytogenetic testing in marrow samples can help classify the disease and predict how aggressive the disease is. Different mutations have been associated with shorter or longer survival. Immunohistochemical tests may reveal TdT or CALLA antigen on the surface of leukemia cells. TdT is a protein expressed early in the development of pre-T and pre-B cells, whereas CALLA is an antigen found in 80% of ALL cases and also in the "blast crisis" of CML.
Medical imaging (such as ultrasound or CT scan) can find other invasive organs that are usually the lungs, liver, spleen, lymph nodes, brain, kidneys, and reproductive organs.
Immunophenotyping
In addition to cell morphology and cytogenetics, immunophenotyping, a laboratory technique used to identify proteins expressed on the surface of their cells, is a key component of ALL diagnosis. The preferred method of immunophenotyping is through flow cytometry. In ALL malignant lymphoblasts, the expression of deoxynucleotidyl transferase (TdT) terminals on the cell surface can help distinguish malignant lymphocyte cells from reactive lymphocytes, white blood cells that react normally to infections in the body. On the other hand, myeloperoxidase (MPO), a marker for myeloid lineage, is usually not disclosed. Because B cell precursors and T-cell precursors appear to be the same, immunophenotyping can help distinguish ALT subtypes and levels of malignant white blood cell maturity. ALT Subtypes as determined by immunophenotype and according to the maturation stage.
An extensive panel of monoclonal antibodies for cell surface markers, especially CD or cluster differentiation markers, are used to classify cells by lineage. Below is an immunological marker associated with B cells and ALL T cells.
Cytogenetics
Cytogenetic analysis shows the different proportions and frequency of genetic disorders in ALL cases of different age groups. This information is very valuable for classification and some may explain the different prognosis of these groups. In terms of genetic analysis, cases can be grouped by ploidy, the number of sets of chromosomes in the cell, and certain genetic abnormalities, such as translocation. Hyperdiploid cells are defined as cells with more than 50 chromosomes, whereas hypodiploids are defined as cells with fewer than 44 choromosomes. Hyperdiploid cases tend to carry a good prognosis while cases of hypodiploid are not. For example, the most common specific disorder of childhood B-ALL is translocation t (12; 21) ETV6 - RUNX1 , where RUNX1 > genes, encoding proteins involved in the control of hemopoiesis transcription, have been translocated and suppressed by ETV6 - RUNX1 fusion proteins.
Below is a table with the frequency of some cytogenetic translocation and molecular genetic abnormalities in ALL.
Classification
French-American-English
Historically, prior to 2008, ALL was morphologically classified using a French-American-English (FAB) system that relied heavily on morphological assessments. The FAB system considers the size information, cytoplasm, nucleolus, basophilia (cytoplasmic color), and vacuolation (bubble-like properties).
While some physicians still use FAB schemes to describe the appearance of tumor cells, many of these classifications have been abandoned due to their limited impact on treatment options and prognostic values.
World Health Organization
In 2008, the World Health Organization classification for acute lymphoblastic leukemia was developed in an attempt to create a more clinically relevant classification system and can result in meaningful prognostic and treatment decisions. This system recognizes the differences in genetic features, immunophenotypes, molecules, and morphology found through cytogenetic and molecular diagnostic tests. This subtype helps determine the most appropriate prognosis and treatment for each specific case of ALL.
The WHO subtype associated with ALL is:
- B-lymphoblastic leukemia/lymphoma
- No other mention (NOS)
- with repeated genetic disorders
- with t (9; 22) (q34.1; q11.2); BCR-ABL1
- with t (v; 11q23.3); KMT2A reset
- with t (12; 21) (p13.2; q22.1); Ã, ETV6-RUNX1
- with t (5; 14) (q31.1; q32.3) Ã, IL3-IGH
- with t (1; 19) (q23; p13.3); TCF3-PBX1
- with hyperdiploidy
- with hypodiploidy
- T-lymphoblastic leukemia/lymphoma
- Acute leukemia from ambiguous lineage
- Acute non-differentiated leukemia
- Acute leukemia phenotype blend (MPAL) with t (9; 22) (q34.1; q11.2); Ã, BCR-ABL1
- MPAL with t (v; 11q23.3); Ã, KMT2A Ã, reorganized
- MPAL, B/myeloid, NOS
- MPAL, T/myeloid, NOS
Treatment
The goal of treatment is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% of blast cells in the bone marrow).
Over the last few decades, there have been measures to improve the effectiveness of treatment regimens, so that survival rates are increasing. Possible treatments for acute leukemia include chemotherapy, steroids, radiation therapy, intensive combined care (including bone marrow or stem cell transplantation), and/or growth factors.
Chemotherapy
Chemotherapy is the initial treatment of choice, and most ALL patients receive a combination of drugs. There is no choice of operation due to the distribution of vicious cells. In general, cytotoxic chemotherapy for ALL combines several antileukemic drugs that are tailored for each patient. Chemotherapy for ALL consists of three phases: remission induction, intensification, and maintenance therapy.
Due to CNS involvement in 10-40% of adult patients at diagnosis, most providers initiate central nervous system (CNS) prophylaxis and treatment during the induction phase, and continue during the consolidation/intensification period.
Adult chemotherapy regimens imitate people from ALL childhood; However, it is associated with a higher risk of recurrence of the disease with chemotherapy alone. Note that 2 ALT subtypes (SEM-B-ALL cells and AL-T cells) require special consideration when it comes to choosing the appropriate treatment regimen in adult patients. ALL B-ALL cells are often associated with cytogenetic abnormalities (in particular, t (8, 14), t (2; 8) and t (8; 22)), requiring aggressive therapy consisting of short-intensity regimens. T-cell ALL responds to most cyclophosphamide-containing agents.
Because chemotherapy regimens can be intensive and protracted, many patients have intravenous catheters inserted into large veins (called central venous catheters or Hickman lines), or Portakath, usually placed near the collarbone, for lower risk of infection and viability length of device.
Men usually last longer than female treatment as the testes can act as reservoirs for cancer.
Radiation therapy
Radiation therapy (or radiotherapy) is used in areas of painful bone, at high disease burden, or as part of preparation for bone marrow transplantation (total body irradiation). In the past, GPs used radiation in the form of whole brain radiation for central nervous system prophylaxis, to prevent the occurrence and/or recurrence of leukemia in the brain. Recent studies have shown that CNS chemotherapy provides favorable results but with less developed side effects. As a result, the use of radiation throughout the brain becomes more limited. Most adult leukemia specialists have abandoned the use of radiation therapy for CNS prophylaxis, instead using intrathecal chemotherapy.
Biological therapy
The selection of biological targets on the basis of their combinatorial effects on lymphoblast leukemia can lead to clinical trials for the improvement of ALL effects of treatment. Tirosin-kinase inhibitors (TKI), such as imatinib, are often incorporated into treatment plans for patients with ALL-BLE-ABL1 (PH) . However, subtypes of ALL are often resistant to a combination of chemotherapy and labor migrants and allogeneic stem cell transplantation is often recommended at the time of recurrence.
Blinatumomab, a specific murine monoclonal antibody CD19-CD3, currently shows promise as a new pharmacotherapy. By involving CD3 T cells with CD19 receptor on B cells, it triggers a response to induce the release of inflammatory cytokines, cytotoxic proteins and T cell proliferation to kill CD19 B cells.
Immunotherapy
Chimeric antigen receptor (CAR) has been developed as promising immunotherapy for ALL. This technology uses single-chain variable fragments (scFv) designed to recognize CD19 cell surface markers as a method of treating ALL.
CD19 is a molecule found in all B cells and can be used as a means to differentiate a potentially malignant B-cell population. In this therapy, mice were immunized with CD19 antigen and produced anti-CD19 antibodies. Hybridoma developed from mouse spleen cells that blend with myeloma cell line can be developed as a source for cDNA that encodes specific CD19 antibodies. CDNA sequencing and light chain variable encoding sequences and variables of these antibodies are cloned together using a small peptide linker. The resulting sequence encodes scFv. These can be cloned into transgenes, encoding what would be the CAR endodomain. Variable subunit settings serve as endodomain, but they generally consist of a hinge region attached to scFv, transmembrane region, intracellular region of a costimulatory molecule such as CD28, and a CD3-zeta intracellular domain containing ITAM repetition. Other sequences that are often included are: 4-1bb and OX40. The final transgene sequence, containing the sequence of scFv and endodomain, is then fed into the immune-effector cells obtained from the patient and expanded in vitro . In this trial is a type of T-cell capable of cytotoxicity.
Inserting DNA into effector cells can be done by several methods. Most commonly, this is done using a lentivirus that encodes transgene. Pseudotyped, self-inactivating lentiviruses are an effective method for the stable insertion of the desired transgene into the target cell. Other methods include electroporation and transfection, but these are limited in their efficacy as reduced transgene expression over time.
The gene-modified effector cells are then transplanted back into the patient. Usually this process is performed in conjunction with a conditioning regimen such as cyclophosphamide, which has been shown to potentiate the effects of infused T-cells. This effect has been attributed to making the immunological space in which cells fill. The process as a whole results in effector cells, usually T-cells, which can recognize tumor cell antigens in a way independent of the main histocompatibility complex and which can initiate cytotoxic responses.
In 2017 tisagenlecleucel is approved by the FDA as CAR-T therapy for patients with acute B cell lymphoblastic leukemia who do not respond adequately to other treatments or relapse. In the 22-day process, "medicine" is adjusted for each patient. The purified T cells of each patient are modified by a virus that inserts a gene that encodes a chimaeric antigen receptor into their DNA, which recognizes leukemia cells.
Tear down ALL
Usually, people who experience relapse in ALL those after initial treatment have a worse prognosis than those who remain in complete remission after induction therapy. It is unlikely that recurrent leukemia will respond positively to a standard chemotherapy regimen initially implemented, and this patient should be tested on reinduction chemotherapy followed by an alogeniec bone marrow transplant. These patients in relapse can also receive blinatumomab, as it has been shown to increase remission rates and overall survival rates, without increasing toxic effects.
Low-dose palliative radiation can also help reduce the burden of tumors inside or outside the central nervous system and relieve some symptoms.
More recently, there is also evidence and approval of use for dasatinib, a tyrosine kinase inhibitor. It has shown efficacy in cases of patients with ALL who are positive and imatinib-resistant, but more research needs to be done on long-term survival and time to relapse.
Prognosis
Prior to the development of chemotherapy regimens and hematopoietic stem cell transplants, children survived an average of 3 months, mostly from infection or bleeding. Since the advent of chemotherapy, the prognosis for leukemia in childhood has increased greatly and children with ALL are estimated to have a 95% chance of achieving successful remission after 4 weeks of starting treatment. Patients with ALL children in developed countries have a five-year survival rate greater than 80%. It is estimated that 60-80% of adults who underwent induction chemotherapy achieved complete remission after 4 weeks, and those over the age of 70 had a 5% healing rate.
However, there is a different prognosis for ALL among individuals depending on various factors:
- Gender: Women tend to be better than men.
- Ethnicity: Caucasians are more likely to develop acute leukemia than African-Americans, Asians, or Hispanics. However, they also tend to have a better prognosis than non-Caucasians.
- Age at diagnosis: children aged 1-10 years are likely to develop ALL and be cured. Cases in older patients are more likely to result from chromosomal abnormalities (eg, Philadelphia chromosomes) that make treatment more difficult and prognosis worse. Older patients also tend to have co-morbid medical conditions that make it even more difficult to tolerate ALL treatments.
- The number of white blood cells at diagnosis of more than 30,000 (B-ALL) or 100,000 (T-ALL) is associated with worse outcomes
- Cancer spread to the central nervous system (brain or spinal cord) has a worse outcome.
- Morphology, immunology, and genetic subtypes
- The patient's response to early treatment and longer periods is required (more than 4 weeks) to achieve complete remission
- Initial relapse ALL
- Minimal residual disease
- Genetic disorders, such as Down syndrome, and other chromosomal abnormalities (aneuoploidy and translocation)
Cytogenetics, the study of major changes in cancer cell chromosomes, is an important predictor of outcomes. Some cytogenetic subtypes have a worse prognosis than others. These include:
- Patients with an ALL (9.22) positive (30% of ALL adult cases) and other leukemia that are Bcr-abl- rearranged are more likely to have a poor prognosis, but survival rates may increase with treatment consisting of chemotherapy and bcr-abl tyrosine kinase inhibitor.
- Translation between chromosomes 4 and 11 occurs in about 4% of cases and is most common in infants under 12 months.
- Hyperdiploidy (& gt; 50 chromosomes) and t (12; 21) are good prognostic factors and also make up 50% of ALL pediatric cases.
Unclassified ALLs are considered to have an intermediate prognosis risk, somewhere between good and bad risk categories.
Epidemiology
Acute lymphoblastic leukemia affects about 876,000 people and results in 111,000 deaths globally by 2015. Occurs in children and adults with the highest rates seen between the ages of three and seven. Approximately 75% of cases occur before the age of 6 years with a secondary increase after the age of 40 years. It is estimated to affect 1 in 1500 children.
Accounting for the broad age profile of those affected, ALL only takes place around 1.7 per 100,000 people per year. ALL represent about 20% of adults and 80% of leukemia in childhood, making it the most common childhood cancer. Although 80 to 90% of children will have long-term complete response with treatment, it remains a leading cause of cancer-related deaths among children. 85% of cases are line B-cells and have the same incidence in men and women. The remaining 15% of T-cell lineages have male dominance.
Globally ALL, it is usually more common in Caucasians, Hispanics, and Latin Americans than in Africa. In the US, ALL is more common in children from Caucasians (36 cases/million) and Hispanic descendants (41 cases/million) when compared with African descent (15 cases/million).
Pregnancy
Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women. Leukemia management in pregnant patients is highly dependent on the type of leukemia. Acute leukemia usually requires rapid and aggressive treatment, although there is a significant risk of loss of pregnancy and birth, especially if chemotherapy is given during the first trimester progressively progresses.
References
External links
- Acute Lymphocytic Leukemia in the American Cancer Society
- Treatment of ALL Children at National Cancer Institute
Source of the article : Wikipedia
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