Hairy cell leukemia

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Hair-celled leukemia is a rare hematological malignancy characterized by abnormal B lymphocyte accumulation. It is usually classified as a sub-type of chronic lymphocytic leukemia (CLL). Hairy cell leukemia makes up about 2% of all leukemia, with less than 2,000 new cases diagnosed each year in North America and Western Europe combined.

Hair-cell leukemia was originally described as histiocytic leukemia, malignant reticulum, or lymphoid myelofibrosis in a publication dating from the 1920s. The disease is formally called leukemic reticuloendotheliosis and a characterization significantly enhanced by Bertha Bouroncle and his colleagues at Ohio State University College of Medicine in 1958. The common name, created in 1966, comes from the malignant "furry" appearance of B. cells under a microscope.

Video Hairy cell leukemia

Signs and symptoms

In hairy cell leukemia, "hairy cells" (harmful B lymphocytes) accumulate in the bone marrow, interfering with the production of normal white blood cells, red blood cells, and platelets. As a result, patients can develop infections associated with low white blood cell count, anemia and fatigue due to lack of red blood cells, or easy bleeding due to low platelet counts. Leukemia cells may collect in the spleen and cause it to swell; this can have side effects making people feel full even when he has not eaten much.

Hair-celled leukemia is commonly diagnosed after routine blood counting indicates an unexpected number of one or more normal blood cell types, or after unexplained bruising or recurrent infections in apparently healthy patients.

Platelet function may be somewhat impaired in HCL patients, although this does not seem to have a significant practical effect. This may result in a slightly lighter bruise than expected for a given platelet count or slightly increased bleeding time for minor injuries. The likelihood of results from producing a slightly abnormal platelets in depressed bone marrow tissue.

Patients with high tumor burden may also experience a decrease in cholesterol levels, especially in patients with an enlarged spleen. Cholesterol levels return to a more normal value with successful HCL treatment.

Maps Hairy cell leukemia

Cause

Like many cancers, the cause of hairless cell leukemia is unknown. Exposure to tobacco smoke, ionizing radiation, or industrial chemicals (with the possible exception of diesel) does not seem to increase the risk of developing HCL. Farming and gardening seem to increase the risk of HCL in some studies.

Recent studies have identified a somatic BR80 V600E mutation in all patients with the classic form of sequenced haired cell leukemia, but no patients with variant forms.

The US Institute of Medicine (IOM) announced "sufficient evidence" about the relationship between herbicidal exposure and the development of chronic leukemia and chronic lymphoma in general. The IOM report emphasizes that neither animal nor human studies show no herbicidal relationship with HCL in particular. However, IOM extrapolates data from chronic lymphocytic leukemia and non-Hodgkin's lymphoma to conclude that HCL and other rare B-cell neoplasms may share these risk factors. As a result of the IOM report, the US Department of Veterans Affairs considers HCL a disease considered a service-related disability (see Agent Orange).

Human T-lymphotropic virus 2 (HTLV-2) has been isolated in a small number of patients with HCL form variants. In the 1980s, HTLV-2 was identified in patients with T cell lymphoproliferative disease; The patient then developed hair-celled leukemia (B-cell disease), but HTLV-2 was not found in hairy clonal cells. There is no evidence that HTLV-II causes any kind of hematologic malignancy, including HCL.

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Pathophysiology

Pancitopenia in HCL is caused primarily by bone marrow failure and splenomegaly. Bone marrow failure is caused by the accumulation of hairy cells and reticular fibrosis in the bone marrow, as well as by the adverse effects of unregulated cytokine production. Splenomegaly reduces the amount of blood through sequestration, marginalization, and destruction of healthy blood cells in the spleen.

Hairy cells are nearly mature B cells, which are clonal cells that are activated by signs of differentiation of the VH gene. They may be related to B cells of the pre-plasma marginal zone or memory cells.

The production of cytokines is impaired in HCL. Hairy cells produce and thrive in TNF-alpha. This cytokine also suppresses normal production of healthy blood cells in the bone marrow.

Unlike healthy B cells, hairy cells express and secrete immune system proteins called Interleukin-2 receptors (IL-2R). In HCL-V, only a portion of these receptors are expressed. As a result, disease status can be monitored by measuring changes in the amount of IL-2R in blood serum. The rate increases as hairy cells proliferate, and decrease when they are killed. Although rarely used in North America and Northern Europe, these tests correlate better with disease status and predict relapse more accurately than other tests.

Hairy cells respond to normal production of some cytokines by T cells with increased growth. Treatment with Interferon-alpha suppresses the production of these pro-growth cytokines from T cells. Low T-cell levels, usually seen after treatment with cladribine or pentostatin, and reduction of these cytokines, are also associated with reduced hairy cell levels.

In June 2011, E Tiacci et al found that 100% of haired leukemia sample samples analyzed had a BRIMA oncogenic mutation V600E, and proposed that this was a driver mutation. Up to this point, only some genomic imbalance has been found in hairy cells, as trisomy 5 has been found. Gene expression is also not regulated in complex and specific patterns. The cells below express 3p24, 3p21, 3q13.3-q22, 4p16, 11q23, 14q22-q24, 15q21-q22, 15q24-q25, and 17q22-q24 and overexpress 13q31 and Xq13.3-q21. It has not been shown that these changes have a practical meaning to the patient.

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Diagnosis

The diagnosis of HCL may be suggested by abnormal results in a complete blood count (CBC), but additional testing is needed to confirm the diagnosis. A CBC usually shows a low amount for white blood cells, red blood cells, and platelets in HCL patients. However, if a large number of furry cells are in the bloodstream, then normal or even high lymphocyte counts can be found.

On physical examination, 80-90% of patients have an enlarged spleen, which can be very large. This is less likely among patients diagnosed at an early stage. Peripheral lymphadenopathy (enlarged lymph nodes) is rare (less than 5% of patients), but abdominal lymphadenopathy is a relatively common finding in computed tomography (CT) scans.

The most important laboratory finding is the presence of hairy cells in the bloodstream. Hairy cells are abnormal white blood cells with hair-like cytoplasm projection; they can be seen by examining blood samples or bone marrow biopsy specimens. Blood film examination is done by staining the blood cells with Wright's stains and seeing them under a microscope. Hairy cells are seen in this test in about 85% of cases.

Most patients require a bone marrow biopsy for a final diagnosis. Bone marrow biopsy is used both to confirm the presence of HCL as well as the absence of additional diseases, such as Lymph node marginal lymphoma or pro-bymphocytic leukemia B-cells. Diagnosis can be confirmed by looking at cells with a special stain known as TRAP (tartrate resistant acid phosphatase). More recently, DB44 testing ensures more accurate results.

It is also possible to diagnose definitive hair-defining leukemia through the flow of cytometry in the blood or bone marrow. Furry cells are larger than normal and positive for CD19, CD20, CD22, CD11c, CD25, CD103, and FMC7. (CD103, CD22, and CD11c are highly expressed.)

Leukemia-Hair-cell variant (HCL-V), which has some characteristics with pro-phosphositic cell leukemia B (B-PLL), does not show CD25 (also called Interleukin-2 receptor, alpha). Since this is a relatively new and expensive technology, its adoption by doctors is not uniform, although there are advantages of patient comfort, simplicity, and safety when compared to bone marrow biopsy. The presence of additional lymphoproliferative disease is easily examined during flow cytometry tests, where they characteristically show different results.

The differential diagnosis includes: several types of anemia, including myelophthisis and aplastic anemia, and most types of blood neoplasms, including hypoplastic myelodysplastic syndrome, atypical chronic lymphocytic leukemia, pro-lymphocytic leukemia B-cell, or idiopathic myelofibrosis.

Classification

When not specified further, the "classical" form is often implied. However, two variants have been described: Leukemia variants of hair cells and Japanese variants. Non-Japanese variants are more difficult to treat than the classic HCL or Japanese variant HCL.

Leukemia-haired cell variant

Leukemia-haired hairline variant, or HCL-V, is usually described as a prolymphocytic variant of haired leukemia cells. It was first formally described in 1980 by a paper from the Hayhoe University of Cambridge lab. About 10% of people with HCL have a variant of this form of the disease, representing about 60-75 new cases of HCL-V every year in the US. While classical HCL mainly affects men, HCL-V is divided more evenly between men and women. While the disease may appear at any age, the median age at diagnosis is over 70.

Similar to B-cell prolymphocytic leukemia ("B-PLL") in chronic lymphocytic leukemia, HCL-V is a more aggressive disease. Historically, it was considered less successfully treated than the classic HCL, and remissions tend to be shorter.

However, the introduction of combination therapy with concurrent rituximab therapy and cladribine therapy has shown excellent results at the beginning of follow-up. By 2016, this therapy is considered a first-line treatment option for many people with HCL-V.

Many older treatment approaches, such as Interferon-alfa , combination of chemotherapy regimens "CHOP", and common alkylating agents such as cyclophosphamide show very little benefit. Pentostatin and cladribine administered as monotherapy (without concurrent rituximab) provide some benefit for many people with HCL-V, but usually induce shorter remission periods and lower response rates than when they are used in classical HCL. More than half of people responded partially to splenectomy.

In terms of B-cell development, prolymphocytes are less developed than lymphocytes or plasma cells, but are still more mature than their lymphoblastic precursors.

HCL-V differs from classical HCL especially in the following points:

• Higher white blood cell count, sometimes exceeding 100,000 cells per microliter;
• More aggressive diseases that require more frequent treatment;
• Furry cells with extraordinarily large nucleoli for their size;
• Production of slightly excess fibronectin produced by classical feather cells; to disrupt bone marrow biopsy; and
• Low or no surface expression of CD25 cells (also called interleukin-2 (IL-2) alpha chains, or p55).

Low CD25 levels, part of the receptor for key immunoregulatory hormones, may explain why HCL-V cases are generally much more resistant to treatment by the hormone immune system.

HCL-V, which usually has a high proportion of hairy cells without a functional p53 tumor suppressor gene, is somewhat more likely to turn into higher class malignancy. Typical transformation rates of 5% -6% have been postulated in the UK, similar to the Richter transformation rates for SLVL and CLL. Among HCL-V patients, the most aggressive cases usually had the least amount of p53 gene activity. Hairless cells without the p53 gene tend to, over time, to replace the less aggressive p53 () hairy cells.

There is some evidence to suggest that the rearrangement of the immunoglobulin gene VH4-34, which is found in about 40% of HCL-V patients and 10% of classical HCL patients, may be a more important prognostic factor than variance status, with HCL-V patients without structuring repeated VH4-34 responded about as well as classic HCL patients.

Japanese-celled leukemia variant

There is a variant called Leukemia variant-Hairy cell or HCL-J, which is more easily treated.

Treatment with cladribine has been reported.

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Prevention

Since the cause is unknown, no effective preventive measures can be taken.

Because the disease is rare, regular checkups are not cost-effective.

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Treatment

Some treatments are available, and successful control of the disease is common.

Not everyone needs immediate treatment. Treatment is usually given when symptoms of the disease interfere with the daily life of the patient, or when the white blood cell or platelet count decreases to very low levels, such as the absolute number of neutrophils. below one thousand cells per microliter (1.0 K/uL). Not all patients need treatment immediately after diagnosis.

Delayed treatment is less important than in solid tumors. Unlike most cancers, treatment success does not depend on the treatment of the disease at an early stage. Because delays do not affect treatment success, there is no standard for how quickly patients should receive treatment. However, waiting too long can cause problems of its own, such as infections that might be avoided with proper treatment to restore immune system function. Also, having higher hair cell counts at the time of treatment can make certain side effects worse, as some side effects are mainly caused by the body's natural response to the dying hairy cells. This may result in hospitalization of patients whose treatment will be performed entirely in the hematology office.

A single drug treatment is typical. Unlike most cancers, only one drug is usually given to the patient at a time. While normal monotherapy, combination therapy - usually using a first-line therapy and one second-line therapy - is being studied in current clinical trials and more commonly used for refractory cases. Combining rituximab with cladribine or pentostatin may or may not produce a practical benefit for the patient. Combination therapy is almost never used with new patients. Because success rates with purine analogue monotherapy are already very high, the added benefit of immediate treatment with a second drug in patients taking medication is assumed to be very low. For example, a single round of either cladribine or pentostatin gives the median patient the first time for a decade of forgiveness; the addition of rituximab, which gives median patients only three or four years, may not provide additional value for this treatable patient. However, in more difficult cases, the benefits of the first drug can be substantially reduced and therefore the combination may provide some benefits.

First-line therapy

Cladribine (2CDA) and pentostatin (DCF) are the two most common first-line treatments. Both have a class of drugs called purine analogues, which have mild side effects compared to traditional chemotherapy regimens.

Cladribine can be administered by injection under the skin, by intravenous infusion for several hours into the blood vessels, or by pumps used by patients who give slow infusion to blood vessels, 24 hours a day for 7 days. Most patients receive cladribine with IV infusions once daily for five to seven days, but more patients are given the option of taking the drug once a week for six weeks. Different dosing schedules used with cladribine are approximately equally effective and equally safe. Relatively few patients have significant side effects other than fatigue and high fever caused by dying cancer cells, although complications like infection and acute renal failure have been seen.

Pentostatin is chemically similar to cladribine, and has similar success rates and side effects profiles, but is always given over a longer period of time, usually one dose with IV infusions every two weeks for three to six months.

During the weeks after treatment, the patient's immune system is very weak, but their bone marrow will begin to produce normal blood cells again. Treatment often results in long-term remission. Approximately 85% of patients achieve complete response from treatment with cladribine or pentostatin, and another 10% receive some benefit from these drugs, although there is no permanent cure for this disease. If cancer cells return, treatment may be repeated and should again produce remission, although the likelihood of success decreases with recurrent treatment. The length of remission varies significantly, from one year to over twenty years. Median patients can expect maintenance-free intervals for about ten years.

It does not seem to be a matter of which drug the patient receives. A patient who is not successfully treated with either of these two medications has little chance of successfully treated with another. However, there are other options.

Second-line therapy

If a patient is resistant to cladribine or pentostatin, then second-line therapy is pursued.

Monoclonal antibodies The most common treatment for cladribine-resistant diseases is to infect monoclonal antibodies that destroy cancerous B cells. Rituximab is by far the most commonly used. Most patients receive one IV infusion for several hours each week for four to eight weeks. A 2003 publication found two partial complete answers and ten of 15 patients with recurrent disease, with a total of 80% responding. Median patients (including non-responders) did not require further treatment for more than three years. This eight-dose study had a higher response rate than the four-dose study at Scripps, which only achieved 25% response rate. Rituximab has succeeded in inducing a complete response to Hairy Cell Variants.

The main side effect of Rituximab is serum sickness, commonly described as an "allergic reaction," which can be severe, especially in the first infusion. Serum disease is primarily caused by antibodies that agglomerate during infusion and trigger a complement cascade. Although most patients find that side effects are moderately controlled by anti-allergic drugs, some severe, and even fatal, reactions have occurred. As a result, the first dose is always given in the hospital, although subsequent infusions may be given at the doctor's office. Remission is usually shorter than the first-line option, but haematological remission for several years is not uncommon.

Other monoclonal B-cell-destroying antibodies such as Alemtuzumab, Ibritumomab tiuxetan and I-131 Tositumomab may be considered for refractory cases.

Interferon-alpha Interferon-alpha is a very helpful immune system hormone for a small number of patients, and it helps most patients. In about 65% of patients, medications help stabilize the disease or produce slow minor improvement for partial responses.

The typical dosing schedule injects at least 3 million units of interferon-alpha (not the pegylated version) three times a week, although the initial protocol begins with a six-month daily injection.

Some patients tolerate IFN-alpha very well after the first few weeks, while others find that their flu-like symptoms persist. Approximately 10% of patients experience depression levels. It is possible that, by maintaining a more stable level of the hormone in the body, daily injections may cause fewer side effects in certain patients. Drinking at least two liters of water daily, while avoiding caffeine and alcohol, can reduce many of the side effects.

A decrease in blood count is usually seen during the first one to two months of treatment. Most patients found that their blood cell counts deteriorated for several weeks immediately after starting treatment, although some patients found their blood counts began to improve within just two weeks.

It usually takes six months to see if this therapy is useful. Common criteria for treatment success include:

• normalizing hemoglobin levels (above 12.0 g/dL),
• normal or rather low platelet count (above 100 K/Ã,ÂμL), and
• the number of absolute neutrophils is normal or rather low (above 1.5 K/Ã,ÂμL).

If well tolerated, patients usually take hormones for 12 to 18 months. An attempt may be made later to end the treatment, but most patients find that they need to continue using the drug to be successful. These patients often continue to use the drug indefinitely, until the disease becomes resistant to this hormone, or the body produces an immune system response that limits the drug's ability to function. Some patients can achieve sustained clinical remission after taking this drug for six months to a year. This may be more likely when IFN-alpha has started soon after another therapy. Interferon-alpha is considered the drug of choice for pregnant women with active HCL, although it carries some risks, such as the potential decrease in blood flow to the placenta.

Interferon-alpha works by sensitizing hairy cells to the killing effect of the TNF-alpha immune system hormone, whose production is promoted. IFN-alpha works best in unprotected protective classic cells against vitronectin or fibronectin, which suggests that patients who find fewer fibrous tissue in their bone marrow biopsy may be more likely to respond to Interferon-alpha therapy. It also explains why non-swollen hairy cells, such as those in the bloodstream, disappear during the treatment of IFN-alpha before the reduction is seen in adherent hairy cells, such as the bone marrow and spleen.

Other treatments

Splenectomy may produce long-term remission in patients whose spleen appears to be highly involved, but the success rate is noticeably lower than cladribine or pentostatin. Splenectomies are also performed for patients whose spleen is constantly enlarged causing significant discomfort or in patients whose low platelet counts suggest an idiopathic thrombocytopenic purpura.

Bone marrow transplantation is usually shunned in this treatable disease because of the inherent risks in the procedure. They can be considered for refractory cases in younger individuals, if not healthy. "Mini-transplant" is possible.

People with anemia or thrombocytopenia may also receive red blood cells and platelets through blood transfusions. Blood transfusions are always irradiated to remove white blood cells and thereby reduce the risk of graft-versus-host disease. Patients can also receive hormones to stimulate the production of red blood cells. This treatment may be medically necessary, but do not kill hairy cells.

People with low neutrophil counts may be given filgrastim or similar hormones to stimulate the production of white blood cells. However, a 1999 study showed that regular administration of expensive injecting drugs had no practical value for HCL patients after cladribine administration. In this study, patients who received filgrastim both experienced high fever and were hospitalized as those who did not, although this drug artificially increased their white blood cell count. This study opens up the possibility that filgrastim may still be appropriate for patients who have symptoms of infection, or sometimes other than immediately after cladribine treatment.

Although hairy cells are technically long-lived, rather than rapidly dividing, some end-stage patients are treated with broad-spectrum chemotherapy agents such as methotrexate that effectively kill cells rapidly divide. This is usually not attempted unless all other options have run out and usually do not work.

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Prognosis

The success of treatment

More than 95% of new patients are treated well or at least enough with cladribine or pentostatin. The majority of new patients can expect a time-free remission span of about ten years, or sometimes longer after taking one of these drugs only once. If re-treatment is needed in the future, drugs are usually effective again, although the average length of remission is somewhat shorter in subsequent treatments.

As with chronic lymphocytic leukemia of B-cells, mutations in IGHV in hairy cells are associated with a better response to early treatment and with prolonged survival.

How soon after treatment, the patient feels "normal" again depends on several factors, including:

• the extent of the illness at the time of treatment;
• the underlying patient's health status;
• whether the patient has a "complete response" or only partial response to treatment;
• whether the patient has any of the rare but serious side effects such as kidney failure;
• how aggressive a person's disease is;
• whether the patient had an unusual psychological trauma from a diagnosis of "cancer"; and
• how the patient feels the energy level of his or her pre-treatment and daily functions.

Age

With the right treatment, the entire life span projected for the patient is normal or near normal. In all patients, the first two years after diagnosis have the highest risk for fatal outcomes; Generally, five-year survival predicts good control of disease. After five years of clinical remission, patients in the United States with normal blood counts can often qualify for personal life insurance with several US companies.

Accurate survival measures for patients with disease-form variants (HCL-V) were complicated by a relatively high median age (70 years) at diagnosis. However, HCL-V patients routinely survive for more than 10 years, and younger patients may be able to expect a long life.

Worldwide, about 300 HCL patients per year are expected to die. Some of these patients were diagnosed with HCL because of a serious illness that prevented them from receiving early treatment on time; many died after living a normal life and experienced years of good disease control. Perhaps as many as five of the six HCL patients died of other causes.

Follow-up care

Although it is a long time ago that remission and years of life are very normal after the treatment, hairless leukemia cells are officially regarded as incurable diseases. While survivors of solid tumors are generally declared permanently cured after two, three, or five years, people who have hairless leukemia cells have never been considered 'cured'. HCL relapse has occurred even after more than twenty years of continuous forgiveness. Patients will need lifelong monitoring and should be aware that the disease can recur even after decades of good health.

People in forgiveness require routine follow-up after their care is over. Most doctors insist on seeing the patient at least once a year for the rest of the patient's life, and get a blood count about twice a year. Regular follow-up care ensures that patients are carefully monitored, any changes in health are discussed, and new or recurrent cancers can be detected and treated as soon as possible. Between regularly scheduled appointments, people who have hairy cell leukemia should report any health problems, especially viral or bacterial infections, as soon as they appear.

HCL patients are also slightly higher than the average risk for developing a second type of cancer, such as colon cancer or lung cancer, at some point during their lifetime (including before their HCL diagnosis). This seems to relate best to the number of hairy cells, and not to the various forms of treatment. On average, patients may expect to have as much as double the risk of developing another cancer, with a peak about two years after HCL diagnosis and subsequent fall, assuming that HCL is successfully treated. Aggressive monitoring and prevention efforts are generally required, although the lifetime opportunity to develop a second cancer after HCL diagnosis is still less than 50%.

There is also a higher risk of developing autoimmune diseases. Autoimmune diseases can also experience remission after HCL treatment.

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Epidemiology

The disease is rare, with less than 1 in 10,000 people diagnosed with HCL during their lifetime. Men four to five times more likely to develop leukemia haired cells than women. In the United States, the annual incidence is about 3 cases per 1,000,000 men each year, and 0.6 cases per 1,000,000 women annually.

Most of the patients were white men aged over 50 years, although they had been diagnosed in at least one adolescent. It is less common in people of African and Asian descent than those of European descent.

This disorder does not appear to be hereditary, although occasional familial cases that show predisposition, usually indicate a common type of human leukocyte antigen (HLA).

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Direction of research

The Hairy Cell Leukemia Consortium was established in 2008 to address the researchers' concerns about the long-term future of research on the disease. Partly because the treatments are so successful, this field has attracted very few new researchers.

In 2013, Leukemia Hairy Hair Foundation was created when Haircut Leukemia Consortium and Hairy Hair Leukemia Research Foundation joined together. HCLF is dedicated to improving outcomes for patients by promoting research into the causes and treatment of furry leukemia cells, as well as by providing educational and comfort resources for all people affected by hairless leukemia.

Three immunotoxin drugs have been studied in patients at NIHNational Cancer Institute in the US: BL22, HA22 and LMB-2. All of these protein-based drugs combine parts of anti-B cell antibodies with bacterial toxins to kill cells in internalization. BL22 and HA22 invade a common protein called CD22, which is present in hairy cells and healthy B cells. LMB-2 attacks a protein called CD25, which is not present in the HCL-variant, so LMB-2 is only useful for patients with HCL-classical or Japanese variants. HA-22, now renamed moxetumab pasudotox, is being studied in patients with hairy cell leukemia relapse at the National Cancer Institute in Bethesda, Maryland, MD Anderson Cancer Center in Houston, Texas, and Ohio State University in Columbus, Ohio. Other sites for the study are expected to begin receiving patients by the end of 2014, including The Royal Marsden Hospital in London, England.

Other clinical trials are studying the effectiveness of cladribine followed by rituximab in removing the remaining hairy cells that remain after treatment with cladribine or pentostatin. It is not currently known whether the elimination of such residual cells would result in a more durable remission.

BRAF mutations have been frequently detected in HCL (Tiacci et al. NEJM 2011) and some patients may respond to Vemurafenib

The main remaining research question is to identify the cause of HCL and determine what prevents the hairy cells from maturing normally.

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See also

• Annexin A1
• List of skin conditions

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References

src: www.leukemia-cell.org

External links

• About HCL at the US National Cancer Institute
• HCL and Baptist HCL Histories

Source of the article : Wikipedia