Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain. As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.
Most cases occur due to an unknown reason. Genetic risk factors may include Down syndrome, Li-Fraumeni syndrome, or neurofibromatosis type 1. Environment risk factors may include significant radiation exposure or prior chemotherapy. Evidence regarding electromagnetic fields or pesticides is unclear.Some hypothesize that an abnormal immune response to a common infection may be a trigger.The underlying mechanism involves multiple genetic mutations that results in rapid cell division.The excessive immature lymphocytes in the bone marrow interfere with the production of new red blood cells, white blood cells, and platelets.Diagnosis is typically based on blood tests and bone marrow examination.
ALL is typically treated initially with chemotherapy aimed at bringing about remission. This is then followed by further chemotherapy typically over a number of 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 following standard treatment.Additional treatments such as immunotherapy are being studied.
ALL affected about 876,000 people globally in 2015 and resulted in about 111,000 deaths.It occurs most commonly in children, particularly those between the ages of two and five. In the United States it is the most common cause of cancer and death from cancer among children. ALL is notable for being the first disseminated cancer to be cured.Survival for children increased from under 10% in the 1960s to 90% in 2015.Survival rates remain lower for babies (50%) and adults (35%).
Signs and symptoms
Initial symptoms can be nonspecific, particularly in children. Over 50% of children with leukemia had one or more of five features: a liver one can feel (64%), a spleen one can feel (61%), pale complexion (54%), fever (53%), and bruising (52%). Additionally, recurrent infections, feeling tired, arm or leg pain, and enlarged lymph nodes can be prominent features. The B symptoms, such as fever, night sweats, and weight loss, are often present as well.
Central nervous system (CNS) symptoms such cranial neuropathies due to meningeal infiltration are identified in less than 10% of adults and less than 5% of children, particularly mature B-cell ALL (Burkitt leukemia) at presentation.
The signs and symptoms of ALL are variable and include:
Generalized weakness and feeling tired
Headache, vomiting, lethargy, nuchal rigidity,or cranial nerve palsies(CNS involvement)
Frequent or unexplained fever and infection
Weight loss and/or loss of appetite
Excessive and unexplained bruising
Bone pain, joint pain (caused by the spread of “blast” cells to the surface of the bone or into the joint from the marrow cavity)
Enlarged lymph nodes, liver and/or spleen
Pitting edema (swelling) in the lower limbs and/or abdomen
Petechiae, which are tiny red spots or lines in the skin due to low platelet levels
In ALL, lymphoid cell development stops at the lymphoblast (arrow), which are also overproduced
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. Evidence for the role of the environment is seen in childhood ALL among twins, where only 10–15% of both genetically identical twins get ALL. 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. KMT2A (formerly MLL) gene rearrangements are most common and occur in the embryo or fetus before birth.These rearrangements result in increased expression of blood cell development genes by promoting gene transcription and through epigenetic changes.In contrast to childhood ALL, environmental factors are not thought to play a significant role. Aside from the KMT2A rearrangement, only one extra mutation is typically found.Environmental exposures are not needed to help create more mutations.
Genetic risk factors
Common inherited risk factors include mutations in ARID5B, CDKN2A/2B, CEBPE, IKZF1, GATA3, PIP4K2A and, more rarely, TP53. These genes play important roles in cellular development, proliferation, and differentiation.Individually, most of these mutations are low risk for ALL. 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. For instance, the ARID5B mutation is less common in ethnic African populations.
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.Fewer than 5% of cases are associated with a known genetic syndrome.
Rare mutations in ETV6 and PAX5 are associated with a familial form of ALL with autosomal dominant patterns of inheritance.
Environmental risk factors
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.Evidence whether less radiation, as from x-ray imaging during pregnancy, increases risk of disease remains inconclusive.Studies that have identified an association between x-ray imaging during pregnancy and ALL found only a slightly increased risk.Exposure to strong electromagnetic radiation from power lines has also been associated with a slightly increased risk of ALL. This result is questioned as no causal mechanism linking electromagnetic radiation with cancer is known.
High birth weight (greater than 4000g or 8.8lbs) is also associated with a small increased risk. 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.
Delayed infection hypothesis
There is some evidence that a common infection, such as influenza, may indirectly promote emergence of ALL.The delayed-infection hypothesis states that ALL results from an abnormal immune response to infection in a person with genetic risk factors. 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.
The aim of treatment is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells in the bone marrow).
Over the past several decades, there have been strides to increase the efficacy of treatment regimens, resulting in increased survival rates. Possible treatments for acute leukemia include chemotherapy, steroids, radiation therapy, intensive combined treatments (including bone marrow or stem cell transplants), and/or growth factors.