Leukemia limfoblastik akut LLA adalah keganasan hematologi yang disebabkan oleh proliferasi prekursor sel limfoid yang menyebabkan akumulasi sel blas di darah tepi dan sumsum tulang. Berbagai kemajuan dalam terapi, seperti targeted therapy , telah berhasil menurunkan angka kematian pasien dengan LLA. Pasien dengan keterlibatan SSP seringkali underdiagnosed baik secara klinis maupun laboratoris. Peranan laboratorium sangat penting untuk deteksi keterlibatan SSP mengingat sulitnya gejala klinis tidak khas bahkan sebagian pasien justru asimtomatis.
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Acute lymphoblastic leukemia ALL is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. In most cases, the cause is unknown. ALL is typically treated initially with chemotherapy aimed at bringing about remission. ALL affected about , people globally in and resulted in about , deaths. Initial symptoms can be nonspecific, particularly in children. The B symptoms , such as fever, night sweats, and weight loss, are often present as well.
The signs and symptoms of ALL are variable and include: . The cancerous cell in ALL is the lymphoblast. Normal lymphoblasts develop into mature, infection-fighting B-cells or T-cells, also called lymphocytes. Signals in the body control the number of lymphocytes so neither too few nor too many are made. In ALL, both the normal development of some lymphocytes and the control over the number of lymphoid cells become defective. ALL emerges when a single lymphoblast gains many mutations to genes that affect blood cell development and proliferation.
In childhood ALL, this process begins at 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, like Down Syndrome , have the same effect.
Environmental risk factors are also needed to help create enough genetic mutations to cause disease. Since they have the same genes, different environmental exposures explain why one twin gets ALL and the other does not.
Infant ALL is a rare variant that occurs in babies less than one year old. Aside from the KMT2A rearrangement, only one extra mutation is typically found. These genes play important roles in cellular development, proliferation, and differentiation. Significant risk of disease occurs when a person inherits several of these mutations together. The uneven distribution of genetic risk factors may help explain differences in disease rate among ethnic groups.
Several genetic syndrome also carry increased risk of ALL. 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. The environmental exposures that contribute to emergence of ALL is contentious and a subject of ongoing debate. High levels of radiation exposure from nuclear fallout is a known risk factor for developing leukemia.
This result is questioned as no causal mechanism linking electromagnetic radiation with cancer is known. High birth weight greater than g or 8. The mechanism connecting high birth weight to ALL is also not known. Evidence suggests that secondary leukemia can develop in individuals treated with certain types of chemotherapy, such as epipodophyllotoxins and cyclophosphamide.
There is some evidence that a common infection, such as influenza , may indirectly promote emergence of ALL. Delayed development of the immune system due to limited disease exposure may result in excessive production of lymphocytes and increased mutation rate during an illness.
Several studies have identified lower rates of ALL among children with greater exposure to illness early in life. Very young children who attend daycare have lower rates of ALL. Evidence from many other studies looking at disease exposure and ALL is inconclusive. Several characteristic genetic changes lead to the creation of a leukemic lymphoblast.
These changes include chromosomal translocations , intrachromosomal rearrangements , changes in the number of chromosomes in leukemic cells, and additional mutations in individual genes. This move 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 a cell that divides more often. An example of this includes the translocation of C-MYC , a gene that encodes a transcription factor that leads to increased cell division, next to the immunoglobulin heavy - or light-chain gene enhancers , leading to increased C-MYC expression and increased cell division.
The result is the combination of two usually separate proteins into a new fusion protein. This protein can have a new function that promotes the development of cancer. These mutations produce a cell that divides more often, even in the absence of growth factors. Other genetic changes in B-cell ALL include changes to the number of chromosomes within the leukemic cells. Gaining at least five additional chromosomes, called high hyperdiploidy, occurs more commonly.
Less often, chromosomes are lost, called hypodiploidy , which is associated with a poorer prognosis. ALL results when enough of these genetic changes are present in a single lymphoblast. In childhood ALL, for example, one fusion gene translocation is often found along with six to eight other ALL-related genetic changes. These lymphoblasts build up in the bone marrow and may spread to other sites in the body, such as lymph nodes , the mediastinum , the spleen , the testicles , and the brain , leading to the common symptoms of disease.
Diagnosing ALL begins with a thorough medical history, physical examination , complete blood count , and blood smears. While many symptoms of ALL can be found in common illnesses, persistent or unexplained symptoms raise suspicion of cancer. Because many features on the medical history and exam are not specific to ALL, further testing is often needed.
A large number of white blood cells and lymphoblasts in the circulating blood can be suspicious for ALL because they indicate a rapid production of lymphoid cells in the marrow. The higher these numbers typically points to a worse prognosis. Brain and spinal column involvement can be diagnosed either through confirmation of leukemic cells in the lumbar puncture or through clinical signs of CNS leukemia as described above.
Laboratory tests that might show abnormalities include blood count, kidney function, electrolyte, and liver enzyme tests. Pathological examination, cytogenetics in particular the presence of Philadelphia chromosome , and immunophenotyping establish whether the leukemic cells are myeloblastic neutrophils, eosinophils, or basophils or lymphoblastic B lymphocytes or T lymphocytes. Cytogenetic testing on the marrow samples can help classify disease and predict how aggressive the disease course will be.
Different mutations have been associated with shorter or longer survival. Medical imaging such as ultrasound or CT scanning can find invasion of other organs commonly the lung , liver, spleen, lymph nodes, brain, kidneys, and reproductive organs.
In addition to cell morphology and cytogenetics, immunophenotyping , a laboratory technique used to identify proteins that are expressed on their cell surface, is a key component in the diagnosis of ALL. The preferred method of immunophenotyping is through flow cytometry. In the malignant lymphoblasts of ALL, expression of terminal deoxynucleotidyl transferase TdT on the cell surface can help differentiate malignant lymphocyte cells from reactive lymphocytes , white blood cells that are reacting normally to an infection in the body.
On the other hand, myeloperoxidase MPO , a marker for the myeloid lineage, is typically not expressed. Because precursor B cell and precursor T cells look the same, immunophenotyping can help differentiate the subtype of ALL and the level of maturity of the malignant white blood cells.
The subtypes of ALL as determined by immunophenotype and according to the stages of maturation. An extensive panel of monoclonal antibodies to cell surface markers, particularly CD or cluster of differentiation markers, are used to classify cells by lineage.
Cytogenetic analysis has shown different proportions and frequencies of genetic abnormalities in cases of ALL from different age groups. This information is particularly valuable for classification and can in part explain different prognosis of these groups. In regards to genetic analysis, cases can be stratified according to ploidy , number of sets of chromosomes in the cell, and specific genetic abnormalities, such as translocations.
Hyperdiploid cells are defined as cells with more than 50 chromosomes, while hypodiploid is defined as cells with less than 44 chromosomes. Hyperdiploid cases tend to carry good prognosis while hypodiploid cases do not. Below is a table with the frequencies of some cytogenetic translocations and molecular genetic abnormalities in ALL.
The FAB system takes into account information on size, cytoplasm , nucleoli , basophilia color of cytoplasm , and vacuolation bubble-like properties. While some clinicians still use the FAB scheme to describe tumor cell appearance, much of this classification has been abandoned because of limited impact on treatment choice and prognostic value. In , the World Health Organization classification of acute lymphoblastic leukemia was developed in an attempt to create a classification system that was more clinically relevant and could produce meaningful prognostic and treatment decisions.
This system recognized differences in genetic, immunophenotype , molecular, and morphological features found through cytogenetic and molecular diagnostics tests.
Over the past several decades, there have been strides to increase the efficacy of treatment regimens, resulting in increased survival rates. Chemotherapy is the initial treatment of choice, and most people with ALL receive a combination of medications. There are no surgical options because of the body-wide distribution of the malignant cells.
In general, cytotoxic chemotherapy for ALL combines multiple antileukemic drugs tailored to each person. Chemotherapy for ALL consists of three phases: remission induction, intensification, and maintenance therapy. Must monitor closely for tumor lysis syndrome after initiating therapy. Monitoring initial response to treatment is important as failure to show clearance of blood or bone marrow blasts within the first 2 weeks of therapy has been associated with higher risk of relapse.
Start CNS prophylaxis and administer intrathecal chemotherapy via Ommaya reservoir or multiple lumbar punctures. Central nervous system prophylaxis can be achieved via: . In Philadelphia chromosome -positive ALL, the intensity of initial induction treatment may be less than has been traditionally given.
Central nervous system relapse is treated with intrathecal administration of hydrocortisone , methotrexate, and cytarabine. Adult chemotherapy regimens mimic those of childhood ALL; however, are linked with a higher risk of disease relapse with chemotherapy alone. B-cell ALL is often associated with cytogenetic abnormalities specifically, t 8;14 , t 2;8 and t 8;22 , which require aggressive therapy consisting of brief, high-intensity regimens.
T-cell ALL responds to cyclophosphamide-containing agents the most. As the chemotherapy regimens can be intensive and protracted, many people have an intravenous catheter inserted into a large vein termed a central venous catheter or a Hickman line , or a Portacath , usually placed near the collar bone, for lower infection risks and the long-term viability of the device. Males usually endure a longer course of treatment than females as the testicles can act as a reservoir for the cancer.
Radiation therapy or radiotherapy is used on painful bony areas, in high disease burdens, or as part of the preparations for a bone marrow transplant total body irradiation.
Recent studies showed that CNS chemotherapy provided results as favorable but with less developmental side-effects. As a result, the use of whole-brain radiation has been more limited. Most specialists in adult leukemia have abandoned the use of radiation therapy for CNS prophylaxis, instead using intrathecal chemotherapy. Selection of biological targets on the basis of their combinatorial effects on the leukemic lymphoblasts can lead to clinical trials for improvement in the effects of ALL treatment.
However, this subtype of ALL is frequently resistant to the combination of chemotherapy and TKIs and allogeneic stem cell transplantation is often recommended upon relapse.
What Is Acute Lymphocytic Leukemia (ALL)?
Acute lymphoblastic leukemia ALL is the second most common acute leukemia in adults, with an incidence of over cases per year in the United States alone. The hallmark of ALL is chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of lymphoid precursor cells. Traditionally, risk stratification has been based on clinical factors such age, white blood cell count and response to chemotherapy; however, the identification of recurrent genetic alterations has helped refine individual prognosis and guide management. Despite advances in management, the backbone of therapy remains multi-agent chemotherapy with vincristine, corticosteroids and an anthracycline with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens and carry a particularly poor prognosis.
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia ALL is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. In most cases, the cause is unknown. ALL is typically treated initially with chemotherapy aimed at bringing about remission. ALL affected about , people globally in and resulted in about , deaths.
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