Treatment may involve some combination ofchemotherapy,radiation therapy,targeted therapy, andbone marrow transplant, withsupportive andpalliative care provided as needed.[3][6] Certain types of leukemia may be managed withwatchful waiting.[3] The success of treatment depends on the type of leukemia and the age of the person. Outcomes have improved in the developed world.[10]Five-year survival rate was 67% in the United States in the period from 2014 to 2020.[4] In children under 15 infirst-world countries, the five-year survival rate is greater than 60% or even 90%, depending on the type of leukemia. For infants (those diagnosed under the age of 1), the survival rate is around 40%.[13] In children who are cancer-free five years after diagnosis of acute leukemia, thecancer is unlikely to return.[13]
In 2015, leukemia was present in 2.3 million people worldwide and caused 353,500 deaths.[7][8] In 2012, it had newly developed in 352,000 people.[10] It is the most common type of cancer in children, with three-quarters of leukemia cases in children being the acute lymphoblastic type.[3] However, over 90% of all leukemias are diagnosed in adults, CLL and AML being most common.[3][14] It occurs more commonly in thedeveloped world.[10]
Clinically and pathologically, leukemia is subdivided into a variety of large groups. The first division is between itsacute andchronic forms:[15]
Acute leukemia is characterized by a rapid increase in the number of immature blood cells. The crowding that results from such cells makes the bone marrow unable to produce healthy blood cells resulting in lowhemoglobin and lowplatelets. Immediate treatment is required in acute leukemia because of the rapid progression and accumulation of themalignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms ofleukemia in children.
Chronic leukemia is characterized by the excessive buildup of relatively mature, but still abnormal,white blood cells (or, more rarely,red blood cells). Typically taking months or years to progress, the cells are produced at a much higher rate than normal, resulting in many abnormal white blood cells. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy. Chronic leukemia mostly occurs in older people but can occur in any age group.
In lymphoblastic orlymphocytic leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to formlymphocytes, which are infection-fighting immune system cells. Most lymphocytic leukemias involve a specific subtype of lymphocyte, theB cell.
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]
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 isB-cell prolymphocytic leukemia, a more aggressive disease.
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]
T-cell prolymphocytic leukemia (T-PLL) is a very rare and aggressive leukemia affecting adults; somewhat more men than women are diagnosed with this disease.[24] Despite its overall rarity, it is the most common type of matureT cell leukemia;[25] nearly all other leukemias involveB cells. It is difficult to treat, and the median survival is measured in months.
Adult T-cell leukemia is caused byhuman T-lymphotropic virus (HTLV), a virus similar toHIV. 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]
Transient myeloproliferative disease, also termed transient leukemia, involves the abnormal proliferation of aclone of non-cancerousmegakaryoblasts. The disease is restricted to individuals withDown syndrome or genetic changes similar to those in Down syndrome, develops in a baby during pregnancy or shortly after birth, and resolves within 3 months or, in ~10% of cases, progresses toacute megakaryoblastic leukemia. Transient myeloid leukemia is a pre-leukemic condition.[30][31][32]
Clonal hematopoiesis is a common age-related phenomenon with a low risk of progression tomyelodysplastic syndrome (MDS) and leukemia.[33] Once MDS has developed, the risk of progression to acute leukemia can be assessed using the International Prognostic Scoring System (IPSS).
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 bloodplatelets, which are important in theblood clotting process. This means people with leukemia may easily becomebruised,bleed excessively, or develop pinprick bleeds (petechiae).[36]
White blood cells, which are involved in fightingpathogens, may be suppressed or dysfunctional. This could cause the person's immune system to be unable to fight off a simple infection or to start attacking other body cells. Because leukemia prevents the immune system from working normally, some people experience frequentinfection, ranging from infectedtonsils,sores in the mouth, ordiarrhea to life-threateningpneumonia oropportunistic infections.[37]
Finally, the red blood cell deficiency leads toanemia, which may causedyspnea andpallor.[38]
Some people experience other symptoms, such as fevers, chills, night sweats, weakness in the limbs, feelingfatigued and other commonflu-like symptoms. Some people experience nausea or a feeling of fullness due to an enlargedliver andspleen; this can result in unintentionalweight loss.Blasts affected by the disease may come together and become swollen in the liver or in thelymph nodes causing pain and leading to nausea.[39]
If the leukemic cells invade thecentral nervous system, then neurological symptoms (notablyheadaches) can occur. Uncommon neurological symptoms likemigraines,seizures, orcoma 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 throughmedical tests.
The wordleukemia, 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 isviewed 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.[40]
Some people diagnosed with leukemia do not have high white blood cell counts visible during a regular blood count. This less-common condition is calledaleukemia. 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 inhairy cell leukemia.[41]
Studies in 2009 and 2010 have shown a positive correlation between exposure toformaldehyde and the development of leukemia, particularlymyeloid leukemia.[42][43] The different leukemias likely have different causes.[44]
Leukemia, like other cancers, results frommutations in theDNA. Certain mutations can trigger leukemia by activatingoncogenes or deactivatingtumor suppressor genes, and thereby disrupting the regulation of cell death, differentiation or division. These mutations may occur spontaneously or as a result of exposure toradiation orcarcinogenic substances.[45]
Among adults, the known causes are natural and artificialionizing radiation and petrochemicals, notablybenzene and alkylatingchemotherapy agents for previous malignancies.[46][47][48] Use oftobacco is associated with a small increase in the risk of developingacute myeloid leukemia in adults.[46] Cohort and case-control studies have linked exposure to somepetrochemicals andhair 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.[49]
A few cases ofmaternal-fetal transmission (a baby acquires leukemia because its mother had leukemia during the pregnancy) have been reported.[46] Children born to mothers who usefertility drugs to induce ovulation are more than twice as likely to develop leukemia during their childhoods than other children.[51]
In a recent systematic review and meta-analysis of any type of leukemia in neonates usingphototherapy, typically to treatneonatal 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.[52]
Some people have a genetic predisposition towards developing leukemia. This predisposition is demonstrated by family histories andtwin studies.[46] The affected people may have a single gene or multiple genes in common. In some cases, families tend to develop the same kinds of leukemia as other members; in other families, affected people may develop different forms ofleukemia or related blood cancers.[46]
In addition to these genetic issues, people with chromosomal abnormalities or certain other genetic conditions have a greater risk of leukemia.[47] For example, people withDown syndrome have a significantly increased risk of developing forms of acute leukemia (especiallyacute myeloid leukemia), andFanconi anemia is a risk factor for developing acute myeloid leukemia.[46] Mutation inSPRED1 gene has been associated with a predisposition to childhood leukemia.[54]
Inheritedbone marrow failure syndromes represent a kind of premature aging of the bone marrow. In people with these syndromes and in older adults, mutations associated withclonal hematopoiesis may arise as an adaptive response to a progressively deteriorating hematopoietic niche, i.e., a depleting pool ofHematopoietic stem cells. The mutated stem cells then acquire a self-renewal advantage.[55]
Whether or not non-ionizing radiation causes leukemia has been studied for several decades. TheInternational Agency for Research on Cancer expert working group undertook a detailed review of all data on static andextremely low frequency electromagnetic energy, which occurs naturally and in association with the generation, transmission, and use of electrical power.[60] They concluded that there is limited evidence that high levels ofELF magnetic (but not electric) fields might cause some cases ofchildhood leukemia.[60] No evidence for a relationship to leukemia or another form of malignancy in adults has been demonstrated.[60] Since exposure to such levels of ELFs is relatively uncommon, theWorld 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).[61]
Diagnosis is usually based on repeatedcomplete blood counts and abone 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. Alymph node biopsy can be performed to diagnose certain types of leukemia in certain situations.[62]
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 anX-ray,MRI, orultrasound. These can potentially show leukemia's effects on such body parts as bones (X-ray), the brain (MRI), or the kidneys, spleen, and liver (ultrasound).CT scans can be used to check lymph nodes in the chest, though this is uncommon.[63]
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.[41]
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 thecentral nervous system (CNS); periodic lumbar punctures are used for diagnostic purposes and to administer intrathecal prophylactic methotrexate.[64] In general, ALL treatment is divided into several phases:
Induction chemotherapy to bring about bone marrow remission. For adults, standard induction plans includeprednisone,vincristine, and ananthracycline drug; other drug plans may includeL-asparaginase orcyclophosphamide. For children with low-risk ALL, standard therapy usually consists of three drugs (prednisone, L-asparaginase, and vincristine) for the first month of treatment.
Consolidation therapy orintensification therapy to eliminate any remaining leukemia cells. There are many different approaches to consolidation, but it is typically a high-dose, multi-drug treatment that is undertaken for a few months. People with low- to average-risk ALL receive therapy withantimetabolite drugs such asmethotrexate and6-mercaptopurine (6-MP). People who are high-risk receive higher drug doses of these drugs, plus additional drugs.
CNS prophylaxis (preventive therapy) to stop cancer from spreading to the brain and nervous system in high-risk people. Standardprophylaxis may include radiation of the head and/or drugs delivered directly into the spine.
Maintenance treatments with chemotherapeutic drugs to prevent disease recurrence once remission has been achieved. Maintenance therapy usually involves lower drug doses and may continue for up to three years.
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:
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.[69]
In general, most oncologists rely on combinations of drugs for the initial,induction phase of chemotherapy. Such combination chemotherapy usually offers the benefits of earlyremission and a lower risk of disease resistance.Consolidation andmaintenance 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.[70]
There are many possible treatments for CML, but the standard of care for newly diagnosed people isimatinib (Gleevec) therapy.[71] Compared to most anti-cancer drugs, it has relatively few side effects and can be takenorally at home. With this drug, more than 90% of people will be able to keep the disease in check for at least five years,[71] 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.[71]
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.[72]
Typical treatment approach People who need treatment usually receive either one week ofcladribine, given daily by intravenous infusion or a simple injection under the skin, or six months ofpentostatin, given every four weeks by intravenous infusion. In most cases, one round of treatment will produce a prolonged remission.[73]
Other treatments includerituximab infusion or self-injection withInterferon-alpha. In limited cases, the person may benefit fromsplenectomy (removal of thespleen). These treatments are not typically given as the first treatment because their success rates are lower than cladribine or pentostatin.[74]
Most people with T-cell prolymphocytic leukemia, a rare and aggressive leukemia with a median survival of less than one year, require immediate treatment.[75]
T-cell prolymphocytic leukemia is difficult to treat, and it does not respond to most available chemotherapeutic drugs.[75] Many different treatments have been attempted, with limited success in certain people:purine analogues (pentostatin, fludarabine, cladribine),chlorambucil, and various forms of combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisoneCHOP, cyclophosphamide, vincristine, prednisone [COP], vincristine, doxorubicin, prednisone, etoposide, cyclophosphamide, bleomycinVAPEC-B).Alemtuzumab (Campath), amonoclonal antibody that attacks white blood cells, has been used in treatment with greater success than previous options.[75]
Some people who successfully respond to treatment also undergostem cell transplantation to consolidate the response.[75]
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 averagefive-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 ofanemia orthrombocytopenia, the degree of tissue abnormality, the presence ofmetastasis andlymph node andbone 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.[77]
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.[78] In 2000, approximately 256,000 children and adults around the world developed a form of leukemia, and 209,000 died from it.[79] This represents about 3% of the almost seven million deaths due to cancer that year, and about 0.35% of all deaths from any cause.[79] Of the sixteen separate sites the body compared, leukemia was the 12th most common class ofneoplastic disease and the 11th most common cause of cancer-related death.[79] Leukemia occurs more commonly in thedeveloped world.[10]
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.[80] Approximately 44,270 new cases of leukemia were diagnosed in the year 2008 in the US.[81] This represents 2.9% of all cancers (excluding simple basal cell and squamous cell skin cancers) in the United States, and 30.4% of allblood cancers.[82]
Among children with some form of cancer, about a third have a type of leukemia, most commonlyacute lymphoblastic leukemia.[81] 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.[83] 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.[83] 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.[81]
In Australia, leukemia is the eleventh most common cancer.[86] In 2014–2018, Australians diagnosed with leukemia 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.[86]
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).[87]
Leukemia was first described by anatomist and surgeonAlfred-Armand-Louis-Marie Velpeau in 1827. A more complete description was given by pathologistRudolf Virchow in 1845. Around ten years after Virchow's findings, pathologistFranz 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.[88]
By 1900, leukemia was viewed as a family of diseases as opposed to a single disease. By 1947, Boston pathologistSidney Farber believed from past experiments thataminopterin, 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.[89]
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.[90]
Observing an abnormally large number of white blood cells in a blood sample from a person, Virchow called the conditionLeukämie inGerman, which he formed from the twoGreek wordsleukos (λευκός), meaning 'white', andhaima (αἷμα), meaning 'blood'.[91] It was formerly also calledleucemia.[92]
According toSusan 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 totuberculosis, which held this cultural position until it was discovered to be an infectious disease.[93] The 1970 romance novelLove Story is an example of this romanticization of leukemia.[94]
In the United States, around $5.4 billion is spent on treatment a year.[95]
Significant research into the causes, prevalence, diagnosis, treatment, and prognosis of leukemia is being performed. Hundreds ofclinical trials are being planned or conducted at any given time.[96] Studies may focus on effective means of treatment, better ways of treating the disease, improving the quality of life for people, or appropriate care inremission or after cures.[97]
In general, there are two types of leukemia research: clinical ortranslational research andbasic 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.[98]
Treatment throughgene therapy is currently being pursued. One such approach used genetically modifiedT cells, known aschimeric 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[99] and in 2013, three of five subjects who had acute lymphocytic leukemia were reported to be in remission for five months to two years.[100] Subsequent studies with a variety of CAR-T types continue to be promising.[101] As of 2018, two CAR-T therapies have been approved by theFood and Drug Administration. CAR-T treatment has significant side effects,[102] and loss of theantigen targeted by the CAR-T cells is a common mechanism for relapse.[101] The stem cells that cause different types of leukemia are also being researched.[103]
Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women.[104] How it is handled depends primarily on the type of leukemia. Nearly all leukemias appearing in pregnant women are acute leukemias.[105] Acute leukemias normally require prompt, aggressive treatment, despite significant risks ofpregnancy loss andbirth defects, especially if chemotherapy is given during the developmentally sensitivefirst trimester.[104] Chronic myelogenous leukemia can be treated with relative safety at any time during pregnancy withInterferon-alpha hormones.[104] Treatment for chronic lymphocytic leukemias, which are rare in pregnant women, can often be postponed until after the end of the pregnancy.[104][105]
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