Leukemia

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Leukaemia
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For the journal, see Leukemia (journal). For animal diseases, see Leucosis.

Leukemia
Other namesLeukaemia
supportive care[3][6]
PrognosisFive-year survival rate 57% (U.S.)[4]
Frequency2.3 million (2015)[7]
Deaths353,500 (2015)[8]

Leukemia (

bone marrow biopsy.[2]

The exact cause of leukemia is unknown.

tumors that affect the blood, bone marrow, and lymphoid system, known as tumors of the hematopoietic and lymphoid tissues.[11][12]

Treatment may involve some combination of

cancer is unlikely to return.[13]

In 2015, leukemia was present in 2.3 million people worldwide and caused 353,500 deaths.

developed world.[10]

Classification

Four major kinds of leukemia
Cell type Acute Chronic
Lymphocytic leukemia
(or "lymphoblastic")		 Acute lymphoblastic leukemia
(ALL)
Chronic lymphocytic leukemia

(CLL)
Myelogenous leukemia
("myeloid" or "nonlymphocytic")		 Acute myelogenous leukemia
(AML or myeloblastic)		 Chronic myelogenous leukemia
(CML)
An explanation of acute leukemia

General classification

Clinically and pathologically, leukemia is subdivided into a variety of large groups. The first division is between its

chronic forms:[15]

Additionally, the diseases are subdivided according to which kind of blood cell is affected. This divides leukemias into

myelogenous leukemias:[15]

Combining these two classifications provides a total of four main categories. Within each of these main categories, there are typically several subcategories. Finally, some rarer types are usually considered to be outside of this classification scheme.[15][16]

Specific types

  • acute biphenotypic leukemia. While most cases of ALL occur in children, 80% of deaths from ALL occur in adults.[17]
  • Chronic lymphocytic leukemia (CLL) most often affects adults over the age of 55. It sometimes occurs in younger adults, but it almost never affects children. Two-thirds of affected people are men. The five-year survival rate is 85%.[18] It is incurable, but there are many effective treatments. One subtype is B-cell prolymphocytic leukemia, a more aggressive disease.
  • acute myeloblastic leukemia, and acute megakaryoblastic leukemia
    .
  • Chronic myelogenous leukemia (CML) occurs mainly in adults; a very small number of children also develop this disease. It is treated with imatinib (Gleevec in United States, Glivec in Europe) or other drugs.[20] The five-year survival rate is 90%.[21][22] One subtype is chronic myelomonocytic leukemia.
  • Hairy cell leukemia (HCL) is sometimes considered a subset of chronic lymphocytic leukemia, but does not fit neatly into this category. About 80% of affected people are adult men. No cases in children have been reported. HCL is incurable but easily treatable. Survival is 96% to 100% at ten years.[23]
  • B cells
    . It is difficult to treat, and the median survival is measured in months.
  • NK cells; like hairy cell leukemia, which involves solely B cells, it is a rare and indolent (not aggressive) leukemia.[26]
  • HIV. Like HIV, HTLV infects CD4+ T-cells and replicates within them; however, unlike HIV, it does not destroy them. Instead, HTLV "immortalizes" the infected T-cells, giving them the ability to proliferate abnormally. Human T-cell lymphotropic virus types I and II (HTLV-I/II) are endemic in certain areas of the world.[citation needed
    ]
  • myelofibrosis, or the myelodysplastic syndrome.[28][29][27]

Pre-leukemia

Signs and symptoms

Common symptoms of chronic or acute leukemia[33]

The most common symptoms in children are easy

enlarged spleen or liver.[34]

Damage to the bone marrow, by way of displacing the normal bone marrow cells with higher numbers of immature white blood cells, results in a lack of blood

bleed excessively, or develop pinprick bleeds (petechiae).[35]

sores in the mouth, or diarrhea to life-threatening pneumonia or opportunistic infections.[36]

Finally, the red blood cell deficiency leads to

dyspnea and pallor.[37]

Some people experience other symptoms, such as fevers, chills, night sweats, weakness in the limbs, feeling

lymph nodes causing pain and leading to nausea.[38]

If the leukemic cells invade the

seizures, or coma can occur as a result of brain stem pressure. All symptoms associated with leukemia can be attributed to other diseases. Consequently, leukemia is always diagnosed through medical tests
.

The word leukemia, which means 'white blood', is derived from the characteristic high white blood cell count that presents in most affected people before treatment. The high number of white blood cells is apparent when a blood sample is

viewed under a microscope, with the extra white blood cells frequently being immature or dysfunctional. The excessive number of cells can also interfere with the level of other cells, causing further harmful imbalance in the blood count.[39]

Some people diagnosed with leukemia do not have high white blood cell counts visible during a regular blood count. This less-common condition is called aleukemia. The bone marrow still contains cancerous white blood cells that disrupt the normal production of blood cells, but they remain in the marrow instead of entering the bloodstream, where they would be visible in a blood test. For a person with aleukemia, the white blood cell counts in the bloodstream can be normal or low. Aleukemia can occur in any of the four major types of leukemia, and is particularly common in hairy cell leukemia.[40]

Causes

Studies in 2009 and 2010 have shown a positive correlation between exposure to formaldehyde and the development of leukemia, particularly myeloid leukemia.[41][42] The different leukemias likely have different causes.[43]

Leukemia, like other cancers, results from mutations in the DNA. Certain mutations can trigger leukemia by activating oncogenes or deactivating tumor suppressor genes, and thereby disrupting the regulation of cell death, differentiation or division. These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances.[44]

Among adults, the known causes are natural and artificial

hair dyes to the development of some forms of leukemia. Diet has very limited or no effect, although eating more vegetables may confer a small protective benefit.[48]

Viruses have also been linked to some forms of leukemia. For example,

adult T-cell leukemia.[49]

A few cases of

maternal-fetal transmission (a baby acquires leukemia because its mother had leukemia during the pregnancy) have been reported.[45] Children born to mothers who use fertility drugs to induce ovulation are more than twice as likely to develop leukemia during their childhoods than other children.[50]

In a recent systematic review and meta-analysis of any type of leukemia in neonates using phototherapy, typically to treat neonatal jaundice, a statistically significant association was detected between using phototherapy and myeloid leukemia. However, it is still questionable whether phototherapy is genuinely the cause of cancer or simply a result of the same underlying factors that gave rise to cancer. [51]

Radiation

Large doses of Sr-90 (called a bone seeking radioisotope) from nuclear reactor accidents, increases the risk of bone cancer and leukemia in animals and is presumed to do so in people.[52]

Genetic conditions

Some people have a genetic predisposition towards developing leukemia. This predisposition is demonstrated by family histories and

leukemia or related blood cancers.[45]

In addition to these genetic issues, people with chromosomal abnormalities or certain other genetic conditions have a greater risk of leukemia.

SPRED1 gene has been associated with a predisposition to childhood leukemia.[53]

Chronic myelogenous leukemia is associated with a genetic abnormality called the Philadelphia translocation; 95% of people with CML carry the Philadelphia mutation, although this is not exclusive to CML and can be observed in people with other types of leukemia.[54][55][56][57]

Non-ionizing radiation

Whether or not non-ionizing radiation causes leukemia has been studied for several decades. The International Agency for Research on Cancer expert working group undertook a detailed review of all data on static and extremely low frequency electromagnetic energy, which occurs naturally and in association with the generation, transmission, and use of electrical power.[58] They concluded that there is limited evidence that high levels of ELF magnetic (but not electric) fields might cause some cases of childhood leukemia.[58] No evidence for a relationship to leukemia or another form of malignancy in adults has been demonstrated.[58] Since exposure to such levels of ELFs is relatively uncommon, the World Health Organization concludes that ELF exposure, if later proven to be causative, would account for just 100 to 2400 cases worldwide each year, representing 0.2 to 4.9% of the total incidence of childhood leukemia for that year (about 0.03 to 0.9% of all leukemias).[59]

Diagnosis

The increase in white blood cells in leukemia.

Diagnosis is usually based on repeated complete blood counts and a bone marrow examination following observations of the symptoms. Sometimes, blood tests may not show that a person has leukemia, especially in the early stages of the disease or during remission. A lymph node biopsy can be performed to diagnose certain types of leukemia in certain situations.[60]

Following diagnosis, blood chemistry tests can be used to determine the degree of liver and kidney damage or the effects of chemotherapy on the person. When concerns arise about other damages due to leukemia, doctors may use an

CT scans can be used to check lymph nodes in the chest, though this is uncommon.[61]

Despite the use of these methods to diagnose whether or not a person has leukemia, many people have not been diagnosed because many of the symptoms are vague,

non-specific, and can refer to other diseases. For this reason, the American Cancer Society estimates that at least one-fifth of the people with leukemia have not yet been diagnosed.[40]

Treatment

Most forms of leukemia are treated with pharmaceutical

bone marrow transplant
is effective.

Acute lymphoblastic

Further information: Acute lymphoblastic leukemia § Treatment

Management of ALL is directed towards control of bone marrow and systemic (whole-body) disease. Additionally, treatment must prevent leukemic cells from spreading to other sites, particularly the central nervous system (CNS) e.g. monthly lumbar punctures.[clarification needed] In general, ALL treatment is divided into several phases:

Chronic lymphocytic

Further information: Chronic lymphocytic leukemia § Treatment

Decision to treat

Hematologists
base CLL treatment on both the stage and symptoms of the individual person. A large group of people with CLL have low-grade disease, which does not benefit from treatment. Individuals with CLL-related complications or more advanced disease often benefit from treatment. In general, the indications for treatment are:

Treatment approach

Most CLL cases are incurable by present treatments, so treatment is directed towards suppressing the disease for many years, rather than curing it. The primary chemotherapeutic plan is

bone marrow transplantation in the hope of a permanent cure.[65]

Acute myelogenous

Further information: Acute myeloid leukemia § Treatment

Many different anti-cancer drugs are effective for the treatment of AML. Treatments vary somewhat according to the age of the person and according to the specific subtype of AML. Overall, the strategy is to control bone marrow and systemic (whole-body) disease, while offering specific treatment for the central nervous system (CNS), if involved.[66]

In general, most oncologists rely on combinations of drugs for the initial, induction phase of chemotherapy. Such combination chemotherapy usually offers the benefits of early remission and a lower risk of disease resistance. Consolidation and maintenance treatments are intended to prevent disease recurrence. Consolidation treatment often entails a repetition of induction chemotherapy or the intensification of chemotherapy with additional drugs. By contrast, maintenance treatment involves drug doses that are lower than those administered during the induction phase.[67]

Chronic myelogenous

Further information: Chronic myelogenous leukemia § Treatment

There are many possible treatments for CML, but the standard of care for newly diagnosed people is imatinib (Gleevec) therapy.[68] Compared to most anti-cancer drugs, it has relatively few side effects and can be taken orally at home. With this drug, more than 90% of people will be able to keep the disease in check for at least five years,[68] so that CML becomes a chronic, manageable condition.

In a more advanced, uncontrolled state, when the person cannot tolerate imatinib, or if the person wishes to attempt a permanent cure, then an allogeneic bone marrow transplantation may be performed. This procedure involves high-dose chemotherapy and radiation followed by infusion of bone marrow from a compatible donor. Approximately 30% of people die from this procedure.[68]

Hairy cell

Further information: Hairy cell leukemia § Treatment

Decision to treat
People with hairy cell leukemia who are symptom-free typically do not receive immediate treatment. Treatment is generally considered necessary when the person shows signs and symptoms such as low blood cell counts (e.g., infection-fighting neutrophil count below 1.0 K/µL), frequent infections, unexplained bruises, anemia, or fatigue that is significant enough to disrupt the person's everyday life.[69]

Typical treatment approach
People who need treatment usually receive either one week of cladribine, given daily by intravenous infusion or a simple injection under the skin, or six months of pentostatin, given every four weeks by intravenous infusion. In most cases, one round of treatment will produce a prolonged remission.[70]

Other treatments include

Interferon-alpha. In limited cases, the person may benefit from splenectomy (removal of the spleen). These treatments are not typically given as the first treatment because their success rates are lower than cladribine or pentostatin.[71]

T-cell prolymphocytic

Further information: T-cell prolymphocytic leukemia § Treatment

Most people with T-cell prolymphocytic leukemia, a rare and aggressive leukemia with a median survival of less than one year, require immediate treatment.[72]

T-cell prolymphocytic leukemia is difficult to treat, and it does not respond to most available chemotherapeutic drugs.

VAPEC-B). Alemtuzumab (Campath), a monoclonal antibody that attacks white blood cells, has been used in treatment with greater success than previous options.[72]

Some people who successfully respond to treatment also undergo

stem cell transplantation to consolidate the response.[72]

Juvenile myelomonocytic

Treatment for

bone marrow transplantation.[73]

Prognosis

The success of treatment depends on the type of leukemia and the age of the person. Outcomes have improved in the developed world.[10] The average five-year survival rate is 65% in the United States.[4] In children under 15, the five-year survival rate is greater (60 to 85%), depending on the type of leukemia.[13] In children with acute leukemia who are cancer-free after five years, the cancer is unlikely to return.[13]

Outcomes depend on whether it is acute or chronic, the specific abnormal white blood cell type, the presence and severity of anemia or thrombocytopenia, the degree of tissue abnormality, the presence of metastasis and lymph node and bone marrow infiltration, the availability of therapies and the skills of the health care team. Treatment outcomes may be better when people are treated at larger centers with greater experience.[74]

Epidemiology

Deaths due to leukemia per million persons in 2012
  0-7
  8-13
  14–22
  23–29
  30–34
  35–39
  40–46
  47–64
  65–85
  86–132

In 2010, globally, approximately 281,500 people died of leukemia.

developed world.[77]

United States

About 245,000 people in the United States are affected with some form of leukemia, including those that have achieved remission or cure. Rates from 1975 to 2011 have increased by 0.7% per year among children.

blood cancers.[80]

Among children with some form of cancer, about a third have a type of leukemia, most commonly acute lymphoblastic leukemia.[79] A type of leukemia is the second most common form of cancer in infants (under the age of 12 months) and the most common form of cancer in older children.[81] Boys are somewhat more likely to develop leukemia than girls, and white American children are almost twice as likely to develop leukemia than black American children.[81] Only about 3% cancer diagnoses among adults are for leukemias, but because cancer is much more common among adults, more than 90% of all leukemias are diagnosed in adults.[79]

Race is a risk factor in the United States. Hispanics, especially those under the age of 20, are at the highest risk for leukemia, while whites, Native Americans, Asian Americans, and Alaska Natives are at higher risk than African Americans.[82]

More men than women are diagnosed with leukemia and die from the disease. Around 30 percent more men than women have leukemia.[83]

Australia

In Australia, leukemia is the eleventh most common cancer.[84] In 2014–2018, Australians diagnosed with leukaemia had a 64% chance (65% for males and 64% for females) of surviving for five years compared to the rest of the Australian population–there was a 21% increase in survival rates between 1989–1993.[84]

UK

Overall, leukemia is the eleventh most common cancer in the UK (around 8,600 people were diagnosed with the disease in 2011), and it is the ninth most common cause of cancer death (around 4,800 people died in 2012).[85]

History

Photo of the upper body of a bespectacled man
Rudolf Virchow

Leukemia was first described by anatomist and surgeon Alfred-Armand-Louis-Marie Velpeau in 1827. A more complete description was given by pathologist Rudolf Virchow in 1845. Around ten years after Virchow's findings, pathologist Franz Ernst Christian Neumann found that the bone marrow of a deceased person with leukemia was colored "dirty green-yellow" as opposed to the normal red. This finding allowed Neumann to conclude that a bone marrow problem was responsible for the abnormal blood of people with leukemia.[86]

By 1900, leukemia was viewed as a family of diseases as opposed to a single disease. By 1947, Boston pathologist Sidney Farber believed from past experiments that aminopterin, a folic acid mimic, could potentially cure leukemia in children. The majority of the children with ALL who were tested showed signs of improvement in their bone marrow, but none of them were actually cured. Nevertheless, this result did lead to further experiments.[87]

In 1962, researchers Emil J. Freireich, Jr. and Emil Frei III used combination chemotherapy to attempt to cure leukemia. The tests were successful with some people surviving long after the tests.[88]

Etymology

Observing an abnormally large number of white blood cells in a blood sample from a person, Virchow called the condition Leukämie in

German, which he formed from the two Greek words leukos (λευκός), meaning 'white', and haima (αἷμα), meaning 'blood'.[89] It was formerly also called leucemia.[90]

Society and culture

According to Susan Sontag, leukemia was often romanticized in 20th-century fiction, portrayed as a joy-ending, clean disease whose fair, innocent and gentle victims die young or at the wrong time. As such, it was the cultural successor to tuberculosis, which held this cultural position until it was discovered to be an infectious disease.[91] The 1970 romance novel Love Story is an example of this romanticization of leukemia.[92]

In the United States, around $5.4 billion is spent on treatment a year.[93]

Research directions

Significant research into the causes, prevalence, diagnosis, treatment, and prognosis of leukemia is being performed. Hundreds of

clinical trials are being planned or conducted at any given time.[94] Studies may focus on effective means of treatment, better ways of treating the disease, improving the quality of life for people, or appropriate care in remission or after cures.[95]

In general, there are two types of leukemia research: clinical or translational research and basic research. Clinical/translational research focuses on studying the disease in a defined and generally immediately applicable way, such as testing a new drug in people. By contrast, basic science research studies the disease process at a distance, such as seeing whether a suspected carcinogen can cause leukemic changes in isolated cells in the laboratory or how the DNA changes inside leukemia cells as the disease progresses. The results from basic research studies are generally less immediately useful to people with the disease.[96]

Treatment through

chimeric antigen receptor T cells (CAR-T cells), to attack cancer cells. In 2011, a year after treatment, two of the three people with advanced chronic lymphocytic leukemia were reported to be cancer-free[97] and in 2013, three of five subjects who had acute lymphocytic leukemia were reported to be in remission for five months to two years.[98] Subsequent studies with a variety of CAR-T types continue to be promising.[99] As of 2018, two CAR-T therapies have been approved by the Food and Drug Administration. CAR-T treatment has significant side effects,[100] and loss of the antigen targeted by the CAR-T cells is a common mechanism for relapse.[99] The stem cells that cause different types of leukemia are also being researched.[101]

Pregnancy

Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women.

Interferon-alpha hormones.[102] Treatment for chronic lymphocytic leukemias, which are rare in pregnant women, can often be postponed until after the end of the pregnancy.[102][103]

See also

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    .

External links

Wikimedia Commons has media related to Leukemias.
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