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Friday, June 21, 2019

Leukemia

From Wikipedia, the free encyclopedia

Leukemia
Other namesLeukaemia
Acute leukemia-ALL.jpg
A Wright's stainled bone marrow aspirate smear from a person with precursor B-cell acute lymphoblastic leukemia.
Pronunciation
SpecialtyHematology and oncology
SymptomsBleeding, bruising, feeling tired, fever, increased risk of infections
Usual onsetAll ages
CausesInherited and environmental factors
Risk factorsSmoking, family history, ionizing radiation, some chemicals, prior chemotherapy, Down syndrome.
Diagnostic methodBlood tests, bone marrow biopsy
TreatmentChemotherapy, radiation therapy, targeted therapy, bone marrow transplant, supportive care
PrognosisFive-year survival rate 57% (USA)
Frequency2.3 million (2015)
Deaths353,500 (2015)

Leukemia, also spelled leukaemia, is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, feeling tired, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.

The exact cause of leukemia is unknown. A combination of genetic factors and environmental (non-inherited) factors are believed to play a role. Risk factors include smoking, ionizing radiation, some chemicals (such as benzene), prior chemotherapy, and Down syndrome. People with a family history of leukemia are also at higher risk. There are four main types of leukemia—acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML)—as well as a number of less common types. Leukemias and lymphomas both belong to a broader group of tumors that affect the blood, bone marrow, and lymphoid system, known as tumors of the hematopoietic and lymphoid tissues.

Treatment may involve some combination of chemotherapy, radiation therapy, targeted therapy, and bone marrow transplant, in addition to supportive care and palliative care as needed. Certain types of leukemia may be managed with watchful waiting. The success of treatment depends on the type of leukemia and the age of the person. Outcomes have improved in the developed world. The average five-year survival rate is 57% in the United States. In children under 15, the five-year survival rate is greater than 60 to 85%, depending on the type of leukemia. In children with acute leukemia who are cancer-free after five years, the cancer is unlikely to return.

In 2015, leukemia was present in 2.3 million people and caused 353,500 deaths. In 2012 it newly developed in 352,000 people. It is the most common type of cancer in children, with three quarters of leukemia cases in children being the acute lymphoblastic type. However, about 90% of all leukemias are diagnosed in adults, with AML and CLL being most common in adults. It occurs more commonly in the developed world.

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)

General classification

Clinically and pathologically, leukemia is subdivided into a variety of large groups. The first division is between its acute and chronic forms:
  • 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. Immediate treatment is required in acute leukemia because of the rapid progression and accumulation of the malignant 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 of leukemia in children.
  • Chronic leukemia is characterized by the excessive buildup of relatively mature, but still abnormal, white 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.
Additionally, the diseases are subdivided according to which kind of blood cell is affected. This divides leukemias into lymphoblastic or lymphocytic leukemias and myeloid or myelogenous leukemias:
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.

Specific types

Pre-leukemia

Signs and symptoms

Common symptoms of chronic or acute leukemia
 
The most common symptoms in children are easy bruising, pale skin, fever, and an enlarged spleen or liver.

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 platelets, which are important in the blood clotting process. This means people with leukemia may easily become bruised, bleed excessively, or develop pinprick bleeds (petechiae). 

White blood cells, which are involved in fighting pathogens, 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 frequent infection, ranging from infected tonsils, sores in the mouth, or diarrhea to life-threatening pneumonia or opportunistic infections

Finally, the red blood cell deficiency leads to anemia, which may cause dyspnea and pallor

Some people experience other symptoms, such as feeling sick, having fevers, chills, night sweats, feeling fatigued and other flu-like symptoms. Some people experience nausea or a feeling of fullness due to an enlarged liver and spleen; this can result in unintentional weight loss. Blasts affected by the disease may come together and become swollen in the liver or in the lymph nodes causing pain and leading to nausea.

If the leukemic cells invade the central nervous system, then neurological symptoms (notably headaches) can occur. Uncommon neurological symptoms like migraines, 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 afflicted 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. 

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 which 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.

Causes

There is no single known cause for any of the different types of leukemias. The few known causes, which are not generally factors within the control of the average person, account for relatively few cases. The cause for most cases of leukemia is unknown. The different leukemias likely have different causes. 

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.

Among adults, the known causes are natural and artificial ionizing radiation, a few viruses such as human T-lymphotropic virus, and some chemicals, notably benzene and alkylating chemotherapy agents for previous malignancies. Use of tobacco is associated with a small increase in the risk of developing acute myeloid leukemia in adults. Cohort and case-control studies have linked exposure to some petrochemicals and 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.

Viruses have also been linked to some forms of leukemia. For example, human T-lymphotropic virus (HTLV-1) causes adult T-cell leukemia.

A few cases of maternal-fetal transmission (a baby acquires leukemia because its mother had leukemia during the pregnancy) have been reported. 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.

Radiation

Large doses of Sr-90 emission from nuclear reactor accidents, nicknamed bone seeker increases the risk of bone cancer and leukemia in animals, and is presumed to do so in people.

Genetic conditions

Some people have a genetic predisposition towards developing leukemia. This predisposition is demonstrated by family histories and twin studies. 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 of leukemia or related blood cancers.

In addition to these genetic issues, people with chromosomal abnormalities or certain other genetic conditions have a greater risk of leukemia. For example, people with Down syndrome have a significantly increased risk of developing forms of acute leukemia (especially acute myeloid leukemia), and Fanconi anemia is a risk factor for developing acute myeloid leukemia. Mutation in SPRED1 gene has been associated with a predisposition to childhood leukemia.

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.

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. They concluded that there is limited evidence that high levels of ELF magnetic (but not electric) fields might cause some cases of childhood leukemia. No evidence for a relationship to leukemia or another form of malignancy in adults has been demonstrated. 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).

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.

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 X-ray, MRI, or ultrasound. 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.

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.

Treatment

Most forms of leukemia are treated with pharmaceutical medication, typically combined into a multi-drug chemotherapy regimen. Some are also treated with radiation therapy. In some cases, a bone marrow transplant is effective.

Acute lymphoblastic

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. In general, ALL treatment is divided into several phases:
  • Induction chemotherapy to bring about bone marrow remission. For adults, standard induction plans include prednisone, vincristine, and an anthracycline drug; other drug plans may include L-asparaginase or cyclophosphamide. 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 or intensification 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 with antimetabolite drugs such as methotrexate and 6-mercaptopurine (6-MP). People who are high-risk receive higher drug doses of these drugs, plus additional drugs.
  • CNS prophylaxis (preventive therapy) to stop the cancer from spreading to the brain and nervous system in high-risk people. Standard prophylaxis 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.
  • Alternatively, allogeneic bone marrow transplantation may be appropriate for high-risk or relapsed people.

Chronic lymphocytic

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

For most people with CLL, it is incurable by present treatments, so treatment is directed towards suppressing the disease for many years, rather than totally and permanently eliminating it. The primary chemotherapeutic plan is combination chemotherapy with chlorambucil or cyclophosphamide, plus a corticosteroid such as prednisone or prednisolone. The use of a corticosteroid has the additional benefit of suppressing some related autoimmune diseases, such as immunohemolytic anemia or immune-mediated thrombocytopenia. In resistant cases, single-agent treatments with nucleoside drugs such as fludarabine, pentostatin, or cladribine may be successful. Younger and healthier people may choose allogeneic or autologous bone marrow transplantation in the hope of a permanent cure.

Acute myelogenous

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. 

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 chemotherapy with additional drugs. By contrast, maintenance treatment involves drug doses that are lower than those administered during the induction phase.

Chronic myelogenous

There are many possible treatments for CML, but the standard of care for newly diagnosed people is imatinib (Gleevec) therapy. 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, 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.

Hairy cell

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. 

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.

Other treatments include rituximab infusion or self-injection with 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.

T-cell prolymphocytic

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

T-cell prolymphocytic leukemia is difficult to treat, and it does not respond to most available chemotherapeutic drugs. 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, prednisone CHOP, cyclophosphamide, vincristine, prednisone [COP], vincristine, doxorubicin, prednisone, etoposide, cyclophosphamide, bleomycin VAPEC-B). Alemtuzumab (Campath), a monoclonal antibody that attacks white blood cells, has been used in treatment with greater success than previous options.

Some people who successfully respond to treatment also undergo stem cell transplantation to consolidate the response.

Juvenile myelomonocytic

Treatment for juvenile myelomonocytic leukemia can include splenectomy, chemotherapy, and bone marrow transplantation.

Prognosis

The success of treatment depends on the type of leukemia and the age of the person. Outcomes have improved in the developed world. The average five-year survival rate is 61% in the United States. In children under 15, the five-year survival rate is greater (60 to 85%), depending on the type of leukemia. In children with acute leukemia who are cancer-free after five years, the cancer is unlikely to return.

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.

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. In 2000, approximately 256,000 children and adults around the world developed a form of leukemia, and 209,000 died from it. 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. Of the sixteen separate sites the body compared, leukemia was the 12th most common class of neoplastic disease, and the 11th most common cause of cancer-related death. Leukemia occurs more commonly in the developed world.

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. Approximately 44,270 new cases of leukemia were diagnosed in the year 2008 in the US. This represents 2.9% of all cancers (excluding simple basal cell and squamous cell skin cancers) in the United States, and 30.4% of all blood cancers.

Among children with some form of cancer, about a third have a type of leukemia, most commonly acute lymphoblastic leukemia. 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. 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. 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.

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.

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

UK

Overall, leukaemia 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).

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. 

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. This, however, led to further experiments. 

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.

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".

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. The 1970 romance novel Love Story is an example of this romanticization of leukemia. 

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

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. 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. 

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.

Treatment through gene therapy is currently being pursued. One such approach used genetically modified T cells, known as 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 and in 2013, three of five subjects who had acute lymphocytic leukemia were reported to be in remission for five months to two years. Subsequent studies with a variety of CAR-T types continue to be promising. As of 2018, two CAR-T therapies have been approved by the Food and Drug Administration. CAR-T treatment has significant side effects, and loss of the antigen targeted by the CAR-T cells is a common mechanism for relapse. The stem cells that cause different types of leukaemia are also being researched.

Pregnancy

Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women. How it is handled depends primarily on the type of leukemia. Nearly all leukemias appearing in pregnant women are acute leukemias. Acute leukemias normally require prompt, aggressive treatment, despite significant risks of pregnancy loss and birth defects, especially if chemotherapy is given during the developmentally sensitive first trimester. Chronic myelogenous leukemia can be treated with relative safety at any time during pregnancy with Interferon-alpha hormones. Treatment for chronic lymphocytic leukemias, which are rare in pregnant women, can often be postponed until after the end of the pregnancy.

Hematopoietic stem cell transplantation

From Wikipedia, the free encyclopedia

Hematopoietic stem cell transplantation
KM Transplantat.JPEG
Bone marrow transplant
ICD-9-CM41.0
MeSHD018380
MedlinePlus003009

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous (the patient's own stem cells are used), allogeneic (the stem cells come from a donor) or syngeneic (from an identical twin).

It is most often performed for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia. In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease are major complications of allogeneic HSCT.

Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer to autoimmune diseases and hereditary skeletal dysplasias; notably malignant infantile osteopetrosis and mucopolysaccharidosis.

Medical uses

Indications

Indications for stem cell transplantation are as follows:

Malignant (cancerous)

Non-malignant (non-cancerous)

Many recipients of HSCTs are multiple myeloma or leukemia patients who would not benefit from prolonged treatment with, or are already resistant to, chemotherapy. Candidates for HSCTs include pediatric cases where the patient has an inborn defect such as severe combined immunodeficiency or congenital neutropenia with defective stem cells, and also children or adults with aplastic anemia who have lost their stem cells after birth. Other conditions treated with stem cell transplants include sickle-cell disease, myelodysplastic syndrome, neuroblastoma, lymphoma, Ewing's sarcoma, desmoplastic small round cell tumor, chronic granulomatous disease, Hodgkin's disease and Wiskott–Aldrich syndrome. More recently non-myeloablative, ""mini transplant (microtransplantation)," procedures have been developed that require smaller doses of preparative chemo and radiation. This has allowed HSCT to be conducted in the elderly and other patients who would otherwise be considered too weak to withstand a conventional treatment regimen.

Number of procedures

In 2006 a total of 50,417 first hematopoietic stem cell transplants were reported as taking place worldwide, according to a global survey of 1327 centers in 71 countries conducted by the Worldwide Network for Blood and Marrow Transplantation. Of these, 28,901 (57 percent) were autologous and 21,516 (43 percent) were allogeneic (11,928 from family donors and 9,588 from unrelated donors). The main indications for transplant were lymphoproliferative disorders (55 percent) and leukemias (34 percent), and the majority took place in either Europe (48 percent) or the Americas (36 percent).

The Worldwide Network for Blood and Marrow Transplantation reported the millionth transplant to have been undertaken in December 2012.

In 2014, according to the World Marrow Donor Association (WMDA), stem cell products provided for unrelated transplantation worldwide had increased to 20,604 (4,149 bone marrow donations, 12,506 peripheral blood stem cell donations, and 3,949 cord blood units).

Graft types

Autologous

Autologous HSCT requires the extraction (apheresis) of hematopoietic stem cells (HSC) from the patient and storage of the harvested cells in a freezer. The patient is then treated with high-dose chemotherapy with or without radiotherapy with the intention of eradicating the patient's malignant cell population at the cost of partial or complete bone marrow ablation (destruction of patient's bone marrow's ability to grow new blood cells). The patient's own stored stem cells are then transfused into his/her bloodstream, where they replace destroyed tissue and resume the patient's normal blood cell production. Autologous transplants have the advantage of lower risk of infection during the immune-compromised portion of the treatment since the recovery of immune function is rapid. Also, the incidence of patients experiencing rejection (and graft-versus-host disease is impossible) is very rare due to the donor and recipient being the same individual. These advantages have established autologous HSCT as one of the standard second-line treatments for such diseases as lymphoma.

However, for other cancers such as acute myeloid leukemia, the reduced mortality of the autogenous relative to allogeneic HSCT may be outweighed by an increased likelihood of cancer relapse and related mortality, and therefore the allogeneic treatment may be preferred for those conditions.

Researchers have conducted small studies using non-myeloablative hematopoietic stem cell transplantation as a possible treatment for type I (insulin dependent) diabetes in children and adults. Results have been promising; however, as of 2009 it was premature to speculate whether these experiments will lead to effective treatments for diabetes.

Allogeneic

Allogeneic HSCT involves two people: the (healthy) donor and the (patient) recipient. Allogeneic HSC donors must have a tissue (HLA) type that matches the recipient. Matching is performed on the basis of variability at three or more loci of the HLA gene, and a perfect match at these loci is preferred. Even if there is a good match at these critical alleles, the recipient will require immunosuppressive medications to mitigate graft-versus-host disease. Allogeneic transplant donors may be related (usually a closely HLA matched sibling), syngeneic (a monozygotic or 'identical' twin of the patient – necessarily extremely rare since few patients have an identical twin, but offering a source of perfectly HLA matched stem cells) or unrelated (donor who is not related and found to have very close degree of HLA matching). Unrelated donors may be found through a registry of bone marrow donors such as the National Marrow Donor Program. People who would like to be tested for a specific family member or friend without joining any of the bone marrow registry data banks may contact a private HLA testing laboratory and be tested with a mouth swab to see if they are a potential match. A "savior sibling" may be intentionally selected by preimplantation genetic diagnosis in order to match a child both regarding HLA type and being free of any obvious inheritable disorder. Allogeneic transplants are also performed using umbilical cord blood as the source of stem cells. In general, by transfusing healthy stem cells to the recipient's bloodstream to reform a healthy immune system, allogeneic HSCTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved.

A compatible donor is found by doing additional HLA-testing from the blood of potential donors. The HLA genes fall in two categories (Type I and Type II). In general, mismatches of the Type-I genes (i.e. HLA-A, HLA-B, or HLA-C) increase the risk of graft rejection. A mismatch of an HLA Type II gene (i.e. HLA-DR, or HLA-DQB1) increases the risk of graft-versus-host disease. In addition, a genetic mismatch as small as a single DNA base pair is significant so perfect matches require knowledge of the exact DNA sequence of these genes for both donor and recipient. Leading transplant centers currently perform testing for all five of these HLA genes before declaring that a donor and recipient are HLA-identical. 

Race and ethnicity are known to play a major role in donor recruitment drives, as members of the same ethnic group are more likely to have matching genes, including the genes for HLA.

As of 2013, there were at least two commercialized allogeneic cell therapies, Prochymal and Cartistem.

Sources and storage of cells

To limit the risks of transplanted stem cell rejection or of severe graft-versus-host disease in allogeneic HSCT, the donor should preferably have the same human leukocyte antigens (HLA) as the recipient. About 25 to 30 percent of allogeneic HSCT recipients have an HLA-identical sibling. Even so-called "perfect matches" may have mismatched minor alleles that contribute to graft-versus-host disease.

Bone marrow

Bone marrow harvest.
 
In the case of a bone marrow transplant, the HSC are removed from a large bone of the donor, typically the pelvis, through a large needle that reaches the center of the bone. The technique is referred to as a bone marrow harvest and is performed under general anesthesia.

Peripheral blood stem cells

Peripheral blood stem cells
 
Peripheral blood stem cells are now the most common source of stem cells for HSCT. They are collected from the blood through a process known as apheresis. The donor's blood is withdrawn through a sterile needle in one arm and passed through a machine that removes white blood cells. The red blood cells are returned to the donor. The peripheral stem cell yield is boosted with daily subcutaneous injections of granulocyte-colony stimulating factor, serving to mobilize stem cells from the donor's bone marrow into the peripheral circulation.

Amniotic fluid

It is also possible to extract stem cells from amniotic fluid for both autologous or heterologous use at the time of childbirth.

Umbilical cord blood

Umbilical cord blood is obtained when a mother donates her infant's umbilical cord and placenta after birth. Cord blood has a higher concentration of HSC than is normally found in adult blood. However, the small quantity of blood obtained from an umbilical cord (typically about 50 mL) makes it more suitable for transplantation into small children than into adults. Newer techniques using ex-vivo expansion of cord blood units or the use of two cord blood units from different donors allow cord blood transplants to be used in adults. 

Cord blood can be harvested from the umbilical cord of a child being born after preimplantation genetic diagnosis (PGD) for human leukocyte antigen (HLA) matching (see PGD for HLA matching) in order to donate to an ill sibling requiring HSCT.

Storage of HSC

Unlike other organs, bone marrow cells can be frozen (cryopreserved) for prolonged periods without damaging too many cells. This is a necessity with autologous HSC because the cells must be harvested from the recipient months in advance of the transplant treatment. In the case of allogeneic transplants, fresh HSC are preferred in order to avoid cell loss that might occur during the freezing and thawing process. Allogeneic cord blood is stored frozen at a cord blood bank because it is only obtainable at the time of childbirth. To cryopreserve HSC, a preservative, DMSO, must be added, and the cells must be cooled very slowly in a controlled-rate freezer to prevent osmotic cellular injury during ice crystal formation. HSC may be stored for years in a cryofreezer, which typically uses liquid nitrogen.

Conditioning regimens

Myeloablative

The chemotherapy or irradiation given immediately prior to a transplant is called the conditioning regimen, the purpose of which is to help eradicate the patient's disease prior to the infusion of HSC and to suppress immune reactions. The bone marrow can be ablated (destroyed) with dose-levels that cause minimal injury to other tissues. In allogeneic transplants a combination of cyclophosphamide with total body irradiation is conventionally employed. This treatment also has an immunosuppressive effect that prevents rejection of the HSC by the recipient's immune system. The post-transplant prognosis often includes acute and chronic graft-versus-host disease that may be life-threatening. However, in certain leukemias this can coincide with protection against cancer relapse owing to the graft-versus-tumor effect. Autologous transplants may also use similar conditioning regimens, but many other chemotherapy combinations can be used depending on the type of disease.

Non-myeloablative

A newer treatment approach, non-myeloablative allogeneic transplantation, also termed reduced-intensity conditioning (RIC), uses doses of chemotherapy and radiation too low to eradicate all the bone marrow cells of the recipient. Instead, non-myeloablative transplants run lower risks of serious infections and transplant-related mortality while relying upon the graft versus tumor effect to resist the inherent increased risk of cancer relapse. Also significantly, while requiring high doses of immunosuppressive agents in the early stages of treatment, these doses are less than for conventional transplants. This leads to a state of mixed chimerism early after transplant where both recipient and donor HSC coexist in the bone marrow space. 

Decreasing doses of immunosuppressive therapy then allow donor T-cells to eradicate the remaining recipient HSC and to induce the graft-versus-tumor effect. This effect is often accompanied by mild graft-versus-host disease, the appearance of which is often a surrogate marker for the emergence of the desirable graft versus tumor effect, and also serves as a signal to establish an appropriate dosage level for sustained treatment with low levels of immunosuppressive agents

Because of their gentler conditioning regimens, these transplants are associated with a lower risk of transplant-related mortality and therefore allow patients who are considered too high-risk for conventional allogeneic HSCT to undergo potentially curative therapy for their disease. The optimal conditioning strategy for each disease and recipient has not been fully established, but RIC can be used in elderly patients unfit for myeloablative regimens, for whom a higher risk of cancer relapse may be acceptable.

Engraftment

After several weeks of growth in the bone marrow, expansion of HSC and their progeny is sufficient to normalize the blood cell counts and re-initiate the immune system. The offspring of donor-derived hematopoietic stem cells have been documented to populate many different organs of the recipient, including the heart, liver, and muscle, and these cells had been suggested to have the abilities of regenerating injured tissue in these organs. However, recent research has shown that such lineage infidelity does not occur as a normal phenomenon
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Chimerism monitoring is a method to monitor the balance between the patient's own stem cells and the new stem cells from a donor. In case the patient's own stem cells are increasing in number post-treatment, this might be a sign the treatment did not work as intended.

Complications

HSCT is associated with a high treatment-related mortality in the recipient, which limits its use to conditions that are themselves life-threatening. (The one-year survival rate has been estimated to be roughly 60%, although this figure includes deaths from the underlying disease as well as from the transplant procedure.) Major complications are veno-occlusive disease, mucositis, infections (sepsis), graft-versus-host disease and the development of new malignancies.

Infection

Bone marrow transplantation usually requires that the recipient's own bone marrow be destroyed (myeloablation). Prior to the administration of new cells (engraftment) patients may go for several weeks without appreciable numbers of white blood cells to help fight infection. This puts a patient at high risk of infections, sepsis and septic shock, despite prophylactic antibiotics. However, antiviral medications, such as acyclovir and valacyclovir, are quite effective in prevention of HSCT-related outbreak of herpetic infection in seropositive patients. The immunosuppressive agents employed in allogeneic transplants for the prevention or treatment of graft-versus-host disease further increase the risk of opportunistic infection. Immunosuppressive drugs are given for a minimum of 6-months after a transplantation, or much longer if required for the treatment of graft-versus-host disease. Transplant patients lose their acquired immunity, for example immunity to childhood diseases such as measles or polio. For this reason transplant patients must be re-vaccinated with childhood vaccines once they are off immunosuppressive medications.

Veno-occlusive disease

Severe liver injury can result from hepatic veno-occlusive disease (VOD). Elevated levels of bilirubin, hepatomegaly and fluid retention are clinical hallmarks of this condition. There is now a greater appreciation of the generalized cellular injury and obstruction in hepatic vein sinuses, and hepatic VOD has lately been referred to as sinusoidal obstruction syndrome (SOS). Severe cases of SOS are associated with a high mortality rate. Anticoagulants or defibrotide may be effective in reducing the severity of VOD but may also increase bleeding complications. Ursodiol has been shown to help prevent VOD, presumably by facilitating the flow of bile.

Mucositis

The injury of the mucosal lining of the mouth and throat is a common regimen-related toxicity following ablative HSCT regimens. It is usually not life-threatening but is very painful, and prevents eating and drinking. Mucositis is treated with pain medications plus intravenous infusions to prevent dehydration and malnutrition.

Hemorrhagic cystitis

The mucosal lining of the bladder could also be involved in approximately 5 percent of the children undergoing hematopoietic stem cell transplantation. This causes hematuria, frequency, abdominal pain and thrombocytopnea.

Graft-versus-host disease

Graft-versus-host disease (GVHD) is an inflammatory disease that is unique to allogeneic transplantation. It is an attack by the "new" bone marrow's immune cells against the recipient's tissues. This can occur even if the donor and recipient are HLA-identical because the immune system can still recognize other differences between their tissues. It is aptly named graft-versus-host disease because bone marrow transplantation is the only transplant procedure in which the transplanted cells must accept the body rather than the body accepting the new cells.

Acute graft-versus-host disease typically occurs in the first 3 months after transplantation and may involve the skin, intestine, or the liver. High-dose corticosteroids such as prednisone are a standard treatment; however this immuno-suppressive treatment often leads to deadly infections. Chronic graft-versus-host disease may also develop after allogeneic transplant. It is the major source of late treatment-related complications, although it less often results in death. In addition to inflammation, chronic graft-versus-host disease may lead to the development of fibrosis, or scar tissue, similar to scleroderma; it may cause functional disability and require prolonged immunosuppressive therapy. Graft-versus-host disease is usually mediated by T cells, which react to foreign peptides presented on the MHC of the host.

Graft-versus-tumor effect

Graft-versus-tumor effect (GVT) or "graft versus leukemia" effect is the beneficial aspect of the Graft-versus-Host phenomenon. For example, HSCT patients with either acute, or in particular chronic, graft-versus-host disease after an allogeneic transplant tend to have a lower risk of cancer relapse. This is due to a therapeutic immune reaction of the grafted donor T lymphocytes against the diseased bone marrow of the recipient. This lower rate of relapse accounts for the increased success rate of allogeneic transplants, compared to transplants from identical twins, and indicates that allogeneic HSCT is a form of immunotherapy. GVT is the major benefit of transplants that do not employ the highest immuno-suppressive regimens. 

Graft versus tumor is mainly beneficial in diseases with slow progress, e.g. chronic leukemia, low-grade lymphoma, and in some cases multiple myeloma. However, it is less effective in rapidly growing acute leukemias.

If cancer relapses after HSCT, another transplant can be performed, infusing the patient with a greater quantity of donor white blood cells (Donor lymphocyte infusion).

Oral carcinoma

Patients after HSCT are at a higher risk for oral carcinoma. Post-HSCT oral cancer may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-HSCT patients.

Prognosis

Prognosis in HSCT varies widely dependent upon disease type, stage, stem cell source, HLA-matched status (for allogeneic HSCT) and conditioning regimen. A transplant offers a chance for cure or long-term remission if the inherent complications of graft versus host disease, immuno-suppressive treatments and the spectrum of opportunistic infections can be survived. In recent years, survival rates have been gradually improving across almost all populations and sub-populations receiving transplants.

Mortality for allogeneic stem cell transplantation can be estimated using the prediction model created by Sorror et al., using the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). The HCT-CI was derived and validated by investigators at the Fred Hutchinson Cancer Research Center (Seattle, WA). The HCT-CI modifies and adds to a well-validated comorbidity index, the Charlson Comorbidity Index (CCI) (Charlson et al.) The CCI was previously applied to patients undergoing allogeneic HCT but appears to provide less survival prediction and discrimination than the HCT-CI scoring system.

Risks to donor

The risks of a complication depend on patient characteristics, health care providers and the apheresis procedure, and the colony-stimulating factor used (G-CSF). G-CSF drugs include filgrastim (Neupogen, Neulasta), and lenograstim (Graslopin).

Drug risks

Filgrastim is typically dosed in the 10 microgram/kg level for 4–5 days during the harvesting of stem cells. The documented adverse effects of filgrastim include splenic rupture (indicated by left upper abdominal or shoulder pain, risk 1 in 40000), Acute respiratory distress syndrome (ARDS), alveolar hemorrhage, and allergic reactions (usually expressed in first 30 minutes, risk 1 in 300). In addition, platelet and hemoglobin levels dip post-procedure, not returning to normal until after one month.

The question of whether geriatrics (patients over 65) react the same as patients under 65 has not been sufficiently examined. Coagulation issues and inflammation of atherosclerotic plaques are known to occur as a result of G-CSF injection. G-CSF has also been described to induce genetic changes in mononuclear cells of normal donors. There is no statistically significant evidence either for or against the hypothesis that myelodysplasia (MDS) or acute myeloid leukaemia (AML) can be induced by GCSF in susceptible individuals.

Access risks

Blood was drawn peripherally in a majority of patients, but a central line to jugular/subclavian/femoral veins may be used in 16 percent of women and 4 percent of men. Adverse reactions during apheresis were experienced in 20 percent of women and 8 percent of men, these adverse events primarily consisted of numbness/tingling, multiple line attempts, and nausea.

Clinical observations

A study involving 2408 donors (18–60 years) indicated that bone pain (primarily back and hips) as a result of filgrastim treatment is observed in 80 percent of donors by day 4 post-injection. This pain responded to acetaminophen or ibuprofen in 65 percent of donors and was characterized as mild to moderate in 80 percent of donors and severe in 10 percent. Bone pain receded post-donation to 26 percent of patients 2 days post-donation, 6 percent of patients one week post-donation, and less than 2 percent 1 year post-donation. Donation is not recommended for those with a history of back pain. Other symptoms observed in more than 40 percent of donors include myalgia, headache, fatigue, and insomnia. These symptoms all returned to baseline 1 month post-donation, except for some cases of persistent fatigue in 3 percent of donors.

In one metastudy that incorporated data from 377 donors, 44 percent of patients reported having adverse side effects after peripheral blood HSCT. Side effects included pain prior to the collection procedure as a result of GCSF injections, post-procedural generalized skeletal pain, fatigue and reduced energy.

Severe reactions

A study that surveyed 2408 donors found that serious adverse events (requiring prolonged hospitalization) occurred in 15 donors (at a rate of 0.6 percent), although none of these events were fatal. Donors were not observed to have higher than normal rates of cancer with up to 4–8 years of follow up. One study based on a survey of medical teams covered approximately 24,000 peripheral blood HSCT cases between 1993 and 2005, and found a serious cardiovascular adverse reaction rate of about 1 in 1500. This study reported a cardiovascular-related fatality risk within the first 30 days HSCT of about 2 in 10000. For this same group, severe cardiovascular events were observed with a rate of about 1 in 1500. The most common severe adverse reactions were pulmonary edema/deep vein thrombosis, splenic rupture, and myocardial infarction. Haematological malignancy induction was comparable to that observed in the general population, with only 15 reported cases within 4 years.

History

Georges Mathé, a French oncologist, performed the first European bone marrow transplant in November 1958 on five Yugoslavian nuclear workers whose own marrow had been damaged by irradiation caused by a criticality accident at the Vinča Nuclear Institute, but all of these transplants were rejected. Fortunately, the five treated were able to ultimately recover, perhaps in part due to the transplants. Mathé later pioneered the use of bone marrow transplants in the treatment of leukemia.

Stem cell transplantation was pioneered using bone-marrow-derived stem cells by a team at the Fred Hutchinson Cancer Research Center from the 1950s through the 1970s led by E. Donnall Thomas, whose work was later recognized with a Nobel Prize in Physiology or Medicine. Thomas' work showed that bone marrow cells infused intravenously could repopulate the bone marrow and produce new blood cells. His work also reduced the likelihood of developing a life-threatening complication called graft-versus-host disease. Collaborating with University of Washington Professor Eloise Giblett, he discovered genetic markers that could confirm donor matches. 

The first physician to perform a successful human bone marrow transplant on a disease other than cancer was Robert A. Good at the University of Minnesota in 1968. In 1975, John Kersey, M.D., also of the University of Minnesota, performed the first successful bone marrow transplant to cure lymphoma. His patient, a 16-year-old-boy, is today the longest-living lymphoma transplant survivor.

Donor registration and recruitment

At the end of 2012, 20.2 million people had registered their willingness to be a bone marrow donor with one of the 67 registries from 49 countries participating in Bone Marrow Donors Worldwide. 17.9 million of these registered donors had been ABDR typed, allowing easy matching. A further 561,000 cord blood units had been received by one of 46 cord blood banks from 30 countries participating. The highest total number of bone marrow donors registered were those from the US (8.0 million), and the highest number per capita were those from Cyprus (15.4 percent of the population).

Within the United States, racial minority groups are the least likely to be registered and therefore the least likely to find a potentially life-saving match. In 1990, only six African-Americans were able to find a bone marrow match, and all six had common European genetic signatures.

Africans are more genetically diverse than people of European descent, which means that more registrations are needed to find a match. Bone marrow and cord blood banks exist in South Africa, and a new program is beginning in Nigeria. Many people belonging to different races are requested to donate as there is a shortage of donors in African, Mixed race, Latino, Aboriginal, and many other communities. 

Two registries in the United States recruit unrelated allogeneic donors: NMDP/Be the Match and the Gift of Life Marrow Registry.

Research

HIV

In 2007, a team of doctors in Berlin, Germany, including Gero Hütter, performed a stem cell transplant for leukemia patient Timothy Ray Brown, who was also HIV-positive. From 60 matching donors, they selected a [CCR5]-Δ32 homozygous individual with two genetic copies of a rare variant of a cell surface receptor. This genetic trait confers resistance to HIV infection by blocking attachment of HIV to the cell. Roughly one in 1000 people of European ancestry have this inherited mutation, but it is rarer in other populations. The transplant was repeated a year later after a leukemia relapse. Over three years after the initial transplant, and despite discontinuing antiretroviral therapy, researchers cannot detect HIV in the transplant recipient's blood or in various biopsies of his tissues. Levels of HIV-specific antibodies have also declined, leading to speculation that the patient may have been functionally cured of HIV. However, scientists emphasise that this is an unusual case. Potentially fatal transplant complications (the "Berlin patient" suffered from graft-versus-host disease and leukoencephalopathy) mean that the procedure could not be performed in others with HIV, even if sufficient numbers of suitable donors were found.

In 2012, Daniel Kuritzkes reported results of two stem cell transplants in patients with HIV. They did not, however, use donors with the Δ32 deletion. After their transplant procedures, both were put on antiretroviral therapies, during which neither showed traces of HIV in their blood plasma and purified CD4 T cells using a sensitive culture method (less than 3 copies/mL). However, the virus was once again detected in both patients some time after the discontinuation of therapy.

In 2019, a British man became the second to be cleared of HIV after receiving a bone marrow transplant from a virus-resistant (Δ32) donor. This patient is being called "the London patient" (a reference to the famous Berlin patient).

Multiple sclerosis

Since McAllister's 1997 report on a patient with multiple sclerosis (MS) who received a bone marrow transplant for CML, over 600 reports have been published describing HSCTs performed primarily for MS. These have been shown to "reduce or eliminate ongoing clinical relapses, halt further progression, and reduce the burden of disability in some patients" that have aggressive highly active MS, "in the absence of chronic treatment with disease-modifying agents".

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